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The multifactorial role of leptin in driving the breast cancer microenvironment
Abstract
Adipose-tissue-derived signaling molecules, including the adipokines, are emerging as key candidate molecules that link obesity with cancer. Peritumoral, stromal, adipose tissue and secreted adipokines, particularly leptin, have important roles in breast cancer biology. For example, leptin signaling contributes to the metabolic features associated with breast cancer malignancy, such as switching the cells' energy balance from mitochondrial β-oxidation to the aerobic glycolytic pathway. Leptin also shapes the tumor microenvironment, mainly through its ability to potentiate both migration of endothelial cells and angiogenesis, and to sustain the recruitment of macrophages and monocytes, which in turn secrete vascular endothelial growth factor and proinflammatory cytokines. This article presents an overview of current knowledge on the involvement of leptin in the pathogenesis and progression of breast cancer, highlighted by human, in vitro and animal studies. Data are presented on the functional crosstalk between leptin and estrogen signaling, which further contributes to promotion of breast carcinogenesis. Finally, future perspectives and clinical applications in which leptin and the leptin receptor are considered as potential therapeutic targets for breast cancer are reviewed.
... Among several investigated adipokines that are associated with breast cancer, one of the most notable is leptin. Binding of overexpressed leptin to leptin receptors (LEPRs) in peritumoral fat and breast cancer cells stimulates multiple signaling events, such as JAK2-STAT3, MAPK-ERK, and PI3K-AKT-mTOR pathways, thereby enhancing tumor proliferation and survival [285,288]. These cytosolic signaling events can activate NF-κB and HIF-1α, leading to VEGF-A activation [289]. ...
... These cytosolic signaling events can activate NF-κB and HIF-1α, leading to VEGF-A activation [289]. mTOR signaling activates the translation of pro-inflammatory cytokines such as TNF IL-1, and IL-6 [288]. Leptin-LEPR signaling also cooperatively functions with other multiple signaling pathways, such as EGFR, Notch, IL-1, and the estrogen receptor, to enhance the proliferation, migration, invasion [290], and self-renewal activity of breast cancer stem cells [291]. ...
... [279] Leptin signaling contributes to the metabolic features and shapes the tumor microenvironment. [288] A fasting-mimicking diet promotes long-lasting tumor regression and reverts acquired resistance to drug treatment. [292] JAK-STAT3-regulated fatty acid beta-oxidation is critical for breast cancer stem cell self-renewal and chemoresistance. ...
Inflammation, especially chronic inflammation, plays a pivotal role in tumorigenesis and metastasis through various mechanisms and is now recognized as a hallmark of cancer and an attractive therapeutic target in cancer. In this review, we discuss recent advances in molecular mechanisms of how inflammation promotes tumorigenesis and metastasis and suppresses anti-tumor immunity in various types of solid tumors, including esophageal, gastric, colorectal, liver, and pancreatic cancer as well as hematopoietic malignancies.
... Leptin also enhances the proliferation of BC cells via the PI3K/AKT/SREBP2 signaling pathway [10]. Moreover, AKT phosphorylates and activates endothelial nitric oxide synthase (eNOS), and the PI3K/AKT/eNOS signaling pathway is able to stimulate endothelial cell migration [11]. Collec tively, leptin positively regulates PI3K/AKT signaling pathways and promotes cancer growth and angiogenesis of breast cancer. ...
... Previous investigations have reported that the antiobesity effect of celastrol largely depends on leptin receptor signaling [34]. As a key modulator in the development of obesity along with breast cancer, leptin is able to stimulate the proliferation of malignant breast epithelial cells through several signaling cascades, such as PI3K/AKT, JAK2/STAT3 and MAPK [11]. Additionally, our data show that leptin treatment induced phosphorylation of the leptin receptor and PI3K/AKT in MCF-7 cells, whereas pretreatment with celastrol partly abrogated leptin activation. ...
Leptin is the pivotal modulator in the onset and progression of breast cancer and obesity. Celastrol, which is extracted from the roots of Tripterygium wilfordi plants, exerts various anticancer bioactivities and has recently emerged as a candidate to treat obesity by improving leptin sensitivity. However, the relationship between leptin and celastrol in the treatment of breast cancer is unknown. Here, the growth and migration of MCF-7 cells induced by leptin were tested to demonstrate the antineoplastic activity of celastrol. Transcriptomic analysis and western blotting were conducted to explore the biological roles of leptin in treating breast cancer with celastrol. The present findings showed that celastrol remarkably reversed leptin-triggered cell proliferation and migration in MCF-7 cells. Fifty-two mRNAs with fivefold higher counts and 149 mRNAs with fivefold lower counts were identified in the celastrol-treated MCF-7 cells. According to the GO and KEGG analyses, the effects of celastrol on MCF-7 cells forced lipid metabolism and the endocrine system. Moreover, leptin treatment induced phosphorylation of leptin receptor and PI3K/AKT in MCF-7 cells, whereas pretreatment with celastrol partly abrogated leptin activation. The binding of celastrol to the leptin receptor was also confirmed by molecular docking. The antitumor effect of celastrol is proposed to be mediated by its binding to the leptin receptor and controlled downregulation of the PI3K/AKT pathway.
... Other studies have reported that leptin plays a role in the development of tumor risk, but the results are still debatable [22][23][24][25]. Thus, confirmation is necessary to clear up leptin's specific function in the initiation and progression of urinary bladder cancer. ...
... Therefore, the expression of leptin was suggested as a possible marker for the diagnosis or prognosis of tumors located in different organs. Nevertheless, there is conflict between the outcomes obtained from several neoplasms [22][23][24][25]. ...
This study examined leptin expression in cases of bladder cancer and its diagnostic and prognostic usefulness in bladder malignancies.
A set of 128 urinary bladder cancer cases and 24 normal specimens of bladders were employed for an immunohistochemical investigation of leptin expression in tissue microarrays.
Leptin was up-regulated during transformation and was identified as brown cytoplasmic granules in the malignant urothelium of 123 (96%) bladder neoplasms, of which 68 (53.1%) cases showed high levels (moderate to strong) of staining. Strong staining was found to be associated with high stages (P = 0.001), muscularis propria infiltration (P < 0.001), vascular invasion (P < 0.03), lymph node involvement (P < 0.02), metastases (P < 0.05), and mortality (P < 0.03). Furthermore, various important survival distributions were detected with leptin expression in the malignant urothelium (P < 0.03).
These pilot results suggest that leptin might be a valid marker for predicting the stage and bad prognoses in bladder carcinoma.
... In a first approximation, the risk factors associated with carcinoma development induce an endocrine profile that increases the levels of growth factors, cytokines, and hormones 17, 18 that generate the chronic proliferation of epithelial cells 19,20 . Hormones, growth factors, and cytokines strongly synergize their inflammatory and mitogenic effects 21,22 . Most epithelial tissues are highly susceptible to environmental influences and their chronic exposition induces inflammation and conditions associated with benign proliferative disorders 23-25 . ...
... The effects of this endocrine environment in the glandular epithelium of the breast include increased proliferation and the production of pro-inflammatory cytokines 19,20 . In addition, estrogen, growth factors, and inflammation generate synergistic effects on proliferation and a positive loop in their own transcription 21,22 . The mammary gland is particularly susceptible to environmental influences and inflammatory conditions, that in turn are associated with changes in tissue that lead to breast diseases such as benign proliferative or inflammatory disorders [23][24][25] . ...
The theory of the origin of carcinomas suggests that neoplasias from epithelial tissues are the consequence of the reactivation of developmental programs. It proposes a model in which the epithelial cells undergo cellular transitions due to replicative senescence and inflammation towards a mesenchymal-undifferentiated phenotype with cancerous behavior. The conserved pattern of histological progression and the molecular biology of carcinomas is congruent with the view of cancer as a developmental disease. In support of the theory, the experimental literature regarding the molecular, cellular, and histopathological mechanisms associated with epithelial carcinogenesis were aligned according to the premises of the hypothesis. Thereby identified a generic process in the carcinogenesis of the breast, endometrium, prostate, colon, lung, pancreas, bladder, liver, and cervix. Then, is provided a methodology overview of modeling in systems biology derived from previous research testing the hypothesis. The results illustrate the value of the complex systems approach to recover behavior that cannot be inferred only by traditional methods. Specifically, the model suggests that the consistency in the cell types and the directionality of the observed cellular transitions during epithelial carcinogenesis arise from structural constraints in the molecular networks associated with the carcinomas. Overall, the results of the dynamical analysis agree with the premises of the hypothesis and provide an insightful perspective of the potential mechanisms underlying the cellular plasticity displayed during epithelial carcinogenesis. In an era of big data and yet few advances in the underlying causes of chronic diseases, the manuscript also aims to inspire molecular biologists to integrate existing empirical evidence with systems biology modeling in the pursuit of understanding.
... Adipose tissue occupies 90% of the volume of the mammary gland and can secrete a large number of lipotropic factors, such as leptin, which can promote breast cancer invasion, metastasis, neoangiogenesis and epithelial mesenchymal transition through paracrine secretion (31). Moreover, leptin can accelerate breast cancer progression by recruiting macrophages in the tumor microenvironment (32). The effect of leptin on breast cancer also requires numerous signaling pathways to achieve. ...
Breast cancer is a common tumor encountered in women, and triple-negative breast cancer (TNBC) has an extremely poor prognosis. The effect of leptin on the docetaxel sensitivity of MDA-MB-231 TNBC cells has not been investigated. The present study aimed to clarify the effect of leptin and M2 tumor-associated macrophages (TAMs) on the chemosensitivity of TNBC cell lines and its possible mechanisms. In the present study, the apoptosis of the MDA-MB-231 cell line was detected at 0, 24, 48 and 72 h using a Cell Counting Kit-8 assay to determine the appropriate concentration of docetaxel as well as the IC50 value. After determining the effect of leptin on TAMs, the conditioned medium with an appropriate concentration of docetaxel was collected to treat the breast cancer cells, and flow cytometry was used to detect the cell cycle distribution and apoptosis in different treatment groups. Interleukin 8 (IL-8) expression was detected using ELISA and western blot assay. The IL-8 antibody was used to neutralize IL-8, and invasion and scratch assays were used to detect changes in invasion and migration of breast cancer cells. Statistical analysis was performed using GraphPad Prism 9.0 and SPSS 22.0. It was revealed that the apoptotic rate of MDA-MB-231 cells in the leptin-treated TAMs group was lower than that in other groups. The expression of IL-8 was notably elevated in the group treated with leptin-activated TAMs compared with that in the other groups. The neutralization of IL-8 resulted in a significant reduction in the invasive migration of MDA-MB-231 cells compared with that in the non-neutralized group.
... Leptin, the inaugural adipokine identified, is synthesized by the obese gene. It influences a range of physiological processes by binding to the transmembrane leptin receptor [44][45][46][47]. It is primarily secreted by white adipocytes with a small amount from other tissues [48,49]. ...
Atopic dermatitis (AD) is a chronic skin condition with intense pruritus, eczema, and dry skin. The recurrent intense pruritus and numerous complications in patients with AD can profoundly affect their quality of life. Obesity is one of its comorbidities that has been confirmed to be the hazard factor of AD and also worsen its severity. Nevertheless, the specific mechanisms that explain the connection between obesity and AD remain incompletely recognized. Recent studies have built hopes on various adipokines to explain this connection. Adipokines, which are disturbed by an obese state, may lead to immune system imbalances in people with AD and promote the development of the disease. This review focuses on the abnormal expression patterns of adipokines in patients with AD and their potential regulatory molecular mechanisms associated with AD. The connection between AD and obesity is elucidated through the involvement of adipokines. This conduces to the in-depth exploration of AD pathogenesis and provides a new perspective to develop therapeutic targets.
... The stromal fibroblasts secreted numerous cytokines with a wide variation between individual samples (Fig. S3). The cytokines, CXCL1, CXCL5, and leptin trended towards being higher in the majority of CAFs tested (Fig. 4C), which has also been observed in other studies [43][44][45]. CXCL1, CXCL5 and leptin resulted in basal cell enrichment in the normal tissue compared to the base with CXCL5 producing the largest change in the normalized JSD score (Figs. 4D-4F and Table S10). ...
Purpose
Breast cancer heterogeneity contributes to chemotherapy resistance and decreased patient survival. To improve patient outcomes it is essential to develop a technology that is able to rapidly select the most efficacious therapy that targets the diverse phenotypes present within the tumor. Breast cancer organoid technologies are proposed as an attractive approach for evaluating drug responses prior to patient therapy. However, there remain challenges in evaluating the effectiveness of organoid cultures to recapitulate the heterogeneity present in the patient tumor in situ.
Method
Organoids were generated from seven normal breast and nineteen breast cancer tissues diagnosed as estrogen receptor positive or triple negative. The Jensen-Shannon divergence index, a measure of the similarity between distributions, was used to compare and evaluate heterogeneity in starting tissue and their resultant organoids. Heterogeneity was analyzed using cytokeratin 8 and cytokeratin 14, which provided an easily scored readout.
Results
In the in vitro culture system HER1 and FGFR were able to drive intra-tumor heterogeneity to generate divergent phenotypes that have different sensitivities to chemotherapies.
Conclusion
Our methodology, which focuses on quantifiable cellular phenotypes, provides a tractable system that complements omics approaches to provide an unprecedented view of heterogeneity and will enhance the identification of novel therapies and facilitate personalized medicine.
... Leptin binds to LEPR on cell surface and subsequently regulates various signaling cascades, including PI3K/AKT, JAK2/STAT3, and MAPK/ERK. In cancer, all of these pathways are often dysregulated [39]. Using Western blotting, we examined whether FLLL32 (a JAK2/STAT3 inhibitor), LY294002 (a PI3K/AKT inhibitor), or PD98059 (a MAPK/ERK inhibitor) influence the elevated JARID2 expression in leptin-treated breast cancer cells. ...
Background:
Proteins containing the Jumonji C (JmjC) domain participated in tumorigenesis and cancer progression. However, the mechanisms underlying this effect are still poorly understood. Our objective was to investigate the role of Jumonji and the AT-rich interaction domain-containing 2 (JARID2) - a JmjC family protein - in breast cancer, as well as its latent association with obesity.
Methods:
Immunohistochemistry, The Cancer Genome Atlas, Gene Expression Omnibus, and other databases were used to analyze the expression of JARID2 in breast cancer cells. Growth curve, 5-ethynyl-2-deoxyuridine (EdU), colony formation, and cell invasion experiments were used to detect whether JARID2 affected breast cancer cell proliferation and invasion. Spheroidization-based experiments and xenotumor transplantation in NOD/SCID mice were used to examine the association between JARID2 and breast cancer stemness. RNA-sequencing, Kyoto Encyclopedia of Genes and Genomes, and Gene Set Enrichment Analysis were used to identify the cell processes in which JARID2 participates. Immunoaffinity purification and silver staining mass spectrometry were conducted to search for proteins that might interact with JARID2. The results were further verified using co-immunoprecipitation and glutathione S-transferase (GST) pull-down experiments. Using chromatin immunoprecipitation (ChIP) sequencing, we sought the target genes that JARID2 and metastasis-associated protein 1 (MTA1) jointly regulated; the results were validated by ChIP-PCR, quantitative ChIP (qChIP) and ChIP-reChIP assays. A coculture experiment was used to explore the interactions between breast cancer cells and adipocytes.
Results:
In this study, we found that JARID2 was highly expressed in multiple types of cancer including breast cancer. JARID2 promoted glycolysis, lipid metabolism, proliferation, invasion, and stemness of breast cancer cells. Furthermore, JARID2 physically interacted with the nucleosome remodeling and deacetylase (NuRD) complex, transcriptionally repressing a series of tumor suppressor genes such as BRCA2 DNA repair associated (BRCA2), RB transcriptional corepressor 1 (RB1), and inositol polyphosphate-4-phosphatase type II B (INPP4B). Additionally, JARID2 expression was regulated by the obesity-associated adipokine leptin via Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway in the breast cancer microenvironment. Analysis of various online databases also indicated that JARID2/MTA1 was associated with a poor prognosis of breast cancer.
Conclusion:
Our data indicated that JARID2 promoted breast tumorigenesis and development, confirming JARID2 as a target for cancer treatment.
... In vitro findings have shown the pro-oncogenic impact of leptin, including cell proliferation, transformation, apoptosis regulation, self-renewal, and reduced sensitivity to breast cancer treatments (reviewed in [224][225][226]). Particularly, leptin may act by (i) binding its own receptor (ObR) or (ii) by interacting with other different mediators known to be involved in breast cancer biology (e.g., ERα, growth factors, Notch, and inflammatory cytokines) [40]. ...
Obesity, defined as the abnormal or excessive expansion of white adipose tissue, has reached pandemic proportions and is recognized as an important health concern since it is a common root for several comorbidities, including malignancies. Indeed, the current knowledge of the white adipose tissue, which shifts its role from an energy storage tissue to an important endocrine and metabolic organ, has opened up new avenues for the discovery of obesity’s effects on tumor biology. In this review, we will report the epidemiological studies concerning the strong impact of obesity in several types of cancer and describe the mechanisms underlying the heterotypic signals between cancer cell lines and adipocytes, with particular emphasis on inflammation, the insulin/IGF-1 axis, and adipokines. Among the adipokines, we will further describe the in vitro, in vivo, and clinical data concerning the role of leptin, recognized as one of the most important mediators of obesity-associated cancers. In fact, leptin physiologically regulates energy metabolism, appetite, and reproduction, and several studies have also described the role of leptin in affecting cancer development and progression. Finally, we will summarize the newest pharmacological strategies aimed at mitigating the protumorigenic effects of leptin, underlining their mechanisms of action.
... These factors potentiate the expression of aromatase in breast adipose stromal cells, a central enzyme in the production of oestrogens, particularly oestradiol, which is increased as a result [112]. Considering the essential role of these hormones in the normal development of the mammary gland, several studies associated cytokine-induced aromatase upregulation with breast cancer growth and progression [113]. This relationship is supported by the successful results obtained after treating patients with aromatase inhibitors (Ais). ...
Epidemiological observations, experimental studies and clinical data show that obesity is associated with a higher risk of developing different types of cancer; however, proof of a cause–effect relationship that meets the causality criteria is still lacking. Several data suggest that the adipose organ could be the protagonist in this crosstalk. In particular, the adipose tissue (AT) alterations occurring in obesity parallel some tumour behaviours, such as their theoretically unlimited expandability, infiltration capacity, angiogenesis regulation, local and systemic inflammation and changes to the immunometabolism and secretome. Moreover, AT and cancer share similar morpho-functional units which regulate tissue expansion: the adiponiche and tumour-niche, respectively. Through direct and indirect interactions involving different cellular types and molecular mechanisms, the obesity-altered adiponiche contributes to cancer development, progression, metastasis and chemoresistance. Moreover, modifications to the gut microbiome and circadian rhythm disruption also play important roles. Clinical studies clearly demonstrate that weight loss is associated with a decreased risk of developing obesity-related cancers, matching the reverse-causality criteria and providing a causality correlation between the two variables. Here, we provide an overview of the methodological, epidemiological and pathophysiological aspects, with a special focus on clinical implications for cancer risk and prognosis and potential therapeutic interventions.
... 14 The latter is a strong prognostic factor in UM. 31 32 Leptin has also been described as having a role in promoting the aerobic glycolytic pathway and in enhancing epithelial to mesenchymal transition. 33 Thus, one may propose that the prognostic implication of obesity in UM may be related to elevated serum leptin levels, which suppresses tumour leptin receptor expression, which in turn reduces the activity of pathways that are associated with vasculogenic mimicry, extracellular matrix interactions and invasive behaviour. A similar beneficial effect of high serum leptin levels has been found in several other cancers, including pancreatic and colorectal carcinoma (CRC), as well as in cutaneous melanoma. ...
Background
Metabolic factors and obesity may influence the development and progression of cancer. In this study, we examine their association with the risk of developing metastases of uveal melanoma.
Methods
Data on metabolic factors, medications, serum leptin levels, tumour leptin receptor RNA expression and clinical outcomes were examined in three cohorts. HRs for metastasis and cumulative incidences of melanoma-related mortality were calculated, and the levels of tumour leptin receptor expression were compared with prognostic factors including BAP1 mutation, and tumour cell morphology.
Results
Of 581 patients in the main cohort, 116 (20%) were obese and 7 (1 %) had metastatic disease at presentation. In univariate Cox regressions, tumour diameter, diabetes type II and use of insulin were associated with metastases, but patients with obesity had a lower risk. The beneficial prognostic implication of obesity was retained in multivariate regressions. In competing risk analyses, the incidence of melanoma-related mortality was significantly lower for patients with obesity. Serum leptin levels≥median were associated with a reduced risk for metastasis, independent of patient sex and cancer stage in a separate cohort (n=80). Similarly, in a third cohort (n=80), tumours with BAP1 mutation and epithelioid cells had higher leptin receptor RNA expression levels, which have a negative correlation with serum leptin levels.
Conclusion
Obesity and elevated serum leptin levels are associated with a lower risk for developing metastases and dying from uveal melanoma.
... 12 Distant and local adipocytes primarily produce it, but it is also produced by the cells of the epithelial tumor as well as by other stromal cells in the tumor (cancer-associated fibroblasts), numerous intracellular downstream signaling pathways, including the JAK2/STAT3, MAPK, and PI3K/Akt pathways, which are involved in the regulation of cell proliferation, differentiation, survival, migration, and invasion, are activated as a result of leptin binding to the long ObR isoform. 13,14 White adipocyte hypertrophy and hyperplasia limit their vascularization, lowering oxygen availability. Due to the hypoxic state, there is increased oxidative stress, insulin resistance, ischemia, adipocyte necrosis, and the release of inflammatory and angiogenic proteins. ...
Background: Breast cancer is the most common malignant tumor and the second most significant cause of death for women in Iraq, behind cardiovascular diseases. Obesity has been linked to a substantial increase in the risk of breast cancer. Adipose tissue functions as an endocrine gland, controlling the body's metabolism by secreting adipokines, which play a significant role in metabolism and inflammatory reactions.
Methods : Overall, 90 postmenopausal women participated in this research. Of these, 60 patients with breast cancer were recruited at Baghdad's Oncology Teaching Hospital between October 2021 and February 2022: 30 were obese with a body mass index (BMI) of > 30 kg/m2 (group 1), and 30 were not obese (group 2). The third group consisted of 30 participants without breast cancer or obesity (group 3). Each person donated five milliliters of venous blood. The blood levels of adiponectin and leptin are determined using enzyme-linked immunosorbent assay (ELISA) kits.
Results: Control individuals who were not obese (group 3) had greater blood adiponectin levels than patients with cancer who were both obese and non-obese (groups 1 and 2), with no significant difference in serum adiponectin levels seen between groups 1 and 2. The findings also showed that group 1 (patients with breast cancer and obesity) had greater serum leptin levels than both group 2 (patients with breast cancer without obesity) and the control group (group 3), with no significant difference in serum leptin levels between groups 2 and 3.
Conclusions: Adiponectin levels in the blood of women with breast cancer and obesity were low which may be due to high BMI, which reduces adiponectin's protective effects. Conversely, Leptin levels were more significant in the blood of women with breast cancer and obesity than in the control group, which may be due to its pro-inflammatory effects in obesity, among other variables.
... Interestingly, we found lower levels of Retinol Binding Protein 4 (RBP4) and higher levels of Chitinase 3-like 1 (CHI3L1) in the tumor ACM groups. Numerous studies have shown that leptin have multiple roles on breast cancer as it can drive the breast cancer microenvironment, promote the breast cancer cells growth and invasion through activation of ERK1/2, PI3K-Akt and JAK2-STAT3 signaling pathways [25,26]. RBP4 is an adipokine that belongs to the family of lipocalin. ...
Background:
Adipose tissue is a major component of breast stroma. This study focused on delineating the effects of adipose stem cells (ASCs) derived from breast of healthy women and cancer patients with normal or tumor breast cells.
Methods:
The ASCs were induced to differentiate into adipocytes, and the subsequent adipocyte conditioned media (ACM) were evaluated for their fatty acid profile, adipokine secretion and influence on proliferation, migration and invasion on tumoral (MCF-7 and SUM159) and normal (HMEC) human breast cell lines.
Results:
An enrichment of arachidonic acid was observed in ACM from tumor tissues. Adipose tissues from tumor free secrete twice as much leptin than those from proximal or distal to the tumor. All ACMs display proliferative activity and favor invasiveness of SUM159 cells compared to MCF-7 and HMEC. All ACMs induced lipid droplets accumulation in MCF-7 cells and increased CD36 expression in tumor cells.
Conclusion:
We conclude that among secreted factors analyzed, only arachidonic acid and leptin levels did discriminate ASCs from tumor-bearing and tumor-free breasts emphasizing the importance that other cell types could contribute to the adipose tissue secretome in a tumor context.
... Hursting and colleagues have demonstrated that obesity promotes these two pathways, thus suggesting a causal link between obesity and the associated metabolic derangement with TNBC development (82). However, the contribution of other key adipokines and cytokines in this obesity-associated CSC/EMT circuit must be further examined, as preliminary studies indicate that the leptin-adiponectin ratio imbalances do not fully account for all of the observed effects of diet-induced obesity on TNBC (83). ...
Obesity-driven (type 2) diabetes (T2D), the most common metabolic disorder, both increases the incidence of all molecular subtypes of breast cancer and decreases survival in postmenopausal women. Despite this clear link, T2D and the associated dysfunction of diverse tissues is often not considered during the standard of care practices in oncology and, moreover, is treated as exclusion criteria for many emerging clinical trials. These guidelines have caused the biological mechanisms that associate T2D and breast cancer to be understudied. Recently, it has been illustrated that the breast tumor microenvironment (TME) composition and architecture, specifically the surrounding cellular and extracellular structures, dictate tumor progression and are directly relevant for clinical outcomes. In addition to the epithelial cancer cell fraction, the breast TME is predominantly made up of cancer-associated fibroblasts, adipocytes, and is often infiltrated by immune cells. During T2D, signal transduction among these cell types is aberrant, resulting in a dysfunctional breast TME that communicates with nearby cancer cells to promote oncogenic processes, cancer stem-like cell formation, pro-metastatic behavior and increase the risk of recurrence. As these cells are non-malignant, despite their signaling abnormalities, data concerning their function is never captured in DNA mutational databases, thus we have limited insight into mechanism from publicly available datasets. We suggest that abnormal adipocyte and immune cell exhaustion within the breast TME in patients with obesity and metabolic disease may elicit greater transcriptional plasticity and cellular heterogeneity within the expanding population of malignant epithelial cells, compared to the breast TME of a non-obese, metabolically normal patient. These challenges are particularly relevant to cancer disparities settings where the fraction of patients seen within the breast medical oncology practice also present with co-morbid obesity and metabolic disease. Within this review, we characterize the changes to the breast TME during T2D and raise urgent molecular, cellular and translational questions that warrant further study, considering the growing prevalence of T2D worldwide.
... Preclinical models of tumor-bearing mice housed in EE illustrated that eustress can suppress tumor progression by regulating the secretome of adipocytes and oxidative metabolism in tumor cells. Some preclinical studies found that EE eustress activated the hypothalamic-sympathoneural-adipocyte axis and thus decreased leptin secreted by white adipocytes (85), whose role in promoting tumor development and metastasis had been demonstrated (94). In mice inoculated subcutaneously with melanoma or colon cancer cells, EE up-regulated hypothalamic BDNF expression, which reduced the expression and production of leptin in white adipocytes (85). ...
Facing cancer diagnosis, patients with cancer are prone to psychological stress and consequent psychological disorders. The association between psychological stress and cancer has long been a subject of high interest. To date, preclinical studies have gradually uncovered the promotive effects of psychological distress on tumor hallmarks. In contrast, eustress may exert suppressive effects on tumorigenesis and beneficial effects on tumor treatment, which brings a practicable means and psychosocial perspective to cancer treatment. However, the underlying mechanisms remain incompletely understood. Here, by focusing on the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system, as well as stress-related crucial neurotransmitters and hormones, we highlight the effects of distress and eustress on tumorigenesis, the tumor microenvironment, and tumor treatment. We also discuss the findings of clinical studies on stress management in patients with cancer. Last, we summarize questions that remain to be addressed and provide suggestions for future research directions.
... In support of this notion, ASCs isolated from obese individuals secreted significantly higher levels of leptin that stimulated the proliferation of low and high malignant breast cancer cells [121,122]. This is linked to leptin receptor activation, which triggers multiple pathways, such as Janus kinase (JAK) and MAPK, with the expression of downstream target genes involved in cell cycle progression and proliferation, including cyclin D1 (CCND1), VEGF, and proto-oncogene C-Fos (FOS), transcription factor AP-1 subunit jun (JUN), and transcription factor AP-1 subunit JunB (JUNB) [136]. Adipsin is another adipokine upregulated in ASCs derived from obese patients, which stimulates the cell surface receptor complement C3a receptor 1 (C3aR) and the cleavage of factor B, leading to proliferation of breast cancer cells [120]. ...
Breast cancer is the most frequently diagnosed cancer and a common cause of cancer-related death in women. It is well recognized that obesity is associated with an enhanced risk of more aggressive breast cancer as well as reduced patient survival. Adipose tissue is the major microenvironment of breast cancer. Obesity changes the composition, structure, and function of adipose tissue, which is associated with inflammation and metabolic dysfunction. Interestingly, adipose tissue is rich in ASCs/MSCs, and obesity alters the properties and functions of these cells. As a key component of the mammary stroma, ASCs play essential roles in the breast cancer microenvironment. The crosstalk between ASCs and breast cancer cells is multilateral and can occur both directly through cell–cell contact and indirectly via the secretome released by ASC/MSC, which is considered to be the main effector of their supportive, angiogenic, and immunomodulatory functions. In this narrative review, we aim to address the impact of obesity on ASCs/MSCs, summarize the current knowledge regarding the potential pathological roles of ASCs/MSCs in the development of breast cancer, discuss related molecular mechanisms, underline the possible clinical significance, and highlight related research perspectives. In particular, we underscore the roles of ASCs/MSCs in breast cancer cell progression, including proliferation and survival, angiogenesis, migration and invasion, the epithelial–mesenchymal transition, cancer stem cell development, immune evasion, therapy resistance, and the potential impact of breast cancer cells on ASCS/MSCs by educating them to become cancer-associated fibroblasts. We conclude that ASCs/MSCs, especially obese ASCs/MSCs, may be key players in the breast cancer microenvironment. Targeting these cells may provide a new path of effective breast cancer treatment.
... It activates the phosphorylation of the tyrosine residue of the receptor and causes the activation of its effectors Stat3 and MAPK (Figure 3). In this way, the estrogenic pathway is enhanced at the tissue level, since Stat3 induces the generation of estrogens by aromatization of androgens, and MAPK stops the proteasomal degradation of ERα [93], enhancing the estrogenic status [43]. ...
Solid tumors, despite being hypervascularized, are hypoxic. This is due to the imbalance that exists between the inputs of the blood vessels that supply nutrients and O2 and that remove metabolic waste products, on one side; and the demands of the tumor cells that are part of the neoplasm that is forming, on the other. From this perspective, we briefly review the sequence of morphological events that occur during neo-angiogenesis; what chemical mediators are involved in this process; and we emphasize how the IL-6/Jak/Stat signaling pathway is involved in the control of these mediators. At the same time, we review how estrogens intervene in this control procedure, and how it opens the door to understanding the mechanism of action of these mediators. This would make it possible to propose alternative treatments, which can be added to the conventional ones, and which would exploit the findings described here in the search for new antitumor therapies.
... is oncogenic effect is believed to be mediated by the fat tissue-derived adipokine leptin [50,51]. Interestingly, we demonstrated that ET treatment of S1 acini impaired the normal morphogenesis, as indicated by the disrupted formation of monolayered lumen in 3D cultures of S1 cells and the altered localization of β-catenin. ...
Inflammation is associated with the development of several cancers, including breast cancer. However, the molecular mechanisms driving breast cancer initiation or enhancement by inflammation are yet to be deciphered. Hence, we opted to investigate the role of inflammation in initiating and enhancing tumor-like phenotypes in nontumorigenic, pretumorigenic, and tumorigenic breast epithelial cells. Noncytotoxic endotoxin (ET) concentrations capable of inducing an inflammatory phenotype were determined for the different cell lines. Results showed that short-term ET exposure upregulated matrix metalloproteinase-9 (MMP-9) activity in nontumorigenic mammary epithelial cells of mouse (SCp2) and human origins (HMT-3522 S1; S1) and upregulated inflammatory mediators including nitric oxide (NO) and interleukin 1-β in tumorigenic human breast cells (MDA-MB-231), all in a dose-dependent manner. Long-term ET treatment, but not short-term, triggered the migration of SCp2 cells, and proliferation and migration of tumorigenic human breast cells MCF-7 and MDA-MB-231. Both short- and long-term ET exposures preferentially enhanced the invasion of pretumorigenic S1-connexin 43 knockout (Cx43-KO S1) cells compared to their nontumorigenic S1 counterparts. Moreover, both ET exposures disrupted lumen formation and apicolateral distribution of β-catenin in 3D cultures of S1 cells. In conclusion, ET treatment at concentrations that elicited inflammatory phenotype triggered tumor initiation events in nontumorigenic and pretumorigenic breast cells, and increased tumorigenicity of breast cancer cells. Our findings highlight the role of inflammation in enhancing migration, invasion, and loss of normal 3D morphology and suggest that such inflammatory insults can “add injury” to pretumorigenic and tumorigenic breast epithelial cells.
... Leptin has also been reported to cause the proliferation of hepatocellular cancer cells by altering cyclin D1, Bcl-2 (B-cell lymphoma-2)-related X protein (Bax), and apoptotic gene activity [134]. [124]. DOI: http://dx.doi.org ...
Adipose tissue (AT) in the body plays a very important role in the regulation of energy metabolism. AT regulates energy metabolism by secreting adipokines. Some of the adipokines released are vaspin, resistin, adiponectin, visfatin and omentin, and leptin. In addition to regulating energy metabolism, leptin plays a role in the regulation of many physiological functions of the body such as regulation of blood pressure, inflammation, nutrition, appetite, insulin and glucose metabolism, lipid metabolism, coagulation, and apoptosis. Among all these physiological functions, the relationship between leptin, oxidative stress, and apoptosis has gained great importance recently due to its therapeutic effect in various types of cancer. For this reason, in this study, the release of leptin, its cellular effects and its effect on oxida-tive stress, and apoptosis are discussed in line with current information.
... Different proposed therapeutic strategies include the use of soluble OBR, peptide-based leptin antagonists and ObR blocking antibodies [172]. For example, benzyl isothiocyanate can inhibit oncogenic action of leptin in BC cells by suppressing activation of STAT3 [173]. ...
Obesity and its related complications have been the pressing disease pandemic affecting the developed world. It is well-established that the direct consequence of obesity in the cardiovascular system resulting in many diseases. However, its implications in carcinogenesis, cancer treatment and one’s anti-tumour immunity are gradually unfolding. To understand how fat cells can affect these, one needs to explore how the fat cell affects epithelial and immune cells. To this end, we explore the way how the adipocytes, via its production of adipokines, influence these cells, resulting in early epithelial cell transformation into cancer cells and influencing anti-tumour immunity once the cancer is established. In order to simplify our discussion, we focus this review on breast cancer. We propose that to have an effective therapy for cancer treatment, we need to intervene at the adipokine interaction with epithelial cells, cancer cells, and immune cells. In this review we also decipher the potential therapeutic targets in controlling carcinogenesis and disease progression.
... Bidirectional crosstalk had been demonstrated between leptin and oestrogen receptors in the MCF-7 breast cancer cell line also animal studies. Leptin in the MCF-7 breast cancer cell line increases the aromatase activity via extracellular signal-regulated kinase (ERK) and STAT pathways and decreases the expression of the cancer suppression protein p53 acted as a growth hormone (Ando and Catalano, 2012). A meta-analysis of six prospective studies showed that hyperleptinemia is associated with a higher risk of colorectal cancer and in the European prospective investigation into cancer and nutrition study (EPIC), soluble leptin receptor was indicated as one of the main circulating biomarkers of association between obesity and colorectal cancer risk , Aleksandrova et al. 2014 against, a meta-analysis did not find any significant association between leptin and colorectal carcinoma ) also, animal studies had shown that leptin-deficient mice fed with a high-fat diet or when to induce by azoxymethane compared to control mice were less prone to colonic polyp formation (Endo et al. 2011). ...
Adipose tissue is a complex organ that is increasingly being recognised as the largest endocrine organ in the body. Adipocytes among multiple cell types of adipose tissue can secrete a variety of adipokines, which are involved in signalling pathways and these can be changed by obesity and cancer. There are proposed mechanisms to link obesity/adiposity to cancer development including adipocytokine dysregulation. Among these adipokines, leptin acts through multiple pathways including the STAT3, MAPK, and PI3K pathways involved in cell growth. Adiponectin has the opposite action from leptin in tumour growth partly because of increased apoptotic responses of p53 and Bax. Visfatin increases cancer cell proliferation through ERK1/2, PI3K/AKT, and p38 which are stimulated by proinflammatory cytokines. Omentin through the PI3K/Akt-Nos pathway is involved in cancer-tumour development. Apelin might be involved through angiogenesis in tumour progressions. PAI-1 via its anti-fibrinolytic activity on cell adhesion and uPA/uPAR activity influence cancer cell growth.
... In fact, obesity, which is characterized by the excess of adipose tissue, is associated with an increased risk of multiple cancers, including postmenopausal breast, endometrial, and colorectal cancers [29]. Various mechanisms have been proposed to explain how mature adipocytes alter breast cancer cell behavior, including secretion of adipokine, remodeling of the extracellular matrix, enhanced inflammation, and metabolic changes [30][31][32][33]. Furthermore, bone marrow adipocytes are responsible for bone metastasis [34,35]. ...
Adipose tissue is a component of the tumor microenvironment and is involved in tumor progression. We have previously shown that adipokine adipsin (CFD) functions as an enhancer of tumor proliferation and cancer stem cell (CSC) properties in breast cancers. We established the Cfd-knockout (KO) mice and the mammary adipose tissue-derived stem cells (mADSCs) from them. Cfd-KO in mADSCs significantly reduced their ability to enhance tumorsphere formation of breast cancer patient-derived xenograft (PDX) cells, which was restored by the addition of Cfd in the culture medium. Hepatocyte growth factor (HGF) was expressed and secreted from mADSCs in a Cfd-dependent manner. HGF rescued the reduced ability of Cfd-KO mADSCs to promote tumorsphere formation in vitro and tumor formation in vivo by breast cancer PDX cells. These results suggest that HGF is a downstream effector of Cfd in mADSCs that enhances the CSC properties in breast cancers.
... [1][2][3][4] Breast cancer is believed to involve genetic predisposition, but modifiable variables, such as overweight (body mass index 25-30 kg/m 2 ) or obesity (body mass index >30 kg/m 2 ), also play significant roles. [5][6][7] Obesity is a growing public health problem that affects almost all countries. [8] Obesity is regarded as a major risk factor for many severe illnesses, including diabetes mellitus, metabolic syndrome, cardiovascular diseases, and certain cancers. ...
Purpose:
Obesity strongly affects the prognosis of various malignancies, including breast cancer. Leptin (LEP) may be associated with obesity and breast cancer prognosis. The purpose of our study was to determine the prognostic value of LEP in breast cancer.
Method:
We conducted a multi-omic analysis to determine the prognostic role of LEP. Different public bioinformatics platforms (Oncomine, Gene Expression Profiling Interactive Analysis, University of California Santa Cruz Xena, bc-GenExMiner, PrognoScan database, R2-Kaplan-Meier Scanner, UALCAN, Search Tool for the Retrieval of Interacting Genes/Proteins database , and The Database for Annotation, Visualization and Integrated Discovery) were used to evaluate the roles of LEP. Clinicopathological variables were evaluated.
Results:
LEP was downregulated in breast cancer tissues compared to levels in normal tissues. By co-expressed gene analysis, a positive correlation between LEP and SLC19A3 was observed. Based on the clinicopathological analysis, low LEP expression was associated with older age, higher stage, lymph node status, human epidermal growth factor receptor 2 (HER2) status, estrogen receptor (ER+) positivity, and progesterone receptor (PR+) positivity. Kaplan-Meier survival analysis showed that low LEP expression indicated a poorer prognosis. LEP is hypermethylated in breast cancer tissues in PrognoScan and R2-Kaplan Meier Scanner, and low LEP expression was correlated with poor prognosis. LEP protein-protein interactions were analyzed using Search Tool for the Retrieval of Interacting Genes/Proteins database. Gene ontology analysis results showed that cellular component is mainly associated with the endosome lumen, cytosol, and secretory granules and is upregulated. For the biological process energy reserve, metabolic processes exhibited the greatest regulation compared to the others. In molecular function, it was mainly enriched in a variety of combinations, but hormone activity showed the highest regulation.
Conclusion:
Our study provides evidence for the prognostic role of LEP in breast cancer and as a novel potential therapeutic target in such malignancies. Nevertheless, further validation is required.
... Elevated levels of serum leptin have been unequivocally correlated to an increased risk of developing various tumor forms: testicular, breast, prostate, colon, and pancreatic cancers [46,[95][96][97]. Several studies have reported that leptin and leptin receptor are implicated in cancer, mainly via the JAK/STAT pathway, which regulates PI3K/AKT3 and ERK1/2 signaling, angiogenic factors (VEGF), systemic inflammation (TNF-α, IL6), and anti-apoptotic proteins (XIAP) expression [98]. ...
Leptin, a multifunctional hormone primarily, but not exclusively, secreted in adipose tissue, is implicated in a wide range of biological functions that control different processes, such as the regulation of body weight and energy expenditure, reproductive function, immune response, and bone metabolism. In addition, leptin can exert angiogenic and mitogenic actions in peripheral organs. Leptin biological activities are greatly related to its interaction with the leptin receptor. Both leptin excess and leptin deficiency, as well as leptin resistance, are correlated with different human pathologies, such as autoimmune diseases and cancers, making leptin and leptin receptor important drug targets. The development of leptin signaling modulators represents a promising strategy for the treatment of cancers and other leptin-related diseases. In the present manuscript, we provide an update review about leptin-activity modulators, comprising leptin mutants, peptide-based leptin modulators, as well as leptin and leptin receptor specific monoclonal antibodies and nanobodies.
... Several reports have also defined the importance of the release by CAFs of adipokines such as leptin in promoting the malignant aggressiveness of BrCa cells [128]. Giordano et al. described leptin as a regulator of the crosstalk between the stromal and BrCa cells. ...
Breast cancer (BrCa) is the leading cause of death among women worldwide, with about one million new cases diagnosed each year. In spite of the improvements in diagnosis, early detection and treatment, there is still a high incidence of mortality and failure to respond to current therapies. With the use of several well-established biomarkers, such as hormone receptors and human epidermal growth factor receptor-2 (HER2), as well as genetic analysis, BrCa patients can be categorized into multiple subgroups: Luminal A, Luminal B, HER2-enriched, and Basal-like, with specific treatment strategies. Although chemotherapy and targeted therapies have greatly improved the survival of patients with BrCa, there is still a large number of patients who relapse or who fail to respond. The role of the tumor microenvironment in BrCa progression is becoming increasingly understood. Cancer-associated fibroblasts (CAFs) are the principal population of stromal cells in breast tumors. In this review, we discuss the current understanding of CAFs’ role in altering the tumor response to therapeutic agents as well as in fostering metastasis in BrCa. In addition, we also review the available CAFs-directed molecular therapies and their potential implications for BrCa management.
... Inhibition of the CEBPD/MCL1 axis strengthens gemcitabine-induced apoptosis. A recent study showed that PPARγ activation can block activation of OBR and the JAK/STAT3 signaling pathway (34). To clarify the role of the CEBPD/MCL1 axis in leptin-induced survival of GBC cells, a PPARγ agonist, rosiglitazone, was applied to address this issue. ...
Obesity is a risk factor for gallbladder cancer (GBC) development and correlates with shorter overall survival. Leptin, derived from adipocytes, has been suggested to contribute to the growth of cancer cells. However, the detailed mechanism of leptin in GBC drug resistance remains uninvestigated. In this study, it is clinically relevant that GBC patients with a higher BMI (BMI ≥ 24 kg/m2) (n=30) were associated with increased GBC risks, including survival. Moreover, obese NOD/SCID mice exhibited a higher circulating concentration of leptin, which is associated with GBC growth and attenuated gemcitabine efficacy. We further revealed that leptin can inhibit gemcitabine-induced GBC cell death through myeloid cell leukemia 1 (MCL1) activation. The transcription factor CCAAT/enhancer-binding protein delta (CEBPD) is responsive to activated signal transducers and activators of transcription 3 (pSTAT3) and contributes to MCL1 transcriptional activation upon leptin treatment. In addition, MCL1 mediates leptin-induced mitochondrial fusion and is associated with GBC cell survival. This study suggests the involvement of the pSTAT3/CEBPD/MCL1 axis in leptin-induced mitochondrial fusion and survival. It provides a new therapeutic target to improve the efficacy of gemcitabine in GBC patients.
... In line with this, leptin could play a role in vascular remodeling in hypoxia conditions through HIF-1α in human adipocytes and fibroblasts, as occurs in solid tumors [148]. Leptin can regulate angiogenesis via VEGF and IL-6, and fibroblast growth factor (FGF) 2, suppresses apoptosis through a Bcl-2-dependent mechanism and acts as a mitogen or migration factor for many different cell types, including cancer cells, as well as sustaining the recruitment of monocytes and macrophages, that allow leptin to shape the TME [149]. Moreover, leptin signaling may promote oncogenesis through the promotion of the cancer stem cell phenotype [150]. ...
Leptin is an important regulator of basal metabolism and food intake, with a pivotal role in obesity. Leptin exerts many different actions on various tissues and systems, including cancer, and is considered as a linkage between metabolism and the immune system. During the last decades, obesity and leptin have been associated with the initiation, proliferation and progression of many types of cancer. Obesity is also linked with complications and mortality, irrespective of the therapy used, affecting clinical outcomes. However, some evidence has suggested its beneficial role, called the “obesity paradox”, and the possible antitumoral role of leptin. Recent data regarding the immunotherapy of cancer have revealed that overweight leads to a more effective response and leptin may probably be involved in this beneficial process. Since leptin is a positive modulator of both the innate and the adaptive immune system, it may contribute to the increased immune response stimulated by immunotherapy in cancer patients and may be proposed as a good actor in cancer. Our purpose is to review this dual role of leptin in cancer, as well as trying to clarify the future perspectives of this adipokine, which further highlights its importance as a cornerstone of the immunometabolism in oncology.
... Leptin has been acknowledged to be a critical element of the obesity-related progression and malignancy of breast cancer (17). Leptin can directly remodel the tumor microenvironment by inducing metabolic changes in tumor cells and recruiting immune cells such as monocytes, macrophages and myeloid-derived suppressor cells (MDSCs) able to produce proinflammatory cytokines that sustain angiogenesis and tumor growth (18). It was previously shown that the proliferation of 4T1 cells in vitro increased by the addition of leptin; also, that the inhibition of leptin-mediated signaling on these cells reduces its proliferation and the growth of 4T1 tumors in vivo (19). ...
... [5] Leptin is a multifunctional polypeptide molecule which regulates food intake, inflammation, cell differentiation, and proliferation. [6] Leptin is mainly synthesized not only by distant or local adipocytes but also by cancer-associated fibroblasts and plays an important role in breast tumorogenesis and control breast cancer manner as an endocrine, paracrine, and autocrine hormone. [7][8][9][10][11] Leptin effects on breast cancer proliferation independently way and also through insulin signaling pathway. ...
Context: Elevated levels of insulin and leptin can be associated with poor prognosis in breast cancer patients. A safe and effective exercise protocol seems necessary as an adjuvant therapy in breast cancer patients.
Aims: This study aimed to assess the effect of concurrent yoga and Pilates training on insulin and leptin in breast cancer survivors.
Setting and Design: This study was a randomized clinical trial research with control group in a selected oncology and radiotherapy center in Rasht, Iran, in 2019.
Materials and Methods: This clinical trial was performed on thirty breast cancer survivors. The participants were allocated in exercise group (n = 15) and control group (n = 15) by simple randomly. Exercise group underwent 12 weeks of concurrent yoga and Pilates training, 3 sessions/week and 75 min of workout in each session. Every participant completed the demographic questionnaire. Weight, insulin, leptin, carcinoembryonic antigen (CEA), and cancer antigen 15-3 (CA 15-3) levels were measured before and after 12 weeks of exercise in both groups.
Statistical Analysis Used: Data were analyzed using descriptive statistics, one-way ANCOVA, and paired t-test and Wilcoxon.
Results: Mean score of weight in the exercise group decreased from 73.03 ± 16.75 to 69.92 ± 15.46 (P = 0.01), but in control group, there was no significant improvement (from 85.54 ± 11.7 to 85.27 ± 9.71). There was a significant decrease in leptin levels (from 33.70 ± 15.93 to 21.21 ± 15.37) in exercise group (P = 0.02). However, there was no significant effect on insulin (from 7.66 ± 2.96 to 10.67 ± 4.51), CEA, and CA 15-3 (P > 0.05).
Conclusion: Twelve weeks of concurrent yoga and Pilates training have positive effects on leptin levels in breast cancer survivors.
... Leptin is a 16 kDa adipocytokine, encoded by the obese gene and involved in the central regulation of food intake, energy homeostasis, modulation of reproductive function and peripheral metabolic processes, such as breast/mammary gland development, cellular proliferation and angiogenesis (16)(17)(18). In tissues and serum, leptin expression is modulated by fat mass, with healthy cats showing lower serum leptin levels than obese animals (12), as reported in humans (13,14). ...
Obesity is an established risk factor for breast cancer in post-menopausal women, being associated with elevated serum levels of leptin. Although overweight is a common condition in cat, the role of leptin and its receptor in feline mammary carcinoma remains unsettled. In this study, serum leptin and leptin receptor (ObR) levels were investigated in 58 cats with mammary carcinoma and compared with those of healthy animals, as were the expression levels of leptin and ObR in tumor tissues. The results showed that the Free Leptin Index is significantly decreased in cats with mammary carcinoma (p = 0.0006), particularly in those with luminal B and HER2-positive tumors, and that these animals also present significantly lower serum leptin levels (p < 0.0001 and p < 0.005, respectively). Interestingly, ulcerating tumors (p = 0.0005) and shorter disease-free survival (p = 0.0217) were associated to serum leptin levels above 4.17 pg/mL. In contrast, elevated serum ObR levels were found in all cats with mammary carcinoma (p < 0.0001), with levels above 16.89 ng/mL being associated with smaller tumors (p = 0.0118), estrogen receptor negative status (p = 0.0291) and increased serum levels of CTLA-4 (p = 0.0056), TNF-α (p = 0.0025), PD-1 (p = 0.0023), and PD-L1 (p = 0.0002). In tumor samples, leptin is overexpressed in luminal B and triple-negative carcinomas (p = 0.0046), whereas ObR is found to be overexpressed in luminal B tumors (p = 0.0425). Altogether, our results support the hypothesis that serum levels of leptin and ObR can be used as biomarkers of specific feline mammary carcinoma subtypes, and suggests the use of leptin antagonists as a therapeutic tool, reinforcing the utility of the cat as a cancer model.
... Leptin, another adipokine, was also found to shape the TME and contribute to tumor development [140]. In macrophages, leptin induces some inflammatory mediators' production, including TNF-α, IL-6, and leukotriene B4 [141]. ...
Macrophages phagocytize pathogens to initiate innate immunity and products from the tumor microenvironment (TME) to mediate tumor immunity. The loss of tumor-associated macrophage (TAM)-mediated immune responses results in immune suppression. To reverse this immune disorder, the regulatory mechanism of TAMs in the TME needs to be clarified. Immune molecules (cytokines and chemokines) from TAMs and the TME have been widely accepted as mutual mediators of signal transduction in the past few decades. Recently, researchers have tried to seek the intrinsic mechanism of TAM phenotypic and functional changes through metabolic connections. Numerous metabolites derived from the TME have been identified that induce the cell-cell crosstalk with TAMs. The bulk tumor cells, immune cells, and stromal cells produce metabolites in the TME that are involved in the metabolic regulation of TAMs. Meanwhile, some products from TAMs regulate the biological functions of the tumor as well. Here, we review the recent reports demonstrating the metabolic regulation between TME and TAMs.
... For instance, INS1, PI3KR2, PLAGL2, LEP and SMAD6 have been reported as growth factors, promoting somatic evolution, but also oncogenes, enabling tumor progression (Fig. 6B). LEP promotes angiogenesis through VEGF signaling and acts as an autocrine factor in cancer cells promoting proliferation and inhibition of apoptosis (Andò and Catalano 2012). PLAGL2 contributes to cancer by generating loss of cell-cell contact inhibition, maintaining an immature differentiation state in glioblastomas, and inducing proliferation of hematopoietic progenitors in leukemia (Hensen et al. 2002;Zheng et al. 2010;Landrette et al. 2011). ...
Gigantism results when one lineage within a clade evolves extremely large body size relative to its small-bodied ancestors, a common phenomenon in animals. Theory predicts that the evolution of giants should be constrained by two tradeoffs. First, because body size is negatively correlated with population size, purifying selection is expected to be less efficient in species of large body size, leading to increased mutational load. Second, gigantism is achieved through generating a higher number of cells along with higher rates of cell proliferation, thus increasing the likelihood of cancer. To explore the genetic basis of gigantism in rodents and uncover genomic signatures of gigantism-related tradeoffs, we assembled a draft genome of the capybara (Hydrochoerus hydrochaeris), the world’s largest living rodent. We found that the genome-wide ratio of non-synonymous to synonymous mutations (ω) is elevated in the capybara relative to other rodents, likely caused by a generation-time effect and consistent with a nearly-neutral model of molecular evolution. A genome-wide scan for adaptive protein evolution in the capybara highlighted several genes controlling post-natal bone growth regulation and musculoskeletal development, which are relevant to anatomical and developmental modifications for an increase in overall body size. Capybara-specific gene-family expansions included a putative novel anticancer adaptation that involves T cell-mediated tumor suppression, offering a potential resolution to the increased cancer risk in this lineage. Our comparative genomic results uncovered the signature of an intragenomic conflict where the evolution of gigantism in the capybara involved selection on genes and pathways that are directly linked to cancer.
... [60][61][62] Leptin promotes the migration of endothelial cells, secretion of VEGF and cytokines facilitate metastases. 63 Oxidative stress. It is the result of the imbalance between the production of ROS and reactive nitrogen species (RNS) associated with a failure in the antioxidant system responsible for its neutralization. ...
RESUMEN La enfermedad cardiovascular es la primera causa de muerte en la mujer que sobrevive al cáncer de mama. La magnitud de los efectos cardiotóxicos depende no sólo del tratamiento antineoplásico, sino de la susceptibilidad individual, que está determinada por la enfermedad cardiovascular preexistente y los factores de riesgo concurrentes, así como de las interven-ciones en la prevención, identificación y tratamiento oportuno de la cardiotoxicidad. La Asociación Nacional de Cardiólogos de México, inmersa en esta realidad, comparte en el presente documento un abordaje que explica la interacción de las dos entidades desde la perspectiva de la mujer de alto riesgo y resume las estrategias de detección y cardioprotección actuales. ABSTRACT Cardiovascular disease is the leading cause of death in breast cancer survivor women. The magnitude of cardiotoxic effects depends not only on antineoplastic treatment, but also on individual susceptibility, which is determined by pre-existing cardiovascular disease and concurrent risk factors, as well as on prevention interventions , early identification and treatment of cardiotoxicity. The National Association of Cardiologists of Mexico, immersed in this reality, shares in this document an approach that explains the interaction of the two entities from the perspective of high-risk women and summarizes current detection and cardio-protection strategies.
... High CXCR4 expression was associated with increased bone metastasis and poorer prognosis in breast cancer patients. Although leptin receptor antagonist therapies are still undergoing clinical trials, leptin is still considered a candidate cancer treatment due to its unique status as a link between obesity and cancer [23,24]. In addition, leptin can promote recurrence and distant metastasis in breast cancer, ultimately leading to poor overall survival in late stage breast cancer patients [25]. ...
Obesity is associated with an increased risk of tumorigenesis, and increased leptin levels can promote tumor metastasis. However, the effects of leptin on bone metastasis in breast cancer are not fully understood. Here, we examined leptin receptor expression and bone metastasis in tissue samples from 96 breast cancer patients. In addition, we investigated the effects of leptin on the metastatic capacity of breast cancer cells invitro using a transwell assays. The results indicated that higher leptin receptor levels in breast cancer cells are associated with increased incidence of bone metastasis in breast cancer patients. Additionally, leptin promoted migration and invasion of breast cancer cells. The SDF-1/CXCR4 axis activated by leptin also promoted bone metastasis of breast cancer. Finally, increased CXCR4 expression was accompanied by high leptin receptor expression in bone metastatic tissues from breast cancer patients. These results indicate that leptin induces bone metastasis of breast cancer by activating the SDF-1/CXCR4 axis.
The role of mesenchymal stem cells (MSCs) in the breast tumor microenvironment (TME) is significant and multifaceted. MSCs are recruited to breast tumor sites through molecular signals released by tumor sites. Once in the TME, MSCs undergo polarization and interact with various cell populations, including immune cells, cancer-associated fibroblasts (CAFs), cancer stem cells (CSCs), and breast cancer cells. In most cases, MSCs play roles in breast cancer therapeutic resistance, but there is also evidence that indicates their abilities to sensitize cancer cells to chemotherapy and radiotherapy. MSCs possess inherent regenerative and homing properties, making them attractive candidates for cell-based therapies. Therefore, MSCs can be engineered to express therapeutic molecules or deliver anti-cancer agents directly to tumor sites. Unraveling the intricate relationship between MSCs and the breast TME has the potential to uncover novel therapeutic targets and advance our understanding of breast cancer biology.
Immune checkpoint inhibitors (ICI) have deeply changed the therapeutic management of a broad spectrum of solid tumors. Recent observations showed that obese patients receiving ICIs might have better outcomes than those with normal weight, while obesity was historically associated with a worse prognosis in cancer patients. Of note, obesity is associated with alterations in the gut microbiome profile, which interacts with immune and inflammatory pathways, both at the systemic and intratumoral levels. As the influence of the gut microbiota on the response to ICI has been repeatedly reported, a specific gut microbiome profile in obese cancer patients may be involved in their better response to ICI. This review summarizes recent data on the interactions between obesity, gut microbiota, and ICIs. In addition, we highlight possible pathophysiological mechanisms supporting the hypothesis that gut microbiota could be one of the links between obesity and poor response to ICIs.
Molecular links between breast cancer risk factors and pro-oncogenic tissue alterations are poorly understood. The goal of this study was to characterize the impact of overweight and obesity on tissue markers of risk, using normal breast biopsies, a mouse model of diet-induced obesity, and cultured breast acini. Proliferation and alteration of epithelial polarity, both necessary for tumor initiation, were quantified by immunostaining. High BMI (>30) and elevated leptin were associated with compromised epithelial polarity whereas overweight was associated with a modest increase in proliferation in human and mice mammary glands. Human serum with unfavorable adipokine levels altered epithelial polarization of cultured acini, recapitulating the effect of leptin. Weight loss in mice led to metabolic improvements and restored epithelial polarity. In acini cultures, alteration of epithelial polarity was prevented by antioxidants and could be reverted by normalizing culture conditions. This study shows that obesity and/or dietary factors modulate tissue markers of risk. It provides a framework to set target values for metabolic improvements and to assess the efficacy of interventional studies aimed at reducing breast cancer risk.
Obesity is associated with a higher risk of chronic diseases. Breast cancer is one of the malignancies, which has been related to obesity. Patients with a BMI more than 35 kg/m 2 had an 86% greater risk of having breast cancer than those with a normal BMI. Every 5 kg/m 2 rise in BMI has also been demonstrated to increase the risk of postmenopausal breast cancer. Obese people have poorer outcomes in terms of lymph node positivity, disease-free survival, and overall survival, according to research. Leptin, whose circulating levels rise in proportion to BMI and body fat reserves, is usually regarded as the primary driver of the intricate web that connects obesity and breast cancer. The number of studies examining the association between leptin activity and breast cancer genesis and behavior is growing. The effectiveness of bariatric surgery on lessening the risk of developing breast cancer has been proven.
Objective
Breast Cancer (BC) is one of the deadliest diseases in women, causing thousands of deaths annually despite the advent of high-throughput genomic platforms in the recent past. Microarray-based gene expression profiling with different statistical methods have been extensively used to understand the disease at the molecular level. We plan to apply Welch Satterthwaite t- test, Kaplan-Meier estimator plot and Huber Loss robust regression model on microarray data to improve the analysis and find biomarkers for future diagnosis, prognosis, and treatment.
Methods
We retrieved microarray data (GSE10810 dataset) of 31 breast tumor samples and 27 normal breast samples from Gene Expression Omnibus (GEO, NCBI). Welch Satterthwaite t-test was applied to identify the most statistically significant genes, Huber loss robust regression model was applied to investigate the existing mathematical relations between tumor and control variables, and Kaplan-Meier Plotter was used to confirm their association with overall metastatic relapse-free survival of BC patients.
Results
We identified 1837 differentially expressed genes, including 638 overexpressed (COL11A1, KIAA0101, S100P, GJB2, TOP2A, LINC01614, RRM2, INHBA, C15orf48 and CKS2) and 1199 under expressed (LEP, ADIPOQ, PLIN1, PCK1, PCOLCE2, ADH1B,
LYVE1, FABP4, ABCA8, and CHRDL1) genes passing the threshold (fold change ±2 and p value <0.001). KM analysis revealed 12 out of 20 DEGs (log rank p value <0.05) as potential prognostic and therapeutic biomarkers.
Conclusion
Huber loss robust regression model was found to be one of the best performing algorithms for the mathematical relationship between the control and breast tumor samples with co-relation coefficient of 0.4398 and mean absolute error of 1.069±0.020. In conclusion, with high mathematical confidence we detected DEGS has high potential to be BC biomarkers using Welch t-test and Kaplan-Meier plot having minimum underlying assumptions.
Obesity may create a mitogenic microenvironment that influences tumor initiation and progression. The obesity-associated adipokine, leptin regulates energy metabolism and has been implicated in cancer development. It has been shown that some cell types other than adipocytes can express leptin and leptin receptors in tumor microenvironments. It has been shown that peroxisome proliferator-activated receptors (PPAR) agonists can affect leptin levels and vice versa leptin can affect PPARs. Activation of PPARs affects the expression of several genes involved in aspects of lipid metabolism. In addition, PPARs regulate cancer cell progression through their action on the tumor cell proliferation, metabolism, and cellular environment. Some studies have shown an association between obesity and several types of cancer, including breast cancer. There is some evidence that suggests that there is crosstalk between PPARs and leptin during the development of breast cancer. Through a systematic review of previous studies, we have reviewed the published relevant articles regarding leptin signaling in breast cancer and its crosstalk with peroxisome proliferator-activated receptors α and γ.
Tumor extracellular vesicles (EVs), as endocytic vesicles able to transport nucleic acids, proteins, and metabolites in recipient cells, have been recognized fundamental mediators of cell-to-cell communication in breast cancer. The biogenesis and release of EVs are highly regulated processes and both the quantity of EVs and their molecular cargo might reflect the metabolic state of the producing cells. We recently demonstrated that the adipokine leptin, whose circulating levels correlate with adipose tissue expansion, is an inducer of EV release from breast cancer cells. Here, we show a specific proteomic signature of EVs released by MCF-7 breast cancer cells grown in the presence of leptin (Lep-EVs), in attempt to find additional molecular effectors linking obesity to breast cancer biology. An analysis of the proteomic profile of Lep-EVs by LC-MS/MS revealed a significant enrichment in biological processes, molecular functions, and cellular components mainly related to mitochondrial machineries and activity, compared to protein content of EVs from untreated breast cancer cells. Metabolic investigations, carried out to assess the autocrine effects of these vesicles on breast cancer cells, revealed that Lep-EVs were able to increase ATP levels in breast cancer cells. This result is associated with increased mitochondrial respiration evaluated by Seahorse analyzer, supporting the concept that Lep-EVs can modulate MCF-7 breast cancer cell oxidative metabolism. Moreover, taking into account the relevance of tumor immune cell crosstalk in the tumor microenvironment (TME), we analyzed the impact of these vesicles on macrophage polarization, the most abundant immune component in the breast TME. We found that tumor-derived Lep-EVs sustain the polarization of M0 macrophages, derived from the human THP-1 monocytic cells, into M2-like tumor-associated macrophages, in terms of metabolic features, phagocytic activity, and increased expression of CD206-positive population. Overall, our results indicate that leptin by inducing the release of EV-enriched in mitochondrial proteins may control the metabolism of MCF-7 breast cancer cells as well as that of macrophages. Characterization of tumor-derived EV protein cargo in an obesity-associated milieu, such as in the presence of elevated leptin levels, might allow identifying unique features and specific metabolic mechanisms useful to develop novel therapeutic approaches for treatment of breast cancer, especially in obese patients.
Adipocytokines have gained significant attention in the scientific community over the past few decades. They are a family of enzymes, hormones, growth factors, proteins, and other bioactive molecules that are important regulators of many processes. Adipocytokines are predominantly produced by preadipocytes and mature adipocytes to act through a network of autocrine, paracrine, and endocrine pathways. Leptin (LEP) is the first adipocytokine discovered that has a role in modulating adiposity and has been shown to exert pleiotropic effects on many metabolic pathways through the leptin receptors (LEPRs). LEP has pro-tumoral roles; it promotes angiogenesis, proliferation, survival of tumor cells, and inhibits apoptosis. To exercise its role in tumorigenesis, LEP-LEPR signaling and epithelial-mesenchymal transitions (EMTs) play a significant role. LEP is an oncogenic factor mainly due to its proinflammatory and proangiogenic effects. In angiogenesis, LEP acts directly as an endothelial growth factor or indirectly through cellular pathways, such as STAT3/ERK1/2, JAK2/STAT3, MAPK/ERK, PI3K/AKT, p38, p53, MAPK, and Wnt/β-catenin.
The early onset of colorectal cancer (CRC) in individuals younger than 50 years is an emerging phenomenon, and obesity is a strong risk factor. Inflammatory mechanisms are mediated by immune cells, with macrophages and their phenotypical changes playing a significant role in CRC. Obesity-related hormones, such as leptin and adiponectin, affect macrophage polarization and cytokine expression. Macrophage metabolism, and therefore polarization, directly affects tumor progression and survival in patients with CRC. Altered obesity-related hormone levels induce phosphoinositide kinase-3 (PI3K)/serine-threonine-protein kinase (AKT) activation in colon cancer, causing increased cell survival, hyperplasia, and proliferation. Investigating the effects of obesity-related mechanisms on PI3K/Akt signaling can provide new insights for targeting mechanisms in CRC and obesity among the young. Central molecules for the control of cell proliferation, differentiation, and tumorigenesis within the gastrointestinal tract include downstream targets of the PI3K/AKT pathway, such as Neurogenic locus notch homolog 4 (Notch4) and GATA binding proteins (GATA). Leptin and adiponectin both alter gene expression within this pathway, thereby affecting TAM-mediated CRC progression. Our goal is to introduce the NOTCH4-GATA4-IRG1 axis as a link between inflammation and sporadic CRC and to discuss this pathway as a new potential immunotherapeutic target in individuals affected with obesity and early-onset CRC.
Molecular links between breast cancer risk factors and pro-oncogenic tissue alterations are poorly understood. The goal of this study was to characterize the impact of overweight and obesity on tissue markers of risk, using normal breast biopsies, a mouse model of obesity, and cultured breast acini. Proliferation and disruption of epithelial polarity, both necessary for tumor initiation, were quantified by immunostaining. High BMI and elevated leptin were associated with compromised epithelial polarity whereas overweight was associated with proliferation in human and mice mammary glands. Human serum with unfavorable adipokine levels altered epithelial polarization of cultured acini, recapitulating the effect of leptin. Weight loss in mice led to metabolic improvements and restored epithelial polarity. In acini cultures, epithelial polarity loss was prevented by antioxidants and could be reverted by normalizing culture conditions. This study provides a framework to set target values for metabolic improvements and to assess the efficacy of interventional studies aimed at reducing breast cancer risk.
Робота присвячена вивченню епідеміології онкологічних захворювань у хворих на цукровий діабет та дослідженню впливу дисметаболічних порушень за цукрового діабету на внутрішньоклітинні сигнальні системи, залучені до регуляції онкогенезу.
Обгрунтування вибору теми дослідження. Протягом останніх десятиліть зростання захворюваності на цукровий діабет (ЦД) залишається пріоритетним питанням системи охорони здоров’я багатьох країн світу. Згідно з даними Міжнародної діабетичної федерації, cтаном на 2019 рік у світі нараховувалося 463 млн. хворих на ЦД. З огляду на темпи поширеності, експерти Всесвітньої організації охорони здоров’я (ВООЗ) прогнозують, що до 2040 року кількість пацієнтів із ЦД зросте до 625 млн. В Україні, за офіційними даними, зареєстровано близько 1 311 335 хворих на ЦД.
Не менш серйозною та актуальною проблемою клінічної медицини є зростання поширеності онкологічних захворювань.
За даними новітніх досліджень, хворі на ЦД мають підвищений ризик злоякісних новоутворень (ЗН) багатьох локалізацій, доведено збільшення показників смертності хворих на ЦД від раку. Беручи до уваги існування підвищеного онкоризику у хворих на діабет, враховуючи темпи зростання захворюваності на ЦД, у майбутньому закономірно очікувати прогресивне збільшення кількості ЗН.
Доведено, що хронічний вплив позаклітинних дисметаболічних чинників призводить до зміни функціонування внутрішньоклітинних сигнальних шляхів, зокрема шляху PI3K/Akt/mTOR, гіперактивація якого спричиняє mTORС1 – опосередковану стимуляцію кінази p70S6K, порушення синтезу протеїнів та їх ефектів, у тому числі пов’язаних із контролем клітинної проліферації, апоптозу та виживання. Гіперактивацію PI3K/Akt/mTOR доведено для багатьох ЗН.
Хронічний перебіг ЦД, необхідність щоденної цукрознижувальної терапії (ЦЗТ) визначають актуальність дослідження механізмів асоціації ЦД і раку, пов’язаних із впливом цукрознижувальних препаратів (ЦЗП) різних груп.
З огляду на наявність численних чинників активації інсулінового сигналінгу (залученого в онкогенез), дослідження активності PI3K/Akt/mTOR у хворих на ЦД є важливим для визначення ролі дисметаболічних порушень в онкогенезі з метою забезпечення вчасної корекції виявлених розладів для профілактики ЗН. Вивчення активності компонентів PI3K/Akt/mTOR дозволить оцінити їх значення як потенційних біохімічних маркерів онкогенезу на тлі ЦД.
Мета роботи: покращити ефективність діагностики та профілактики злоякісних новоутворень в хворих на цукровий діабет на основі дослідження провідних чинників ризику, механізмів розвитку та особливостей перебігу онкологічних захворювань у хворих на цукровий діабет для з’ясування основних клініко-діагностичних критеріїв формування онкологічної патології в цієї категорії пацієнтів.
Першим етапом наукового дослідження було проведення епідеміологічного аналізу вперше діагностованих ЗН у хворих на ЦД, мешканців Івано-Франківської області за період 2012-2016 років. Вивчення даних за вказаний 5-річний термін обґрунтовано запланованим аналізом 5-річної виживаності хворих.
За отриманими даними, за вказаний період у хворих на ЦД виявлено 551 випадок ЗН. Абсолютну більшість серед усіх пацієнтів становили хворі на ЦД 2-го типу (ЦД2) – 533 особи (96,7%), 18 осіб мали ЦД 1-го типу (ЦД1 – 3,3%). Найчастішою формою раку, виявленого у хворих на ЦД1, була лімфома Ходжкіна (16,67%), а в хворих на ЦД2 – злоякісні пухлини молочної залози (МЗ) – 126 випадків (23,64%), колоректальний рак (КРР) – 72 (13,51%), тіла матки – 65 (12,20%) та підшлункової залози (ПШЗ) – 52 (9,76%).
Враховуючи невелику кількість пацієнтів із ЦД1 із ЗН, статистичний аналіз отриманих даних епідеміологічного дослідження проведено в групі хворих з ЦД2.
За результатами статистичного аналізу у жінок із ЦД2 виявлено підвищений ризик ЗН МЗ в 1,3 рази, тіла матки в 1,4 рази, раку ПШЗ в 1,6 рази, у чоловіків із ЦД2 – панкреатичного раку в 1,9 рази.
Доведено значну поширеність ожиріння серед хворих із ЗН, виявленими на тлі ЦД2 (52,35% хворих), зокрема в хворих із ЗН органів репродуктивної системи та з КРР. За результатами статистичного аналізу у жінок із ЦД2 доведено, асоційований з ожирінням, підвищений ризик раку МЗ в 2,1 рази, а в чоловіків – ЗН простати та КРР в 2,9 рази.
Злоякісні пухлини найбільш поширених локалізацій найчастіше діагностували у хворих на ЦД2 середньої тяжкості (77,48%), в стадії декомпенсації (70,36%), віком 60-70 років, із тривалістю діабету понад 5 років. Найменшу тривалість ЦД до виявлення ЗН мали хворі з панкреатичним раком.
Найбільш поширеною схемою лікування хворих на ЦД2 перед виявленням ЗН була комбінована терапія ЦЗП з позапанкреатичними цукрознижувальними ефектами (метформін, глітазони, гліфлозини) зі стимуляторами синтезу або секреції інсуліну (похідні сульфонілсечовини (СС) і гліптини) (37,71%). У терапії хворих із ЗН ПШЗ переважали монотерапія інсуліном (25,00%) і монотерапія похідними СС (26,92%).
Встановлено, що до виявлення онкологічних захворювань, 397 хворих на ЦД2 (74,48%) в складі ЦЗТ використовували похідні СС чи препарати інсуліну. Вказані препарати частіше застосовували хворі з тривалістю ЦД понад 5 років та хворі без ожиріння. Разом з тим, зазначену терапію застосовували 47,53% пацієнтів з тривалістю ЦД до 5 років (найбільшу частку серед яких становили хворі з панкреатичним раком) та 68,82% хворих з ожирінням.
За допомогою статистичного аналізу у хворих на ЦД2 встановлено, асоційований з інсулінотерапією, підвищений ризик ЗН в 2,4 рази.
За результатами аналізу даних епідеміологічного дослідження виявлені відмінності клінічних характеристик та перебігу діабету у хворих із ЗН ПШЗ, діагностованими на тлі ЦД2. Відсутність ожиріння, незначна тривалість ЦД, швидка потреба в застосуванні секретагогів та інсулінотерапії вказують на перевагу інсулінової недостатності над інсулінорезистентністю (ІР). Зазначені дані дозволяють зробити припущення про наявність у значної частини хворих вторинного, рак-індукованого T3cDM, класифікованого як ЦД2.
На підставі результатів епідеміологічного дослідження створено моделі розрахунку прогнозованого ризику злоякісних пухлин (індекс Y), найчастіше діагностованих у хворих на ЦД: МЗ, тіла матки, ПШЗ і КРР з використанням рівнянь логістичної регресії та логістичного перетворення. Середній та високий ступінь прогнозованого ризику злоякісних пухлин, підтверджений індексом Y = 0,4 – 1 слід вважати показанням для додаткового обстеження та моніторингу хворих на ЦД2 щодо вказаних ЗН, а також є підґрунтям для корекції показників, які впливають на даний ризик (ІМТ, рівень HbA1c, схема ЦЗТ).
Проведено оцінку показників виживання хворих на ЦД із ЗН. Виявлено, що ЦД2 збільшує ризик смерті впродовж 1 року для хворих на рак МЗ, тіла матки та шкіри (немеланомні форми). У випадках ЗН шкіри показники смертності можуть бути зумовлені віком пацієнтів (середній вік хворих 71,75±3,86 років). Порівняльний аналіз із використанням тесту Cox-Mantel і криві кумулятивного виживання Каплана-Майєра демонструють пряму залежність виживання пацієнтів із ЗН, виявленими на тлі ЦД2 від стадії ЗН. Окрім того, виявлено, що ЦЗТ препаратами, які не впливають на рівень інсуліну в крові достовірно позитивно впливає на виживання жінок із ЗН тіла матки І стадії та хворих із панкреатичним раком ІІІ стадії (незалежно від статі). Достовірно довше виживання пацієнтів із рівнем HbA1c<8,0% виявлено для хворих із ЗН тіла матки ІІ стадії, а пацієнти із ЗН ПШЗ ІІІ стадії мали довше виживання при рівні HbA1c>8,0%. Для хворих із колоректальним раком ІІ стадії з тривалістю ЦД <5 років доведено довше виживання порівняно з таким для пацієнтів із тривалістю діабету 5-10 років.
Крім епідеміологічного аналізу, одним із завдань наукової роботи було дослідження активності інсулінового сигналінгу PI3K/Akt/mTOR. З показниками осіб контрольної групи (І) порівнювали відповідні показники пацієнтів трьох груп: ІІ група – хворі на ЦД2 без ЗН; ІІІ група – пацієнти із ЗН без ЦД; ІV група – хворі на ЦД2 із вперше діагностованими ЗН. З огляду на виявлену на етапі епідеміологічного дослідження найбільшу частоту випадків ЗН МЗ, тіла матки, ПШЗ і КРР, до етапу лабораторних досліджень було залучено хворих із цими локалізаціями ЗН.
У хворих на ЦД2 ІІ групи (60,72% серед яких мали ожиріння) виявлено підвищені, у порівнянні з контрольною групою, рівні інсуліну та IGF-1. Виявлено, що інтенсифікація ЦЗТ у хворих на ЦД2 супроводжувалася паралельним збільшенням ІМТ і рівня інсуліну в крові.
У пацієнтів ІІІ групи і в хворих IV групи із злоякісними пухлинами МЗ, тіла матки і товстого кишечника, виявлено ожиріння та підвищені, порівняно з показниками контрольної групи, рівні інсуліну в крові та індекси HOMA-IR. Незалежно від локалізації ЗН у пацієнтів ІІІ і IV груп виявлено підвищені рівні IGF-1 порівняно з такими в контрольній групі. У пацієнтів IV групи виявлено достовірно вищі рівні глікемії натще у порівнянні з хворими ІІ групи.
Активність сигнального каскаду PI3K/Akt/mTOR оцінено шляхом визначення вмісту фосфорильованих протеїнкіназ Akt (Ser473), p70S6K (Thr389) і PRAS40 (pT246) – природнього інгібітору mTORС1 – у мононуклеарах периферичної крові (МНПК). Ступінь фосфорилювання Akt (Ser473) відображає активацію комплексу mTORC2, а p70S6K (Thr389) і PRAS40 (pT246) – mTORC1.
Достовірно вищий, ніж у групі контролю, вміст рhospho-Akt виявлено лише в пацієнтів ІІІ групи із ЗН без ЦД, з ожирінням та підвищеним (порівняно з показником групи контролю) вмістом інсуліну. У хворих ІІ групи вміст рhospho-Akt у МНПК не відрізнявся від показника контрольної групи, що вказує на відсутність mTORC2-опосередкованої гіперактивації Akt (Ser473) за ЦД2.
Підвищені рівні рhospho-PRAS40 і рhospho-p70S6K, порівняно з показниками контрольної групи, виявлені в пацієнтів ІІ і ІІІ груп (з ожирінням), що доводять гіперактивацію каскаду PI3K/Akt/mTOR при ЗН та при ЦД2.
Виявлене достовірне зниження вмісту рhospho-Akt, рhospho-PRAS40 і рhospho-p70S6K в МНПК пацієнтів IV групи порівняно з показниками контрольної групи та інших груп вказує на пригнічення активації інсулінового сигналінгу за поєднання обох захворювань та потребує додаткового вивчення.
Використовуючи отримані в дослідженні результати, створено модель оцінки активації процесів онкогенезу за допомогою методу дискримінантного аналізу. Ця модель може бути використана для виявлення надмірної активації інсулінового сигналінгу в хворих на ЦД2 в майбутньому.
За результатами дослідження підтверджено здатність метформіну впливати на фосфорилювання PRAS40 і пригнічувати mTORC1-опосередковану активацію p70S6K на основі зниженого вмісту phospho-PRAS40 і phospho-p70S6k у хворих на ЦД2 ІІ та IV груп на монотерапії метформіном.
Пряма кореляція рhospho-Akt, phospho-PRAS40 і phospho-p70S6k з інсуліном, IGF-1, ІМТ як в здорових осіб, так і в хворих на ЦД2, із ЗН та за їх поєднання вказує на роль ожиріння та ростових факторів в активації комплексів mTORC1 і mTORC2. В хворих ІІ та IV груп із ЦД2 виявлена пряма кореляція phospho-PRAS40 та phospho-p70S6k із HbA1c.
Наукова новизна. В дослідженні підтверджено наукові дані про вплив ЦД2 на формування онкологічної патології, доповнено наукові дані про вплив ожиріння та інсулінотерапії на розвиток ЗН у хворих на ЦД2. Встановлено вплив ЦД2 на виживання пацієнтів із ЗН та його залежність не тільки від стадії ЗН, а також від ЦЗТ, рівня HbA1c і тривалості ЦД (при окремих стадіях та окремих локалізаціях ЗН).
Встановлено гіперактивацію сигнального шляху PI3K/Akt/mTORС1, залученого до регуляції метаболізму та онкогенезу, в хворих на ЦД2. Доведено відсутність активації шляху PI3K/Akt/mTORС1 у хворих із ЗН, діагностованими на тлі ЦД2. Доведено і науково-обґрунтовано гіпотезу реципрокного фосфорилювання Akt по сериновому (Ser473) та треоніновому (Thr308) залишках в хворих на ЦД2. Встановлено прямий вплив гіперглікемії на активацію mTORC1 за ЦД2. Доповнено наукові дані про вплив інсуліну та IGF-1 в якості позаклітинних активаторів сигнального шляху PI3K/Akt/mTOR.
Вдосконалено спосіб діагностики T3cDM та розширені наукові дані про показання до скринінгу панкреатичного раку, зокрема за ЦД2. Підтверджено наукові дані про онкопротекторні властивості метформіну.
Вперше створено математичні моделі для розрахунку прогнозованого ризику ЗН найбільш поширених локалізацій, використовуючи метод логістичної регресії. Вперше створено математичну модель для оцінки активації процесів онкогенезу, використовуючи метод дискримінантного аналізу.
Практичне значення отриманих результатів. Доведена доцільність підвищення обізнаності пацієнтів про існування схильності до онкологічних захворювань за ЦД2 та про важливість корекції чинників, які збільшують ризик раку за ЦД: ожиріння, гіперглікемії, гіперінсулінемії з метою профілактики ЗН.
Доведено доцільність клінічно-лабораторної верифікації типу ЦД на момент його первинного виявлення в осіб віком понад 50 років, без ожиріння та гіперінсулінемії для виключення вторинного діабету T3cDM. Обґрунтовано необхідність лабораторного підтвердження конкретних механізмів розвитку або декомпенсації діабету і нових підходів до вибору ЦЗП, особливо в пацієнтів з ожирінням. Визначено доцільність додаткового обстеження пацієнтів з ЦД2 та ожирінням за потреби інтенсифікації ЦЗТ шляхом інсулінотерапії для запобігання ятрогенній гіперінсулінемії. Обгрунтовано та рекомендовано призначення метформіну для профілактики ЗН у хворих на ЦД2.
Розроблено та впроваджено в практику новий спосіб оцінки індивідуального прогнозованого ризику найбільш поширених локалізацій раку. Розроблено індивідуальні підходи до обстеження та лікування хворих на ЦД2 залежно від наявності інсулінорезистентності та ожиріння, а також залежно від ступеню прогнозованого ризику ЗН.
Ключові слова: цукровий діабет, епідеміологія злоякісних новоутворень, цукрознижувальна терапія, прогнозований онкологічний ризик, інсулін, IGF-1, сигнальний шлях PI3K/Akt/mTOR, метформін.
ANNOTATION
The work is devoted to the study of the epidemiology of oncological diseases in patients with diabetes mellitus and of the influence of dysmetabolic disorders in diabetes mellitus on intracellular signaling systems involved in the regulation of oncogenesis.
Rationale for choosing a research topic. In recent decades, the incidence of diabetes mellitus (DM) has remained a priority issue in many countries. According to the International Diabetes Federation there were 463 million patients with diabetes worldwide as of 2019. Given the prevalence, experts from the World Health Organization (WHO) predict that by 2040 the number of patients with DM will increase to 625 million. In Ukraine, according to official data, about 1,311,335 patients with diabetes have been registered.
Equally serious and pressing problem of clinical medicine is the growing prevalence of oncological diseases (OD).
According to the latest research, patients with DM have an increased risk of malignant neoplasms (MN) of different localizations; an increase in mortality from cancer among diabetic patients has been proven. Considering the increased cancer risk in patients with diabetes and a high growth of morbidity rate of the latter, it is logical to expect a progressive increase in cancer incidence in the future.
It is proved that the chronic influence of extracellular dysmetabolic factors leads to changes in the functioning of intracellular signaling pathways, particularly of PI3K/Akt/mTOR, hyperactivation of which leads to mTORС1 – dependent stimulation of p70S6K kinase, which causes disruption in synthesis and in the functioning of proteins, including those associated with the control of cell proliferation, apoptosis, and survival. Hyperactivation of PI3K/Akt/mTOR has been proven to occur in many types of cancer.
The chronic course of DM and the need for daily antidiabetic therapy (ADT) determine the relevance of the study of the mechanisms of DM and cancer association connected with the effects of antidiabetic drugs (ADD) of different groups.
Given the numerous factors of insulin signaling activation (involved in oncogenesis), the study of PI3K/Akt/mTOR activity in patients with DM is important for determining the role of dysmetabolic disorders in oncogenesis to ensure timely correction of identified disorders for cancer prevention. The study of the activity of the components of PI3K/Akt/mTOR will allow to evaluate their significance as potential biochemical markers of oncogenesis on the background of DM.
The aim of the study: to improve the effectiveness of diagnosis and prevention of malignant neoplasms in patients with diabetes based on the study of leading risk factors, mechanisms of development and features of the course of cancer in patients with diabetes mellitus in order to define the main clinical and diagnostic criteria for the formation of oncological pathology in this category of patients.
The first phase of the research was an epidemiological analysis of cancer cases diagnosed for the first time in patients with DM in Ivano-Frankivsk region between 2012 and 2016. The study of data for the specified 5-year period is justified by the planned analysis of five-year survival of patients.
According to the data obtained, 551 cases of cancer were detected in patients with DM. Most of the patients were patients with type 2 diabetes (T2D) – 533 people (96.7%), 18 people had type 1 diabetes (T1D – 3.3%). The most common type of cancer diagnosed in patients with T1D was Hodgkin’s lymphoma (16.67%), whereas in patients with T2D prevailed breast cancer – 126 cases (23.64%), colorectal cancer – 72 cases (13.51 %), uterine cancer – 65 cases (12.20%), and pancreatic cancer – 529 cases (9.76%).
Taking into account the insufficient for analysis number of patients with T1D with cancer, statistical analysis of the data obtained in the epidemiological study was conducted in the group of patients with T2D.
According to the results of statistical analysis, an increased risk of breast (1.3 times higher), uterine (1.4 times higher) and pancreatic (1.6 times higher) cancer was revealed in women with T2D, men had 1.9 times higher risk of pancreatic cancer.
There was a significant prevalence of obesity among patients with OD, which were detected on the background of T2D (52.35% of patients) in particular in patients with cancer of the reproductive system and colorectal cancer. According to the results of statistical analysis, women with T2D have an increased risk of breast cancer associated with obesity (2.1 times higher); men with T2D have 2.9 higher risk of prostate and colorectal cancer.
MN of the most common localizations were mostly diagnosed in patients with T2D of moderate severity (77.48%), in the stage of decompensation (70.36%), aged 60-70 years, with duration of DM over 5 years. Patients with pancreatic cancer had the shortest duration of DM before the detection of cancer.
Combination therapy of antidiabetic medications with non-pancreatic hypoglycemic effects (metformin, glitazones, glyflosins) with stimulants of synthesis and secretion of insulin (sulfonylurea derivatives (SUD) and glyptins) was the most common treatment for patients with T2D before detection of OD (37.71 %). Insulin monotherapy (25.00%) and SUD monotherapy (26.92%) predominated in the treatment of patients with pancreatic cancer.
It was found that before the detection of cancer in 397 patients with T2D (74.48%), they were treated with SUD or insulin either as a monotherapy or a combination therapy. These drugs were more often used in patients with diabetes lasting more than 5 years and in those without obesity. At the same time, this therapy was used by 47.53% of patients with DM with the duration of the illness up to 5 years (the most of them were patients with pancreatic cancer) and by 68.82% of obese patients.
An increased risk of cancer in patients with T2D associated with insulin therapy was found using the statistical analysis (2.4 times higher).
According to the results of the epidemiological study analysis, differences in the clinical characteristics and course of diabetes in patients with pancreatic cancer, which was diagnosed on the background of T2D were revealed. Absence of obesity, short
duration of DM, rapid need for secretagogues and insulin therapy indicate the advantage of insulin deficiency over insulin resistance (IR). These data allow us to suggest a presence of secondary cancer induced T3cDM, which was classified as T2D in a significant number of patients with pancreatic cancer.
Based on the results of the epidemiological study, using logistic regression and logistic transformation equations calculation models for the prediction of risk of malignant tumors (index Y), which are most often diagnosed in patients with diabetes (mammary gland, uterine body, pancreas, and colorectal cancer) were created. The medium and high degree of predicted risk of malignant tumors, confirmed by the index Y = 0.4 - 1, should be considered an indication for additional examination and monitoring of patients with DM for mentioned oncological diseases, and is the basis for correction of indicators that affect this risk (BMI, HbA1c level, types of ADT).
The survival rates of patients with DM were assessed. It has been found that T2D increases the risk of death within 1 year for patients with breast, uterine and skin (non-melanoma forms) cancer. In cases of skin cancer, mortality rates may be predetermined by the age of patients (average age of patients is 71.75 ± 3.86 years). Comparative analysis using the Cox-Mantel test and Kaplan-Mayer cumulative survival curves shows a direct dependence of the survival of patients with cancer, which were diagnosed on the background of T2D, on the stage of cancer. In addition, according to the data obtained, women with stage I uterine cancer and in patients with stage III pancreatic cancer (regardless of gender), who were prescribed the drugs that do not affect the level of insulin in the blood had significantly longer life expectancy. Significantly longer survival of patients with HbA1c levels lower than 8.0% was found in patients with stage II uterine cancer, whereas for patients with stage III pancreatic cancer levels of HbA1c had to be higher than 8.0%. Patients with stage II colorectal cancer with a duration of diabetes <5 years have been proved to have a longer survival than patients with the duration of diabetes of 5-10 years.
In addition to epidemiological analysis, one of the tasks of scientific work was to study the activity of insulin signaling PI3K/Akt/mTOR. The corresponding indicators of patients of three groups were compared with the values of the control group (I): group II – patients with T2D without cancer, group III – patients with cancer without diabetes, group IV – patients with T2D with newly diagnosed cancer. Given the highest frequency of cases of breast, uterine, pancreatic, and colorectal cancer, detected at the stage of the epidemiological study, patients with these localizations of tumors were included in the laboratory studies.
Patients with T2D of group II (60.72% of whom were obese) showed increased content of insulin and (IGF-1) compared with the control group as well as a direct dependence of blood insulin level on BMI. It was found that the intensification of ADT in patients with T2D was accompanied by a parallel increase in BMI and insulin levels in the blood.
In patients of groups III and IV, who had malignant tumors of breast, uterus and colon, obesity, elevated blood insulin levels and HOMA-IR indices, compared to the control group, were revealed. Regardless of cancer localization in patients of groups III and IV, the increased levels of IGF-1 compared with those in the control group were detected. Significantly higher fasting blood glucose levels were found in patients of group IV compared with patients of group II.
The activity of the signaling cascade PI3K/Akt/mTOR was evaluated by determining the content of phosphorylated protein kinases Akt (Ser473), p70S6K (Thr389) and PRAS40 (pT246) – natural mTORC1 inhibitor – in peripheral blood mononuclear cells (PBMC). The degree of phosphorylation of Akt (Ser473) indicates activation of the mTORC2, whereas p70S6K (Thr389) and PRAS40 (pT246) – of the mTORC1.
Compared to the control group, significantly higher content of phospho-Akt was revealed only in cancer patients of group III without DM, with obesity and, compared to the control group, elevated insulin content. In patients of group II, the content of phospho-Akt in PBMC did not differ from the values in the control group, which proves the absence of mTORC2-mediated hyperactivation of Akt (Ser473) in T2D.
Elevated levels of phospho-PRAS40 and phospho-p70S6K in obese patients of groups II and III compared with the control group, prove hyperactivation of the cascade PI3K/Akt/mTOR both in cancer and T2D.
A significant decrease in the content of рhospho-Akt, phospho-PRAS40 and phospho-p70S6K in PBMC of patients of group IV, compared with the control group and other groups, indicates the inhibition of insulin signaling activation in the combination of both diseases and requires further study.
Using the results obtained in the study, we created a model for assessing the activation of oncogenesis applying the method of discriminant analysis. This model can be used to detect excessive activation of insulin signaling in patients with T2D in the future.
The study confirmed the ability of metformin to affect the phosphorylation of PRAS40 and inhibit mTORC1-mediated activation of p70S6K based on reduced phospho-PRAS40 and phospho-p70S6k in patients with DM group II and IV on metformin monotherapy.
The direct correlation of phospho-Akt, phospho-PRAS40 and phospho-p70S6k with insulin, IGF-1, BMI in both healthy individuals and patients with diabetes, cancer and combination of both diseases indicates the role of obesity and growth factors in the activation of mTORC1 and mTORC2. A direct correlation of phospho-PRAS40 and phospho-p70S6k with HbA1c in patients of groups II and IV with DM was found
The scientific novelty. Study confirmed scientific data on the influence of T2D on the formation of oncological pathology have been confirmed, scientific data on the influence of obesity and insulin therapy on the development of MN in patients with DM have been supplemented. The influence of T2D on the survival of patients with MN and its dependence not only on the stage of MN, but also on hypoglycemic therapy, HbA1c level and duration of diabetes (at certain stages and localizations of MN) was proved.
Hyperactivation of the PI3K/Akt/mTORC1 signaling pathway involved in the regulation of metabolism and oncogenesis in patients with DM has been determined. The absence of activation of the PI3K/Akt/mTORC1 pathway in patients with MN, which were diagnosed on the background of T2D has been proven. The hypothesis of reciprocal phosphorylation of Akt on serine (Ser473) and threonine (Thr308) residues in patients with T2D was proved and scientifically substantiated. The direct effect of hyperglycemia on the activation of mTORC1 in T2D has been determined. Scientific data on the effect of insulin and IGF-1 as extracellular activators of the PI3K/Akt/mTOR signaling pathway have been supplemented.
The method of diagnosis of T3cDM has been improved and scientific data on indications for screening for pancreatic cancer, in particular by T2D, have been expanded. Scientific data on the oncoprotective properties of metformin have been confirmed.
For the first time were created mathematical models to calculate the predicted risk of MN of the most common localizations, using logistic regression method. For the first time a mathematical model for estimation of the activation of oncogenesis processes using the method of discriminant analysis was created.
The practical significance of the results obtained. The expediency of raising patients' awareness of the predisposition to cancer in T2D and of the importance of correcting the factors that increase the risk of cancer in diabetes: obesity, hyperglycemia, hyperinsulinemia to prevent MN was proved.
The expediency of clinical and laboratory verification of the type of diabetes at the time of its initial detection in persons over 50 years of age, without obesity and hyperinsulinemia to exclude secondary diabetes T3cDM has been proven. The need for laboratory confirmation of specific mechanisms of development or decompensation of diabetes and for new approaches to the choice of ADT, especially in obese patients, is substantiated. The expediency of additional examination of patients with T2D and obesity to prevent iatrogenic hyperinsulinemia in case of the need for intensification of ADT by insulin therapy was determined. The prescription of metformin for the prevention of MN in patients with DM is substantiated and recommended.
A new method of assessing the individual predicted risk of cancer of the most common localizations has been developed and put into practice. Individual approaches to examination and treatment of patients with T2D depending on the presence of IR and obesity, as well as depending on the degree of predicted risk of MN have been developed.
Key words: diabetes mellitus, epidemiology of cancer, antidiabetic therapy, predicted cancer risk, insulin, IGF-1, signaling pathwayPI3K/Akt/mTOR, metformin.
Introduction
High mortality and limited therapeutic efficacy of clinical treatment make breast cancer a stubborn disease in women. Hypovascular issue is the main challenge needed to be overcome in breast cancer treatment.
Method
For this purpose, hyperthermia-sensitive liposomes containing indocyanine green (ICG) and brucea javanica oil (BJO) (LP(BJO/ICG)) were constructed for near-infrared (NIR) laser induced photothermal-/chemo-antitumor therapy. ICG, an FDA approved photothermal agent, was employed in this study to perform photothermal therapy (PTT) effect as well as relieving hypovascular conditions in breast cancer tissue.
Result
BJO triggered release from the hyperthermia-sensitive LP(BJO/ICG) due to disassembly of liposomes under the PTT effect caused by ICG under NIR laser irradiation. It was found that mice in LP(BJO/ICG) group showed the slowest tumor growth under NIR laser irradiation, illustrating the strongest antitumor effect among all groups.
Conclusion
This responsive-release drug delivery platform can be a promising candidate for the treatment of breast cancer.
Human Epidermal growth factor Receptor 2 (HER2) overexpression or HER2 gene amplification defines a subset of breast cancers (BCs) characterized by higher biological and clinical aggressiveness. The introduction of anti-HER2 drugs has remarkably improved clinical outcomes in patients with both early-stage and advanced HER2+ BC. However, some HER2+ BC patients still have unfavorable outcomes despite optimal anti-HER2 therapies. Retrospective clinical analyses indicate that overweight and obesity can negatively affect the prognosis of patients with early-stage HER2+ BC. This association could be mediated by the interplay between overweight/obesity, alterations in systemic glucose and lipid metabolism, increased systemic inflammatory status, and the stimulation of proliferation pathways resulting in the stimulation of HER2+ BC cell growth and resistance to anti-HER2 therapies. By contrast, in the context of advanced disease, a few high-quality studies, which were included in a meta-analysis, showed an association between high body mass index (BMI) and better clinical outcomes, possibly reflecting the negative prognostic role of malnourishment and cachexia in this setting. Of note, overweight and obesity are modifiable factors. Therefore, uncovering their prognostic role in patients with early-stage or advanced HER2+ BC could have clinical relevance in terms of defining subsets of patients requiring more or less aggressive pharmacological treatments, as well as of designing clinical trials to investigate the therapeutic impact of lifestyle interventions aimed at modifying body weight and composition. In this review, we summarize and discuss the available preclinical evidence supporting the role of adiposity in modulating HER2+ BC aggressiveness and resistance to therapies, as well as clinical studies reporting on the prognostic role of BMI in patients with early-stage or advanced HER2+ BC.
Breast cancer is considered the most common malignancy, with the profound ability to perform a wide range of metabolic reprogramming. Within the breast cancer microenvironment, highly available cancer-associated adipocytes interact with cancer cells by releasing various adipocytokines and metabolites. Obesity is also an important factor in this manner, where the accumulation of adipose tissue next to tumor tissue is linked to the increased incidence, progression, and metastasis of breast cancer. The metabolic changes caused by the crosstalk between breast cancer cells and dysfunctional adipose tissue include glucose, lipid, and amino acid metabolism. Thus, preventing this interaction between breast cancer cells and dysfunctional adipose tissue might develop a promising therapeutic strategy against breast cancer. This review focused on the metabolic changes responsible for inducing the crosstalk between breast cancer cells and adipocytes. We also reviewed the recent updates in therapeutics designed to disrupt this interaction.
Estrogen, a steroidal hormone has extensive biological activities and the effect is pleiotropic, affecting multiple systems in the body. Estrogens, the primary female sex hormones function to regulate the reproductive system by binding to specific receptors, the estrogen receptors (ERs). These ERs in turn control the expression of various genes by activating various transcriptional processes or signaling pathways. Given the importance of the role of estrogen in human physiology, they are also found to be involved in the development or control of several diseases which include but not limited to cancer, neurological disorders, obesity, gastrointestinal disorders, osteoporosis, cardiovascular diseases, inflammatory disease, etc. With support from many sophisticated studies, we provide insights on the importance of estrogen in human diseases. We reviewed here the role and the mechanisms of estrogen and its receptors that play a role in the development of severity in several diseases.
Calorie restriction prevents mammary tumor (MT) development in rodents. Usually, chronic calorie restriction (CCR) has been implemented. In contrast, intermittent calorie restriction (ICR) has been less frequently used. Recent studies indicate that when a direct comparison of the same degree of CCR vs. ICR was made using MMTV-TGF-α mice which develop MTs in the second year of life, ICR provided greater protection than CCR in delaying MT detection and reducing tumor incidence. Adiponectin and leptin are two adipocytokines secreted from adipose tissue which have opposite effects on many physiological functions, including proliferation of human breast cancer cells. A recent study indicated that a low adiponectin/leptin ratio was associated with breast cancer. We evaluated the relationship of adiponectin and leptin to MT development in MMTV-TGF-α calorie-restricted mice at several ages. Mice were enrolled at 10 weeks of age and subjected to 25% caloric reduction implemented either chronically or intermittently. Mice were euthanized at designated time points up to 74 weeks of age. Serum samples were collected to measure adiponectin and leptin concentrations. Both CCR and ICR mice had significantly reduced MT incidence. For the groups studied, serum leptin increased over time, while there was a trend for an increase in serum adiponectin levels in ad libitum and ICR mice, with no change in CCR mice between 10 and 74 weeks of age. The adiponectin/leptin ratio was significantly reduced as mice aged, but this ratio in ICR mice was significantly higher than that for ad libitum and CCR mice. No correlation was noted between serum adiponectin and leptin. These findings demonstrate that intermittent calorie restriction delays the early development of MTs. This delay was associated with reduced serum leptin levels following the restriction phases of the protocol. Additionally, serum leptin levels correlated with body weight and body fat in the groups studied.
Vascular endothelial growth factor (VEGF) is a regulator of vasculogenesis and angiogenesis. To investigate the role of nitric oxide (NO) in VEGF-induced proliferation and in vitro angiogenesis, human umbilical vein endothelial cells (HUVEC) were used. VEGF stimulated the growth of HU-VEC in an NO-dependent manner. In addition, VEGF pro-moted the NO-dependent formation of network-like struc-tures in HUVEC cultured in three dimensional (3D) collagen gels. Exposure of cells to VEGF led to a concentration-dependent increase in cGMP levels, an indicator of NO pro-duction, that was inhibited by nitro-L -arginine methyl ester. VEGF-stimulated NO production required activation of ty-rosine kinases and increases in intracellular calcium, since tyrosine kinase inhibitors and calcium chelators attenuated VEGF-induced NO release. Moreover, two chemically dis-tinct phosphoinositide 3 kinase (PI-3K) inhibitors attenu-ated NO release after VEGF stimulation. In addition, HU-VEC incubated with VEGF for 24 h showed an increase in the amount of endothelial NO synthase (eNOS) protein and the release of NO. In summary, both short-and long-term exposure of human EC to VEGF stimulates the release of biologically active NO. While long-term exposure increases eNOS protein levels, short-term stimulation with VEGF pro-motes NO release through mechanisms involving tyrosine and PI-3K kinases, suggesting that NO mediates aspects of VEGF signaling required for EC proliferation and organi-zation in vitro. (J. Clin. Invest. 1997. 100:3131–3139.) Key words: vascular endothelial growth factor • endothelium • nitric oxide • angiogenesis • cGMP
It is well established that cancer is a progressive disease, occurring in a series of well-defined steps, typically arising as a consequence of activating mutations (oncogenes) or deactivating mutations (tumor suppressor genes) in proliferating cells. From studies exploiting cultured tumor cells,
In vitro, leptin secretion is regulated at the level of mRNA translation by the rapamycin-sensitive mammalian target of rapamycin (mTOR) and its agonist leucine (Leu). Studies were conducted on meal-trained rats to evaluate the potential physiological relevance of these in vitro findings and the role of Leu in affecting rises in plasma leptin observed after a meal. In the first study, we correlated changes in plasma insulin and Leu to mTOR-signaling pathway activation and plasma leptin at different times during meal feeding. Rapid rises in plasma insulin and Leu, along with mTOR signaling (phosphorylation of eIF4G, S6K1, rpS6, and 4E-BP1) in adipose tissue were observed during the 3-h meal and declined thereafter. Plasma leptin rose more slowly, peaking at 3 h, and was inhibited by rapamycin (0.75 mg/kg) pretreatment. In another experiment, oral Leu or norleucine was provided instead of a meal. Leu and norleucine stimulated a rise in plasma leptin; however, the magnitude was less than the response to a complete meal. In a third study, rats were provided a meal that lacked Leu, branched-chain amino acids, or all amino acids. Stimulation of leptin secretion was reduced approximately 40% in animals provided the Leu-deficient meal. Further reductions were not observed by removing the other amino acids. Thus Leu appears to regulate most of the effects of dietary amino acids on the postprandial rise in plasma leptin but is responsible only for part of the leptin response to meal feeding.
Obesity increases both the risk and mortality associated with many types of cancer including that of the breast. In mice, obesity increases both incidence of spontaneous tumors and burden of transplanted tumors. Our findings identify leptin, an adipose secreted cytokine, in promoting increased mammary tumor burden in obese mice and provide a link between this adipokine and cancer. Using a transplantable tumor that develops spontaneously in the murine mammary tumor virus-Wnt-1 transgenic mice, we show that tumors transplanted into obese leptin receptor (LepRb)-deficient (db/db) mice grow to eight times the volume of tumors transplanted into lean wild-type (WT) mice. However, tumor outgrowth and overall tumor burden is reduced in obese, leptin-deficient (ob/ob) mice. The residual tumors in ob/ob mice contain fewer undifferentiated tumor cells (keratin 6 immunopositive) compared with WT or db/db mice. Furthermore, tumors in ob/ob mice contain fewer cells expressing phosphorylated Akt, a growth promoting kinase activated by the LepRb, compared with WT and db/db mice. In vivo limiting dilution analysis of residual tumors from ob/ob mice indicated reduced tumor initiating activity suggesting fewer cancer stem cells (CSCs). The tumor cell populations reduced by leptin deficiency were identified by fluorescence-activated cell sorting and found to express LepRb. Finally, LepRb expressing tumor cells exhibit stem cell characteristics based on the ability to form tumorspheres in vitro and leptin promotes their survival. These studies provide critical new insight on the role of leptin in tumor growth and implicate LepRb as a CSC target.
To explore whether treatment with pioglitazone was associated with risk of incident cancer at the 10 most common sites (prostate, female breast, lung/bronchus, endometrial, colon, non-Hodgkin lymphoma [NHL], pancreas, kidney/renal pelvis, rectal, and melanoma).
A cohort study of 252,467 patients aged ≥40 years from the Kaiser Permanente Northern California Diabetes Registry was conducted. All prescriptions for diabetes medications were identified by pharmacy records. Cox proportional hazards models were used to examine the association between risk of incident cancer and ever use, duration, dose, and time since initiation of pioglitazone (modeled as time-dependent variables).
In models adjusted for age, sex, year of cohort entry, race/ethnicity, income, smoking, glycemic control, diabetes duration, creatinine levels, congestive heart failure, and use of other diabetes medications, the hazard ratio (HR) for each cancer associated with ever use of pioglitazone ranged from 0.7 to 1.3, with all 95% CIs including 1.0. There was a suggestion of an increased risk of melanoma (HR 1.3 [95% CI 0.9-2.0]) and NHL (1.3 [1.0-1.8]) and a decreased risk of kidney/renal pelvis cancers (0.7 [0.4-1.1]) associated with ever use of pioglitazone. These associations were unaltered with increasing dose, duration, or time since first use.
We found no clear evidence of an association between use of pioglitazone and risk of the incident cancers examined. Because the maximum duration of follow-up was fewer than 6 years after the initiation of pioglitazone, longer-term studies are needed.
There is increasing evidence that obesity may have pathophysiological effects that extend beyond its well-known co-morbidities; in particular its role in cancer has received considerable epidemiological support. As adipose tissue becomes strongly established as an endocrine organ, two of its most abundant and most investigated adipokines, leptin and adiponectin, are also taken beyond their traditional roles in energy homeostasis, and are implicated as mediators of the effects of obesity on cancer development. This review examines these adipokines in relation to the prostate, breast, colorectal, thyroid, renal, pancreatic, endometrial and oesophageal cancers, and how they may orchestrate the influence of obesity on the development of these malignancies.
Leptin and interleukin-1 (IL-1) upregulate vascular endothelial growth factor (VEGF), promote angiogenesis and are related to worse prognosis of breast cancer. However, it is unknown whether leptin regulates IL-1, and whether these effects are related to leptin-induction of VEGF/VEGFR2 in breast cancer.
Several genetic and pharmacological approaches were used to determine the mechanisms involved in leptin regulation of IL-1 system (IL-1α, IL-1β, IL-1Ra and IL-1R tI) and the impact of IL-1 signalling on leptin-induced VEGF/VEGFR2 expression in mouse mammary cancer 4T1 cells (a model that resembles invasive and highly metastatic human breast cancer).
Leptin increased protein and mRNA levels of all components of the IL-1 system. IL-1 upregulation involved leptin activation of JAK2/STAT3, MAPK/ERK 1/2, PI-3K/AKT1, PKC, p38 and JNK. Leptin-induced phosphorylation of mTOR/4E-BP1 increased IL-1β and IL-1Ra expression, but downregulated IL-1α. Leptin upregulation of IL-1α promoter was linked to SP1 and NF-κB transcription factors. In addition, leptin receptor (Ob-Rb) was upregulated by leptin. Interestingly, leptin upregulation of VEGF/VEGFR2 was partially mediated by IL-1/IL-1R tI signalling.
We show for the first time that leptin induces several signalling pathways to upregulate the translational and transcriptional expression of IL-1 system in breast cancer cells. Moreover, leptin upregulation of VEGF/VEGFR2 was impaired by IL-1 signalling blockade. These data suggest that leptin pro-angiogenic signature in breast cancer is linked to, or regulated, in part by IL-1 signalling.
Leptin is a pleiotropic hormone acting both centrally and peripherally. It participates in a variety of biological processes, including energy metabolism, reproduction, and modulation of the immune response. So far, structural elements affecting leptin binding to its receptor remain unknown. We employed random mutagenesis of leptin, followed by selection of high affinity mutants by yeast surface display and discovered that replacing residue Asp-23 with a non-negatively charged amino acid leads to dramatically enhanced affinity of leptin for its soluble receptor. Rational mutagenesis of Asp-23 revealed the D23L substitution to be most effective. Coupling the Asp-23 mutation with alanine mutagenesis of three amino acids (L39A/D40A/F41A) previously reported to convert leptin into antagonist resulted in potent antagonistic activity. These novel superactive mouse and human leptin antagonists (D23L/L39A/D40A/F41A), termed SMLA and SHLA, respectively, exhibited over 60-fold increased binding to leptin receptor and 14-fold higher antagonistic activity in vitro relative to the L39A/D40A/F41A mutants. To prolong and enhance in vivo activity, SMLA and SHLA were monopegylated mainly at the N terminus. Administration of the pegylated SMLA to mice resulted in a remarkably rapid, significant, and reversible 27-fold more potent increase in body weight (as compared with pegylated mouse leptin antagonist), because of increased food consumption. Thus, recognition and mutagenesis of Asp-23 enabled construction of novel compounds that induce potent and reversible central and peripheral leptin deficiency. In addition to enhancing our understanding of leptin interactions with its receptor, these antagonists enable in vivo study of the role of leptin in metabolic and immune processes and hold potential for future therapeutic use in disease pathologies involving leptin.
Obesity is associated with an increased risk of breast cancer in postmenopausal women. Accumulating evidence suggests that adipose tissue, which is an endocrine organ producing a large range of factors, may interfere with breast cancer development. Leptin and adiponectin are two major adipocyte-secreted hormones. The pro-carcinogenic effect of leptin and conversely, the anti-carcinogenic effect of adiponectin result from two main mechanisms: a modulation in the signalling pathways involved in proliferation process and a subtle regulation of the apoptotic response. This review provides insight into recent findings on the molecular mechanisms of leptin and adiponectin in mammary tumours, and discusses the potential interplay between these two adipokines in breast cancer.
The mammary gland is composed of a diverse array of cell types that form intricate interaction networks essential for its normal development and physiologic function. Abnormalities in these interactions play an important role throughout different stages of tumorigenesis. Branching ducts and alveoli are lined by an inner layer of secretory luminal epithelial cells that produce milk during lactation and are surrounded by contractile myoepithelial cells and basement membrane. The surrounding stroma comprised of extracellular matrix and various cell types including fibroblasts, endothelial cells, and infiltrating leukocytes not only provides a scaffold for the organ, but also regulates mammary epithelial cell function via paracrine, physical, and hormonal interactions. With rare exceptions breast tumors initiate in the epithelial compartment and in their initial phases are confined to the ducts but this barrier brakes down with invasive progression because of a combination of signals emitted by tumor epithelial and various stromal cells. In this article, we overview the importance of cellular interactions and microenvironmental signals in mammary gland development and cancer.
Obesity is associated with an increased risk of breast cancer. A number of adipocytokines are increased in obesity causing low-level chronic inflammation associated with an increased risk of tumors. The adipocytokine leptin shows profound anti-obesity and pro-inflammatory activities. We have hypothesized that in common obesity, high circulating leptin levels might contribute to an increased risk of breast cancer by affecting mammary cell proliferation and survival. Leptin exerts its activity not only through leptin receptor (LepR), but also through crosstalk with other signaling systems implicated in tumorigenesis. In this study, we focused our attention on the relationship between the leptin/LepR axis and the estrogen receptor-alpha (ERalpha). To this aim, we utilized two human breast cancer cell lines, one ERalpha-positive cell line (MCF 7) and the other ERalpha-negative cell line (MDA-MB 231). We observed that the two cell lines had a different sensitivity to recombinant leptin (rleptin): on MCF 7 cells, rleptin induced a strong phosphorylation of the signal transducer and activator of transcription (STAT) 3 and of the extracellular related kinase 1/2 pathways with an increased cell viability and proliferation associated with an increased expression of ERalpha receptor. This response was not present in the MDA-MB 231 cells. The effects induced by leptin were lost when LepR was neutralized using either a monoclonal inhibitory antibody to LepR or LepR gene-silencing siRNA. These data suggest that there is a bidirectional communication between LepR and ERalpha, and that neutralization and/or inactivation of LepR inhibits proliferation and viability of human breast cancer cell lines. This evidence was confirmed by ex vivo studies, in which we analyzed 33 patients with breast cancer at different stages of disease, and observed that there was a statistically significant correlation between the expression of LepR and ERalpha. In conclusion, this study suggests a crosstalk between LepR and ERalpha, and could envisage novel therapeutic settings aimed at targeting the LepR in breast cancers.
What has been will be again, what has been done will be done again; there is nothing new under the sun
(Ecclesiastes 1:9)
Stephen Paget was the conceptual father of the role played by the Tumor Microenvironment (TME) in tumor progression. The focus of this essay is the developmental phase of the post Paget TME research. Attempts will be made to highlight some of the pioneering work of scientists from the late sixties through the eighties of last century who laid the foundations for the contemporary scientific achievements of TME research but whose ground breaking studies are rarely cited. This review should serve as a small tribute to their great work.
Ras, STAT3, and Transformation
The STAT (signal transducer and activator of transcription) proteins are activated in response to receptor stimulation and act in the nucleus to regulate gene expression. Gough et al. (p. 1713 ) found that STAT3 functioned in transformation of cells by the oncogene Ras. However, this activity was maintained in mutants of STAT that fail to activate transcription. Instead, the active STAT3 appeared to be associated with mitochondria. Furthermore, modified STAT3 targeted to the mitochondria promoted transformation by Ras, and mitochondrial function was disrupted in Ras-transformed cells lacking STAT3. Such transformation-specific effects of STAT3 could be a useful target in developing anticancer therapies.
We have shown previously that treatment with pegylated leptin peptide receptor antagonist 2 (PEG-LPrA2) reduced the expression of vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor type 2 (VEGFR2) and growth of 4T1-breast cancer (BC) in syngeneic mice. In this investigation, PEG-LPrA2 was used to evaluate whether the inhibition of leptin signaling has differential impact on the expression of pro-angiogenic and pro-proliferative molecules and growth of human estrogen receptor-positive (ER+) and estrogen receptor-negative (ER-) BC xenografts hosted by immunodeficient mice.
To test the contribution of leptin signaling to BC growth and expression of leptin-targeted molecules, PEG-LPrA2 treatment was applied to severe immunodeficient mice hosting established ER+ (MCF-7 cells; ovariectomized/supplemented with estradiol) and ER- (MDA-MB231 cells) BC xenografts. To further assess leptin and PEG-LPrA2 effects on ER+ and ER- BC, the expression of VEGF and VEGFR2 (protein and mRNA) was investigated in cell cultures.
PEG-LPrA2 more effectively reduced the growth of ER+ (>40-fold) than ER- BC (twofold) and expression of pro-angiogenic (VEGF/VEGFR2, leptin/leptin receptor OB-R, and IL-1 receptor type I) and pro-proliferative molecules (proliferating cell nuclear antigen and cyclin D1) in ER+ than in ER- BC. Mouse tumor stroma in ER+ BC expressed high levels of VEGF and leptin that was induced by leptin signaling. Leptin upregulated the transcriptional expression of VEGF/VEGFR2 in MCF-7 and MDA-MB231 cells.
These results suggest that leptin signaling plays an important role in the growth of both ER+ and ER- BC that is associated with the leptin regulation of pro-angiogenic and pro-proliferative molecules. These data provide support for the potential use of leptin-signaling inhibition as a novel treatment for ER+ and ER- BC.
Epidemiologic evidence supports a correlation between obesity and breast cancer in women. AMP-activated protein kinase plays an important role in energy homeostasis and inhibits the actions of cyclic AMP-responsive element binding protein-regulated transcription coactivator 2 (CRTC2). In postmenopausal women, the cyclic AMP-responsive element binding protein-dependent regulation of aromatase is a determinant of breast tumor formation through local production of estrogens. The present work aimed to examine the effect of adipokines on aromatase expression and identify additional mechanisms by which prostaglandin E(2) causes increased aromatase expression in human breast adipose stromal cells. Treatment of human adipose stromal cells with forskolin and phorbol 12-myristate 13-acetate (PMA), to mimic prostaglandin E(2), resulted in nuclear translocation of CRTC2. Aromatase promoter II (PII) activity assays showed that CRTC2 in addition to forskolin/PMA treatment significantly increased PII-induced activity. CRTC2 binding to PII was examined by chromatin immunoprecipitation, and forskolin/PMA treatment was associated with increased binding to PII. Treatment of human adipose stromal cells with leptin significantly up-regulated aromatase expression associated with nuclear translocation of CRTC2 and increased binding of CRTC2 to PII. Adiponectin treatment significantly decreased forskolin/PMA-stimulated aromatase expression, consistent with the decreased nuclear translocation of CRTC2 and the decreased binding of CRTC2 to PII. The expression and activity of the AMP-activated protein kinase LKB1 was examined and found to be significantly decreased following either forskolin/PMA or leptin treatment. In contrast, adiponectin significantly increased LKB1 expression and activity. In conclusion, the regulation of aromatase by CRTC2, in response to the altered hormonal milieu associated with menopause and obesity, provides a critical link between obesity and breast cancer.
Leptin, a pleiotropic adipokine, is a central regulator of appetite and weight and a key immunomodulatory protein. Although inborn leptin deficiency causes weight gain, it is unclear whether induced leptin deficiency in adult wild-type animals would be orexigenic. Previous work with a potent competitive leptin antagonist did not induce a true metabolic state of leptin deficiency in mice because of a short circulating half-life. In this study, we increased the half-life of the leptin antagonist by pegylation, which resulted in significantly increased bioavailability and retaining of antagonistic activity. Mice administered the pegylated antagonist showed a rapid and dramatic increase in food intake with weight gain. Resulting fat was confined to the mesenteric region with no accumulation in the liver. Serum cholesterol, triglyceride, and hepatic aminotransferases remained unaffected. Weight changes were reversible on cessation of leptin antagonist treatment. The mechanism of severe central leptin deficiency was found to be primarily caused by blockade of transport of circulating leptin across the blood-brain barrier with antagonisms at the arcuate nucleus playing a more minor role. Altogether we introduce a novel compound that induces central and peripheral leptin deficiency. This compound should be useful in exploring the involvement of leptin in metabolic and immune processes and could serve as a therapeutic for the treatment of cachexia.
Cytokines such as interleukin-6 induce tyrosine and serine phosphorylation of Stat3 that results in activation of Stat3-responsive
genes. We provide evidence that Stat3 is present in the mitochondria of cultured cells and primary tissues, including the
liver and heart. In Stat3–/– cells, the activities of complexes I and II of the electron transport chain (ETC) were significantly decreased. We identified
Stat3 mutants that selectively restored the protein's function as a transcription factor or its functions within the ETC.
In mice that do not express Stat3 in the heart, there were also selective defects in the activities of complexes I and II
of the ETC. These data indicate that Stat3 is required for optimal function of the ETC, which may allow it to orchestrate
responses to cellular homeostasis.
Angiogenesis is esential for tumour growth and metastasis. Vascular endothelial growth factor (VEGF) is a potent endothelial cell mitogen and is an important component of the angiogenic stimulus in a range of human neoplasias. In addition to its mitogenic activities, VEGF has also been found to stimulate migration in macrophages via the flt‐1 VEGF receptor. It has previously been shown that increased focal tumour macrophage infiltration is associated with increased angiogenesis and worsened relapse‐free and overall survival in breast cancer. Macrophages are able to stimulate angiogenesis by their production of a range of factors including VEGF, tumour necrosis factor‐α (TNF‐α), and thymidine phosphorylase (TP). Thus, in breast cancer, VEGF could have a dual role in the regulation of angiogenesis, by direct mitogenic stimulation of endothelial cells, and also indirectly by attracting macrophages into avascular tumours. The purpose of this study was to localize VEGF protein in a series of 96 consecutive primary breast carcinomas and to determine its relationship to focal macrophage infiltration (macrophage index). These two variables were also compared with the pathological features of the tumours, as well as oestrogen receptor (ER), epidermal growth factor receptor (EGFR), microvessel density, macrophage index, and survival. An inverse relationship (p=0.0006) was noted between VEGF and EGFR, with high VEGF expression correlating with low EGFR levels. In the EGFR‐negative group of cases (n=56), positive associations were observed between VEGF expression and macrophage index (p=0.005), ER (p=0.05), p53 (p=0.006), tumour grade (p=0.02), and tumour necrosis (p=0.03). Macrophage counts were higher in EGFR‐positive tumours (p=0.0006) and no associations were found between VEGF expression and increased microvessel density. These results show that in breast cancers there are two types of macrophage infiltrates, one associated with the presence of EGFR and low VEGF expression in tumours and the other with high VEGF expression in EGFR‐negative tumours. VEGF expression may be an important factor in the recruitment of tumour‐associated macrophages into breast carcinomas and may thus have an additional, indirect, pathway of angiogenic stimulation in this type of tumour. Copyright © 2000 John Wiley & Sons, Ltd.
Glucose concentration may be an important factor in breast cancer cell proliferation, and the prevalence of breast cancer is high in diabetic patients. Leptin may also be an important factor since plasma levels of leptin correlated with TNM staging for breast cancer patients. The effects of glucose and leptin on breast cancer cell proliferation were evaluated by examining cell doubling time, DNA synthesis, levels of cell cycle related proteins, protein kinase C (PKC) isozyme expression, and peroxisome proliferator-activated receptor (PPAR) subtypes were determined following glucose exposure at normal (5.5 mM) and high (25 mM) concentrations with/without leptin in MCF-7 human breast cancer cells. In MCF-7 cells, leptin and high glucose stimulated cell proliferation as demonstrated by the increases in DNA synthesis and expression of cdk2 and cyclin D1. PKC-alpha, PPARgamma, and PPARalpha protein levels were up-regulated following leptin and high glucose treatment in drug-sensitive MCF-7 cells. However, there was no significant effect of leptin and high glucose on cell proliferation, DNA synthesis, levels of cell cycle proteins, PKC isozymes, or PPAR subtypes in multidrug-resistant human breast cancer NCI/ADR-RES cells. These results suggested that hyperglycemia and hyperleptinemia increase breast cancer cell proliferation through accelerated cell cycle progression with up-regulation of cdk2 and cyclin D1 levels. This suggests the involvement of PKC-alpha, PPARalpha, and PPARgamma.
Background: Obesity is a risk factor for breast cancer in postmenopausal women. As body weight and fat mass increase, circulating leptin
increases. Leptin is an adipocyte-derived cytokine that acts through the long form of its receptor, termed OB-Rb. To investigate
whether leptin is associated with breast cancer, we determined the expression of OB-Rb in human breast epithelial HBL100 cells
and human breast carcinoma-derived T-47D cells, determined whether leptin influenced the proliferation of these cells, and
evaluated the structure of mammary tissue in genetically obese leptin-deficient LepobLepob and leptin receptor-deficient LeprdbLeprdb mice. Methods: Cell numbers and cell colony formation by HBL100 and T-47D cells were determined by anchorage-dependent and anchorage-independent
growth assays. OB-Rb expression was examined by reverse transcription–polymerase chain reaction and immunoblot analyses. Expression
of leptin signaling pathway components was evaluated with immunoblot and electrophoretic mobility shift assays. Mammary gland
development in lean and obese mice was investigated in whole-mount studies. All statistical tests were two-sided. Results: Leptin enhanced anchorage-dependent proliferation by 138% (95% confidence interval [CI] = 108% to 169%) in T-47D cells and
50% (95% CI = 38% to 60%) in HBL100 cells. In both cell lines, OB-Rb was expressed, and leptin increased the expression of
phosphorylated signal transducers and activators of transcription 3 (STAT3), phosphorylated extracellular signal-regulated
kinase (ERK), and transcript activator protein 1 (AP-1). However, leptin increased anchorage-independent cell growth only
in the breast cancer cell line (by 81% [95% CI = 62% to 101%] compared with untreated cells). Obese LepobLepob and LeprdbLeprdb mice had minimal epithelial development in the mature mammary gland compared with their lean counterparts. Conclusions: Leptin appears to be able to control the proliferation of both normal and malignant breast epithelial cells. Consequently,
the leptin pathway should be further studied as a target for interventions to treat or prevent breast cancer.
Glucose concentration may be an important factor in breast cancer cell proliferation, and the prevalence of breast cancer is high in diabetic patients. Leptin may also be an important factor since plasma levels of leptin correlated with TNM staging for breast cancer patients. The effects of glucose and leptin on breast cancer cell proliferation were evaluated by examining cell doubling time, DNA synthesis, levels of cell cycle related proteins, protein kinase C (PKC) isozyme expression, and peroxisome proliferator-activated receptor (PPAR) subtypes were determined following glucose exposure at normal (5.5 mM) and high (25 mM) concentrations with/without leptin in MCF-7 human breast cancer cells. In MCF-7 cells, leptin and high glucose stimulated cell proliferation as demonstrated by the increases in DNA synthesis and expression of cdk2 and cyclin D1. PKC-α, PPARγ, and PPARα protein levels were up-regulated following leptin and high glucose treatment in drug-sensitive MCF-7 cells. However, there was no significant effect of leptin and high glucose on cell proliferation, DNA synthesis, levels of cell cycle proteins, PKC isozymes, or PPAR subtypes in multidrug-resistant human breast cancer NCI/ADR-RES cells. These results suggested that hyperglycemia and hyperleptinemia increase breast cancer cell proliferation through accelerated cell cycle progression with up-regulation of cdk2 and cyclin D1 levels. This suggests the involvement of PKC-α, PPARα, and PPARγ.
Angiogenesis is esential for tumour growth and metastasis. Vascular endothelial growth factor (VEGF) is a potent endothelial cell mitogen and is an important component of the angiogenic stimulus in a range of human neoplasias. In addition to its mitogenic activities, VEGF has also been found to stimulate migration in macrophages via the flt-1 VEGF receptor. It has previously been shown that increased focal tumour macrophage infiltration is associated with increased angiogenesis and worsened relapse-free and overall survival in breast cancer. Macrophages are able to stimulate angiogenesis by their production of a range of factors including VEGF, tumour necrosis factor-α (TNF-α), and thymidine phosphorylase (TP). Thus, in breast cancer, VEGF could have a dual role in the regulation of angiogenesis, by direct mitogenic stimulation of endothelial cells, and also indirectly by attracting macrophages into avascular tumours. The purpose of this study was to localize VEGF protein in a series of 96 consecutive primary breast carcinomas and to determine its relationship to focal macrophage infiltration (macrophage index). These two variables were also compared with the pathological features of the tumours, as well as oestrogen receptor (ER), epidermal growth factor receptor (EGFR), microvessel density, macrophage index, and survival. An inverse relationship (p=0.0006) was noted between VEGF and EGFR, with high VEGF expression correlating with low EGFR levels. In the EGFR-negative group of cases (n=56), positive associations were observed between VEGF expression and macrophage index (p=0.005), ER (p=0.05), p53 (p=0.006), tumour grade (p=0.02), and tumour necrosis (p=0.03). Macrophage counts were higher in EGFR-positive tumours (p=0.0006) and no associations were found between VEGF expression and increased microvessel density. These results show that in breast cancers there are two types of macrophage infiltrates, one associated with the presence of EGFR and low VEGF expression in tumours and the other with high VEGF expression in EGFR-negative tumours. VEGF expression may be an important factor in the recruitment of tumour-associated macrophages into breast carcinomas and may thus have an additional, indirect, pathway of angiogenic stimulation in this type of tumour. Copyright © 2000 John Wiley & Sons, Ltd.
Leptin, a hormone produced by adipose tissue, regulates energy balance in the hypothalamus and is involved in fertility, immune response and carcinogenesis. The existence of disorders related to leptin deficit and leptin overabundance calls for the development of drugs activating or inhibiting the leptin receptor (ObR). We synthesized four proposed receptor-binding leptin fragments (sites I, IIa and IIb, III), their reportedly antagonist analogs, and a peptide chimera composed of the two discontinuous site II arms. To assess the pharmacological utility of leptin fragments, we studied the peptides' ability to stimulate the growth of ObR-positive and ObR-negative cells. The combined site II construct and site III derivatives selectively reversed leptin-induced growth of ObR-positive cells at mid-nanomolar concentrations. However, these peptides appeared to be partial agonists/antagonists as they activated cell growth in the absence of exogenous leptin. A designer site III analog, featuring non-natural amino acids at terminal positions to decrease proteolysis and a blood–brain barrier (BBB) penetration-enhancing carbohydrate moiety, proved to be full agonist to ObR, i.e., stimulated proliferation of different ObR-positive but not ObR-negative cells in the presence or absence of leptin. This glycopeptide bound to isolated ObR on solid-phase assays and activated ERK-1/2 signaling in ObR-positive MCF-7 cells at 100–500 nM concentrations. The glycopeptide was stable in mouse serum, readily crossed endothelial/astrocyte cell layers in a cellular BBB model, and was distributed into the brain of Balb/c mice after intraperitoneal administration. These characteristics suggest a potential pharmaceutical utility of the designer site III glycopeptide in leptin-deficient diseases.
Metastasis is the primary cause of death from many tumors, and novel anti-metastatic therapies are necessary. Recently, we showed that metastatic tumors down-regulate key oxidative phosphorylation (OXPHOS) genes in favor of glycolysis, a further enhancement of the Warburg effect. Therefore, we sought to determine if restriction of glycolysis using 2-deoxy-D-glucose (2DG) would lead to increased utilization of OXPHOS and inhibition of the metastatic phenotype. Noncytotoxic concentrations of 2DG dose-dependently inhibited in vitro migration and invasion in the highly metastatic DLM8-luc-M1 osteosarcoma (OS) cell line, as well as other metastatic human, canine, and murine cancer cells of different histotypes. This was associated with cytoskeletal rearrangement and inhibition of cathepsin L expression. A dose-dependent shift toward OXPHOS was confirmed by demonstrating increased oxygen utilization and decreased lactate production in 2DG treated cells. Finally, 2DG treatment significantly delayed metastasis and prolonged survival in an orthotopic postsurgical OS model. In conclusion, this work suggests that forcing cells away from glycolysis may inhibit key components of the metastatic phenotype, providing a novel avenue for metastasis prevention.
Obesity is a major risk factor for the development and progression of breast cancer. Leptin, a cytokine mainly produced by adipocytes, plays a crucial role in mammary carcinogenesis and is elevated in hyperinsulinemia and insulin resistance. The antidiabetic thiazolidinediones inhibit leptin gene expression through ligand activation of the peroxisome proliferator-activated receptor-γ (PPARγ) and exert antiproliferative and apoptotic effects on breast carcinoma. In this study, we investigated the ability of PPARγ ligands to counteract leptin stimulatory effects on breast cancer growth in either in vivo or in vitro models. The results show that activation of PPARγ prevented the development of leptin-induced MCF-7 tumor xenografts and inhibited the increased cell-cell aggregation and proliferation observed on leptin exposure. PPARγ ligands abrogated the leptin-induced up-regulation of leptin gene expression and its receptors in breast cancer. PPARγ-mediated repression of leptin gene involved the recruitment of nuclear receptor corepressor protein and silencing mediator of retinoid and thyroid hormone receptors corepressors on the glucocorticoid responsive element site in the leptin gene expression regulatory region in the presence of glucocorticoid receptor and PPARγ. In addition, PPARγ ligands inhibited leptin signaling mediated by MAPK/STAT3/Akt phosphorylation and counteracted leptin stimulatory effect on estrogen signaling. These findings suggest that PPARγ ligands may have potential therapeutic benefits in the treatment of breast cancer.
The modern rise in obesity and its strong association with insulin resistance and type 2 diabetes have elicited interest in the underlying mechanisms of these pathologies. The discovery that obesity itself results in an inflammatory state in metabolic tissues ushered in a research field that examines the inflammatory mechanisms in obesity. Here, we summarize the unique features of this metabolic inflammatory state, termed metaflammation and defined as low-grade, chronic inflammation orchestrated by metabolic cells in response to excess nutrients and energy. We explore the effects of such inflammation in metabolic tissues including adipose, liver, muscle, pancreas, and brain and its contribution to insulin resistance and metabolic dysfunction. Another area in which many unknowns still exist is the origin or mechanism of initiation of inflammatory signaling in obesity. We discuss signals or triggers to the inflammatory response, including the possibility of endoplasmic reticulum stress as an important contributor to metaflammation. Finally, we examine anti-inflammatory therapies for their potential in the treatment of obesity-related insulin resistance and glucose intolerance.
Obesity represents a risk factor for certain types of cancer. Leptin, a hormone predominantly produced by adipocytes, is elevated in the obese state. In the context of breast cancer, leptin derived from local adipocytes is present at high concentrations within the mammary gland. A direct physiological role of peripheral leptin action in the tumor microenvironment in vivo has not yet been examined. Here, we report that mice deficient in the peripheral leptin receptor, while harboring an intact central leptin signaling pathway, develop a fully mature ductal epithelium, a phenomenon not observed in db/db mice to date. In the context of the MMTV-PyMT mammary tumor model, the lack of peripheral leptin receptors attenuated tumor progression and metastasis through a reduction of the ERK1/2 and Jak2/STAT3 pathways. These are tumor cell-autonomous properties, independent of the metabolic state of the host. In the absence of leptin receptor signaling, the metabolic phenotype is less reliant on aerobic glycolysis and displays an enhanced capacity for β-oxidation, in contrast to nontransformed cells. Leptin receptor-free tumor cells display reduced STAT3 tyrosine phosphorylation on residue Y705 but have increased serine phosphorylation on residue S727, consistent with preserved mitochondrial function in the absence of the leptin receptor. Therefore, local leptin action within the mammary gland is a critical mediator, linking obesity and dysfunctional adipose tissue with aggressive tumor growth.
High leptin serum levels, overexpression of leptin and its two main receptor isoforms, OBR-L and OBR-S, have been documented in breast cancer patients. In the present study, the relationship between tissue leptin levels and breast cancer was evaluated.
Thirty-three normal breast tissue samples and 33 breast cancer tissue samples from 33 patients with breast cancer were evaluated. The association of tissue leptin levels and important prognostic factors related to breast cancer was analyzed.
Mean tissue leptin levels in breast cancer tissue samples (5.02 + or - 1.06 pg/ml) were significantly higher than those found in normal breast tissue (2.02 + or - 0.83 pg/ml; p=0.01). No correlation was found in tissue leptin levels and menopausal status, hormone receptor and HER-2/neu status, lymph node involvement, and histopathologic features.
High leptin levels were significantly higher in breast cancer tissue compared with normal tissue. No special correlation was found between tissue leptin levels and different clinicopathological characteristics.
Leptin, a multifunctional hormone, controls various processes in both the central nervous system and in peripheral tissues. Because of the presence of multiple leptin/receptor (ObR) interaction sites and diverse leptin activities, the literature lacks truly monofunctional leptin protein derivatives or fragments. To date, selective ObR antagonists have not been reported. We developed short, pharmacologically advantageous peptide analogs of ObR-binding site III of leptin that acted as selective ObR inhibitors without any partial agonistic activity. These reduced leptin-dependent growth and signaling in cancer cell lines at picomolar and low nanomolar concentrations. In immunocompromised mice the peptides suppressed the growth of rapidly proliferating orthotopic human breast cancer xenografts by 50% when administered either intraperitoneally (i.p.) or subcutaneously (s.c.) for 38 days at a 0.1 mg/kg/day dose. The peptides were distributed to the brain, and when added to growing C57BL/6 normal mice i.p., s.c., or orally, the lead antagonist accelerated normal weight increase without producing any toxic effects. Weight gain increases could not be observed after 10-12 days of treatment indicating that the mice became resistant to the central nervous system activity of leptin antagonists. However, in normal growing rats the intranasal administration at 0.1 mg/kg/day for 20 days resulted in a 2% net total body weight gain without signs of resistance induction. In addition to the potential of these peptides in drug development against primary and metastatic tumors and cachexia, our data confirm that resistance to leptin resides at the blood-brain barrier.
Studies to understand the pathogenesis of obesity have revealed mediators that are responsible for the control of food intake and metabolism at the hypothalamic level. However, molecular insight explaining the link between obesity and low-degree chronic inflammation remains elusive. The adipocyte-derived hormone leptin, and thereby the nutritional status, could control immune self-tolerance by affecting regulatory T (Treg) cell responsiveness and function. Furthermore, resident Treg cells, which are capable of modulating metabolism and glucose homeostasis, are abundant in adipose tissue. Here, we provide an update on recent findings relating Treg cells to obesity and discuss how the intricate network of interactions among leptin, Treg cells and adipose tissue might provide new strategies for therapeutic interventions.
High levels of VEGF and leptin are strongly linked to worse prognosis of breast cancer. Leptin signalling upregulates VEGF in human and mouse mammary tumor cells (MT), but the specific molecular mechanisms are largely unknown. Pharmacologic and genetic approaches were used to dissect the mechanism of leptin regulation of VEGF protein and mRNA in MT (4T1, EMT6 and MMT). A series of VEGF-promoter Luc-reporters (full-length and transcription factor-binding deletions) were transfected into MT to analyze leptin regulation of VEGF transcription. Deletion analysis of VEGF promoter and RNA knockdown shows that HIF-1alpha and NFkappaB are essentials for leptin regulation of VEGF. Leptin activation of HIF-1alpha was mainly linked to canonic (MAPK, PI-3K) and non-canonic (PKC, JNK and p38 MAP) signalling pathways. Leptin non-canonic signalling pathways (JNK, p38 MAP and to less extent PKC) were linked to NFkappaB activation. SP1 was involved in leptin regulation of VEGF in 4T1 cells. AP1 was not involved and AP2 repressed leptin-induced increase of VEGF. Overall, these data suggest that leptin signalling regulates VEGF mainly through HIF-1alpha and NFkappaB. These results delineate a comprehensive mechanism for leptin regulation of VEGF in MT. Disruption of leptin signalling could be used as a novel way to treat breast cancer.
Obesity is considered to be an important risk factor for postmenopausal breast cancer. Elevated estrogen levels are thought to be a growth factor associated with this relationship. However, there is increasing evidence that factors produced directly in adipose tissue, adipokines, can also affect breast cancer development. Leptin is one of the adipokines that is measured in serum/plasma in increasing amounts as body weight/body fat increases.
We highlight important aspects of leptin in relationship to mammary/breast tumor development. This includes findings from human, in vitro and animal studies. Information on leptin-related compounds which may have therapeutic use is presented. Additionally strategies to alter serum leptin levels by dietary and pharmacological interventions are discussed.
The reader will gain insights into the relationship of an adipose tissue protein and its potential role in breast cancer development as well as ways to intervene in leptin's actions.
Continued research will determine if interfering with the action of leptin has preventive or therapeutic applications in breast cancer.
It is essential to clarify the interactions of hormones during the progression of human breast cancer. This study examined the effects of exogenous human leptin on estrogen receptor (ER) alpha and beta in human breast tumor tissue in a nude mouse xenograft model.
We created nude mice xenografts of MCF-7 human breast cancer cells, and randomly divided them into an experimental group and a control group. The mice in experimental group were injected subcutaneously around tumors with human leptin, while the control group were injected with the same dose of normal saline. A real-time RT-PCR assay was developed to quantify the mRNA of ERalpha, beta in the tumor tissues. Western blotting analyses were used to assess the relative quantities of the ERalpha, beta proteins.
Leptin-treated xenografted nude mice were successfully established. The amount of ERalpha mRNA was significantly higher in the leptin group than in the control group (P < 0.01), while the amount of ERbeta mRNA was significantly lower in the leptin group than in the control group (P < 0.01). Western blotting analyses revealed that the ERalpha protein level was significantly higher in the leptin group than in the control group (P < 0.01), while the ERbeta protein level was significantly lower in the leptin group than in the control group (P < 0.01).
Nude mouse xenograft model can be safely and serviceably treated with human leptin by subcutaneous injections around tumor. ERalpha, beta were both targets of leptin in breast cancer. Leptin can up-regulate the expression of ERalpha and down-regulate the expression of the ERbeta in human breast tumor.
Adipositas correlates with an enhanced risk of developing malignant diseases such as breast cancer, endometrial tumor or prostate carcinoma, but the molecular basis for this is not well understood. Potential mechanisms include increased bioavailability of adipocytokines (e.g. leptin) and steroid hormones. Here, we investigated cross-talk between ERalpha (estrogen receptor alpha) and leptin-induced activation of signal transducer and activator of transcription 3 (STAT3), a transactivator of important oncogenes. Upon leptin binding to its receptor Ob-RL (obesity receptor), STAT3 tyrosine phosphorylation and transactivation activity were enhanced by simultaneously expressing ERalpha. Downregulation of ERalpha using small interfering RNA abolished leptin-induced STAT3 phosphorylation. Interestingly, leptin-mediated STAT3 activation was unaffected by co-stimulation with the ERalpha ligands estradiol (E2) or estrogen antagonists ICI182,780 and tamoxifen, implying that enhancement of leptin-mediated STAT3 activity is independent of ERalpha ligands. We also detected ERalpha binding to STAT3 and JAK2 (Janus kinase 2), resulting in enhanced JAK2 activity upstream of STAT3 in response to leptin that might lead to an increased ERalpha-dependent cell viability. Altogether, our results indicate that leptin-induced STAT3 activation acts as a key event in ERalpha-dependent development of malignant diseases.
Tyrosine phosphorylation of signal transducers and activators of transcription (STATs) promotes their dimerization and ability to bind target genes in the nucleus. However, evidence shows that one member of the STAT family, STAT3, has an additional property independent of its classical role in the nucleus. STAT3 modifed by serine phosphorylation augmented oxidative phosphorylation in mitochondria and supported cellular transformation by oncogenic Ras. © Copyright 2008 by the American Association for the Advancement of Science; all rights reserved.
Expansion of adipose tissue mass, the distinctive feature of obesity, is associated with low-grade inflammation. White adipose tissue secretes a diverse range of adipokines, a number of which are inflammatory mediators (such as TNFalpha, IL-1beta, IL-6, monocyte chemoattractant protein 1). The production of inflammatory adipokines is increased with obesity and these adipokines have been implicated in the development of insulin resistance and the metabolic syndrome. However, the basis for the link between increased adiposity and inflammation is unclear. It has been proposed previously that hypoxia may occur in areas within adipose tissue in obesity as a result of adipocyte hypertrophy compromising effective O2 supply from the vasculature, thereby instigating an inflammatory response through recruitment of the transcription factor, hypoxic inducible factor-1. Studies in animal models (mutant mice, diet-induced obesity) and cell-culture systems (mouse and human adipocytes) have provided strong support for a role for hypoxia in modulating the production of several inflammation-related adipokines, including increased IL-6, leptin and macrophage migratory inhibition factor production together with reduced adiponectin synthesis. Increased glucose transport into adipocytes is also observed with low O2 tension, largely as a result of the up-regulation of GLUT-1 expression, indicating changes in cellular glucose metabolism. Hypoxia also induces inflammatory responses in macrophages and inhibits the differentiation of preadipocytes (while inducing the expression of leptin). Collectively, there is strong evidence to suggest that cellular hypoxia may be a key factor in adipocyte physiology and the underlying cause of adipose tissue dysfunction contributing to the adverse metabolic milieu associated with obesity.
In contrast to normal differentiated cells, which rely primarily on mitochondrial oxidative phosphorylation to generate the
energy needed for cellular processes, most cancer cells instead rely on aerobic glycolysis, a phenomenon termed “the Warburg
effect.” Aerobic glycolysis is an inefficient way to generate adenosine 5′-triphosphate (ATP), however, and the advantage
it confers to cancer cells has been unclear. Here we propose that the metabolism of cancer cells, and indeed all proliferating
cells, is adapted to facilitate the uptake and incorporation of nutrients into the biomass (e.g., nucleotides, amino acids,
and lipids) needed to produce a new cell. Supporting this idea are recent studies showing that (i) several signaling pathways
implicated in cell proliferation also regulate metabolic pathways that incorporate nutrients into biomass; and that (ii) certain
cancer-associated mutations enable cancer cells to acquire and metabolize nutrients in a manner conducive to proliferation
rather than efficient ATP production. A better understanding of the mechanistic links between cellular metabolism and growth
control may ultimately lead to better treatments for human cancer.
Calorie restriction (CR) and alternate-day fasting (ADF) beneficially affect several aspects of adipose tissue physiology, but direct comparisons between regimens have yet to be performed. The present study evaluated the effects of ADF versus CR on body fat distribution and circulating adiponectin levels and examined the kinetic mechanisms that underlie changes in fat distribution. Thirty female C57BL/6J mice were randomized to one of five groups for 4 weeks: (a) CR-25% (25% energy restriction daily), (b) ADF-75% (75% restriction on fast day), (c) ADF-85% (85% restriction on fast day), (d) ADF-100% (100% restriction on fast day) and (e) control (ad libitum fed). Body weights of the CR mice were lower than that of the ADF and control groups posttreatment. After 4 weeks of diet, the proportion of visceral fat decreased (P<.001) and the proportion of subcutaneous fat increased (P<.001) similarly in ADF and CR animals. Adiponectin increased (P<.05) by 62-86% in the ADF groups and by 69% in the CR group. Triglyceride (TG) synthesis and de novo lipogenesis were augmented (P<.05) in the subcutaneous fat pad of ADF and CR animals, relative to control. No differences in net lipolysis were observed, resulting in greater TG accumulation in the subcutaneous fat pad, with a shift in the ratio of TG between depots. These findings indicate that ADF (both modified and true) produces similar beneficial modulations in body fat distribution and adiponectin levels as daily CR.
Unlabelled:
Leptin signaling is involved in T-cell polarization and is required for profibrotic function of hepatic stellate cells (HSCs). Leptin-deficient ob/ob mice do not develop liver fibrosis despite the presence of severe long-standing steatohepatitis. Here, we blocked leptin signaling with our recently generated mouse leptin antagonist (MLA), and examined the effects on chronic liver fibrosis in vivo using the chronic thioacetamide (TAA) fibrosis model, and in vitro using freshly-isolated primary HSCs. In the chronic TAA fibrosis model, leptin administration was associated with significantly enhanced liver disease and a 100% 5-week to 8-week mortality rate, while administration or coadministration of MLA markedly improved survival, attenuated liver fibrosis, and reduced interferon gamma (IFN-gamma) levels. No significant changes in weight, serum cholesterol, or triglycerides were noted. In vitro administration of rat leptin antagonist (RLA), either alone or with leptin, to rat primary HSCs reduced leptin-stimulated effects such as increased expression of alpha-smooth muscle actin (alpha-SMA), and activation of alpha1 procollagen promoter.
Conclusion:
Inhibition of leptin-enhanced hepatic fibrosis may hold promise as a future antifibrotic therapeutic modality.
Obesity is a risk factor for endometrial cancer in pre- and post-menopausal women. Leptin, an adipocyte-derived hormone, in addition to the control weight homeostasis, is implicated in multiple biological actions. A recent study demonstrated that leptin promotes endometrial cancer growth and invasiveness through STAT/MAPK and Akt pathways, but the molecular mechanism involved in such processes still needs to be elucidated. In an attempt to understand the role of leptin in regulating endometrial cancer cells proliferation, we have demonstrated that leptin treatment reduced the numbers of cells in G0/G1-phase while increased cell population in S-phase. This effect is associated with an up-regulation of cyclin D1 together with a down-regulation of cyclin-dependent kinase inhibitor p21(WAF1/Cip1). Mutagenesis studies, eletrophoretic mobility shift, and chromatin immunoprecipitation analysis revealed that signal transducers and activators of transcription 3 (STAT3) and cyclic AMP-responsive element (CRE) binding protein motifs, within cyclin D1 promoter, were required for leptin-induced cyclin D1 expression in Ishikawa endometrial cancer cells. Silencing of STAT3 and CREB gene expression by RNA interference reversed the up-regulatory effect of leptin on cyclin D1 expression and cells proliferation. These results support the hypothesis that STAT3 and CREB play an important role in leptin signaling pathway that leads to the proliferation of Ishikawa cells, thus establishing a direct association between obesity and endometrial tumorogenesis.
The adipocyte-derived peptide leptin acts through binding to specific membrane receptors, of which six isoforms (obRa-f) have been identified up to now. Binding of leptin to its receptor induces activation of different signaling pathways, including the JAK/STAT, MAPK, IRS1, and SOCS3 signaling pathways. Since the circulating levels of leptin are elevated in obese individuals, and excess body weight has been shown to increase breast cancer risk in postmenopausal women, several studies addressed the role of leptin in breast cancer. Expression of leptin and its receptors has been demonstrated to occur in breast cancer cell lines and in human primary breast carcinoma. Leptin is able to induce the growth of breast cancer cells through activation of the Jak/STAT3, ERK1/2, and/or PI3K pathways, and can mediate angiogenesis by inducing the expression of vascular endothelial growth factor (VEGF). In addition, leptin induces transactivation of ErbB-2, and interacts in triple negative breast cancer cells with insulin like growth factor-1 (IGF-1) to transactivate the epidermal growth factor receptor (EGFR), thus promoting invasion and migration. Leptin can also affect the growth of estrogen receptor (ER)-positive breast cancer cells, by stimulating aromatase expression and thereby increasing estrogen levels through the aromatization of androgens, and by inducing MAPK-dependent activation of ER. Taken together, these findings suggest that the leptin system might play an important role in breast cancer pathogenesis and progression, and that it might represent a novel target for therapeutic intervention in breast cancer.
THE biosynthesis of estrogens appears to occur throughout the entire vertebrate phylum including mammals, birds, reptiles, amphibians, teleost and elasmobranch fish, and Agnatha (hagfish and lampreys) (1–3). It has also been described in the protochordate Amphioxus (4). To our knowledge, estrogen biosynthesis has not been reported in nonvertebrate animal phyla. In most vertebrate species that have been examined, aromatase expression occurs in the gonads and in the brain. This is true of the fish and avian species that have been examined as well as most mammals such as rodents. In many species estrogen biosynthesis in the brain has been implicated in sex-related behavior such as mating responses, and frequently a marked sexually dimorphic difference has been demonstrated. This is true, for example, in avian species in which the song of the male is important in courtship behavior (5). In the case of humans and a number of higher primates, there is a more extensive tissue distribution of estrogen biosynthesi...