ArticleLiterature Review

Lactate acidosis and simultaneous recruitment of TGF-β leads to alter plasticity of hypoxic cancer cells in tumor microenvironment

Authors:
To read the full-text of this research, you can request a copy directly from the authors.

Abstract

Lactate acidosis is often observed in the tumor microenvironment (TME) of solid tumors. This is because glucose breaks down quickly via glycolysis, causing lactate acidity. Lactate is harmful to healthy cells, but is a major oncometabolite for solid cancer cells that do not receive sufficient oxygen. As an oncometabolite, it helps tumor cells perform different functions, which helps solid hypoxic tumor cells spread to other parts of the body. Studies have shown that the acidic TME contains VEGF, Matrix metalloproteinases (MMPs), cathepsins, and transforming growth factor-β (TGF-β), all of which help spread in direct and indirect ways. Although each cytokine is important in its own manner in the TME, TGF-β has received much attention for its role in metastatic transformation. Several studies have shown that lactate acidosis can cause TGF-β expression in solid hypoxic cancers. TGF-β has also been reported to increase the production of fatty acids, making cells more resistant to treatment. TGF-β has also been shown to control the expression of VEGF and MMPs, which helps solid hypoxic tumors become more aggressive by helping them spread and create new blood vessels through an unknown process. The role of TGF-β under physiological conditions has been described previously. In this study, we examined the role of TGF-β, which is induced by lactate acidosis, in the spread of solid hypoxic cancer cells. We also found that TGF-β and lactate work together to boost fatty acid production, which helps angiogenesis and invasiveness.

No full-text available

Request Full-text Paper PDF

To read the full-text of this research,
you can request a copy directly from the authors.

... Studies have reported that TGF-β crosstalk with various cellular mechanisms under the tumor cells. [5] One of the major culprits behind tumor development is hypoxia-induced lactate in the tumor microenvironment (TME), which drives through the TGFβ signaling pathway. Alteration in tumor cells by rendering different mechanisms by TGF-β responsible for neovascularisation, invasiveness, and immune suppressive nature ultimately leads to apoptosis inhibition and creates resistance. ...
... Various inhibitory strategies are employed in each step of signaling, including ligand trapping, ligand-specific antibodies, receptor-ligand complex-specific antibodies, receptor kinase inhibitors, and vaccine-based approaches. [5][6][7] Moreover, inhibitors like Fresolimumab (NCT02581787) (IC 50 = 1.86 nM) and SRK181-mglG (IC 50 = 1.11 nM) are monoclonal antibodies that may have limitations like off-target effects that affect other signalling's and induced immune response could lower the drug's efficacy which further leads to unintended side effects. [5,8] Ligand traps inhibitors such as AVID200 that selectively worked on TGF-β1 and TGF-β3 but blockade the TGF-β2 activity, Bintrafusp α (also known as M7824) could possess immune-related adverse events. ...
... [5][6][7] Moreover, inhibitors like Fresolimumab (NCT02581787) (IC 50 = 1.86 nM) and SRK181-mglG (IC 50 = 1.11 nM) are monoclonal antibodies that may have limitations like off-target effects that affect other signalling's and induced immune response could lower the drug's efficacy which further leads to unintended side effects. [5,8] Ligand traps inhibitors such as AVID200 that selectively worked on TGF-β1 and TGF-β3 but blockade the TGF-β2 activity, Bintrafusp α (also known as M7824) could possess immune-related adverse events. Similarly, receptor kinase inhibitors like Galunisertib (IC 50 = 56 nM) and Vactosertib (IC 50 = 12.9 nM) long-term treatment of targeted sites may develop resistance that affects the drug efficacy. ...
Article
Globally, cancer is one of the leading causes of death. Resistance to conventional medications, such as chemotherapy and radiation, continues to be a significant challenge in the treatment of cancer despite the availability of numerous medicines. Therefore, the highest priority is to hunt for new therapeutic agents. Transforming growth factor‐beta is a pivotal regulatory cytokine that exerts significant influence over cellular processes, particularly emphasizing its role in facilitating and modulating cell proliferation. TGFβ1, identified as most promising active site of the TGF‐β signaling, is a potent drug target site that has garnered wide attention for developing new anticancer agents. The present investigation investigates the potential phytochemicals as TGFβR1 inhibitors. The SB431542 complexed TGFβR1 protein model was used to screen the natural product database to obtain a compound with high binding potential. NPC247629 has emerged as the best‐scored compound among all the screened compounds, demonstrating the highest affinity towards the TGFβR1 regarding docking score ‐17.54 kcal/mol. The MD simulation study indicated that all proposed hits are retained inside the receptor in dynamic states. The best‐screened hits, NPC247629 and NPC60735, have excellent binding affinity and hold a massive potential for TGFβR1 inhibition, paving the way for promising future investigations in cancer treatment.
... Meanwhile, increased lipid levels in the TME also exert immunosuppressive effects. The acidic TME induces the expression of transforming growth factor-beta (TGF-β), which further increases fatty acid production, facilitating angiogenesis and resistance to treatment [147]. Excess fatty acids form lipid droplets and can be oxidized via β-oxidation to promote the EMT process by providing ATP [148]. ...
Article
Full-text available
The Kirsten rat sarcoma viral oncogene homolog (KRAS) protein plays a key pathogenic role in oncogenesis, cancer progression, and metastasis. Numerous studies have explored the role of metabolic alterations in KRAS-driven cancers, providing a scientific rationale for targeting metabolism in cancer treatment. The development of KRAS-specific inhibitors has also garnered considerable attention, partly due to the challenge of acquired treatment resistance. Here, we review the metabolic reprogramming of glucose, glutamine, and lipids regulated by oncogenic KRAS, with an emphasis on recent insights into the relationship between changes in metabolic mechanisms driven by KRAS mutant and related advances in targeted therapy. We also focus on advances in KRAS inhibitor discovery and related treatment strategies in colorectal, pancreatic, and non-small cell lung cancer, including current clinical trials. Therefore, this review provides an overview of the current understanding of metabolic mechanisms associated with KRAS mutation and related therapeutic strategies, aiming to facilitate the understanding of current challenges in KRAS-driven cancer and to support the investigation of therapeutic strategies. Supplementary Information The online version contains supplementary material available at 10.1186/s12943-024-02216-3.
... One of these genes, HOXB9, plays a crucial role in this process by controlling the expression of pro-angiogenic factors such as VEGF and fibroblast growth factor (FGF). This regulation promotes the angiogenic switch, which initiates the formation of new blood vessels within the microenvironment of the secondary tumor [74]. ...
Article
Full-text available
The intricate interplay between Homeobox genes, long non-coding RNAs (lncRNAs), and the development of malignancies represents a rapidly expanding area of research. Specific discernible lncRNAs have been discovered to adeptly regulate HOX gene expression in the context of cancer, providing fresh insights into the molecular mechanisms that govern cancer development and progression. An in-depth comprehension of these intricate associations may pave the way for innovative therapeutic strategies in cancer treatment. The HOX gene family is garnering increasing attention due to its involvement in immune system regulation, interaction with long non-coding RNAs, and tumor progression. Although initially recognized for its crucial role in embryonic development, this comprehensive exploration of the world of HOX genes contributes to our understanding of their diverse functions, potentially leading to immunology, developmental biology, and cancer research discoveries. Thus, the primary objective of this review is to delve into these aspects of HOX gene biology in greater detail, shedding light on their complex functions and potential therapeutic applications.
... One such growth factor is TGF-β, which promotes EMT and metastasis by downregulating E-cadherin expression and angiogenesis. 25 Other similar factors, such as fibroblast growth factor, contribute to the cancer formation niche and are characterized by suppression of the immune system. Just like growth factors, cytokines entangled in ECM, like IL-10, TNF-α, and IL-1, play a crucial role in modifying the immune responses of various tumor cells. ...
Article
Breast cancer (BC) is the second deadliest cancer after lung cancer. Similar to all cancers, it is also driven by a 3-D microenvironment. Extracellular matrix (ECM) is an essential component of the 3-D tumor micro-environment, wherein it functions as a scaffold for cells and provides metabolic support. BC is characterized by alterations in the ECM. Various studies have attempted to mimic BC-specific ECM using artificial materials, such as Matrigel. Nevertheless, research has proven that naturally derived decellularized extracellular matrix (dECM) is superior in providing the essential in vivo-like cues needed to mimic a cancer-like environment. Developing in-vitro 3-D BC models is not straightforward and requires extensive analysis of the data established by a researcher. For the benefit of the researchers in this review, we have tried to highlight all developmental studies that have been conducted by various scientists have done so far. The analysis of the conclusions drawn from these studies is also discussed. The advantages and drawbacks of the decellularization methods employed for generating BC scaffolds will be covered, and the review will shed light on how dECM scaffolds help develop a BC environment. The later stages of the article will also focus on immunogenicity issues arising from decellularization and the origin of the tissue. Finally, this review will also discuss the biofabrication of matrices, which is the core part of the bioengineering process.
... Glycolysis can lead to an increase in HIF-1a levels, which in turn raises VEGF expression (121). Aerobic glycolysis stimulates angiogenesis by producing lactate, which acidifies the extracellular environment and enhances VEGF expression (122). Additionally, the end products of glycolysis, lactate and pyruvate, influence VEGF expression through the augmentation of HIF-1a levels (123)(124)(125). ...
Article
Full-text available
Globally, breast cancer stands as the most prevalent form of cancer among women. The tumor microenvironment of breast cancer often exhibits hypoxia. Hypoxia-inducible factor 1-alpha, a transcription factor, is found to be overexpressed and activated in breast cancer, playing a pivotal role in the anoxic microenvironment by mediating a series of reactions. Hypoxia-inducible factor 1-alpha is involved in regulating downstream pathways and target genes, which are crucial in hypoxic conditions, including glycolysis, angiogenesis, and metastasis. These processes significantly contribute to breast cancer progression by managing cancer-related activities linked to tumor invasion, metastasis, immune evasion, and drug resistance, resulting in poor prognosis for patients. Consequently, there is a significant interest in Hypoxia-inducible factor 1-alpha as a potential target for cancer therapy. Presently, research on drugs targeting Hypoxia-inducible factor 1-alpha is predominantly in the preclinical phase, highlighting the need for an in-depth understanding of HIF-1α and its regulatory pathway. It is anticipated that the future will see the introduction of effective HIF-1α inhibitors into clinical trials, offering new hope for breast cancer patients. Therefore, this review focuses on the structure and function of HIF-1α, its role in advancing breast cancer, and strategies to combat HIF-1α-dependent drug resistance, underlining its therapeutic potential.
... [51][52][53] Importantly, the buildup of lactate in the human organism presents a higher danger in contrast to the buildup of alternative molecular energy sources, since elevated levels of lactate in the bloodstream can lead to lactic acidosis. 42,54 The enzymatic activity of pyruvate dehydrogenase (PDH) ...
Article
Full-text available
Heightened lactate production in cancer cells has been linked to various cellular mechanisms such as angiogenesis, hypoxia, macrophage polarisation and T‐cell dysfunction. The lactate‐induced lactylation of histone lysine residues is noteworthy, as it functions as an epigenetic modification that directly augments gene transcription from chromatin. This epigenetic modification originating from lactate effectively fosters a reliance on transcription, thereby expediting tumour progression and development. Herein, this review explores the correlation between histone lactylation and cancer characteristics, revealing histone lactylation as an innovative epigenetic process that enhances the vulnerability of cells to malignancy. Moreover, it is imperative to acknowledge the paramount importance of acknowledging innovative therapeutic methodologies for proficiently managing cancer by precisely targeting lactate signalling. This comprehensive review illuminates a crucial yet inadequately investigated aspect of histone lactylation, providing valuable insights into its clinical ramifications and prospective therapeutic interventions centred on lactylation.
... Additionally, by enhancing glycolysis, even under aerobic conditions, it suppresses excessive ROS production, which is vital in inhibiting anoikis. Moreover, the substantial lactate produced via the glycolytic pathway (48,49). Recent studies have also highlighted enhanced lipid metabolism as a distinct metabolic feature in some tumors (11,50,51). ...
Article
Full-text available
Background Anoikis presents a significant barrier in the metastasis of cancer. As the most aggressive type of thyroid cancer, anaplastic thyroid cancer (ATC) exhibits a high risk of metastasis and is characterized by high mortality. Therefore, investigating the molecular mechanisms of anoikis resistance in ATC is important for devising therapeutic targets in clinical research. Methods Differentially Expressed Genes were screened in ATC cells under attached and detached culture conditions with RNA-seq. Investigate the impact of enolase 2 (ENO2) on apoptosis and spheroid formation by gain and loss of function. Changes of reactive oxygen species (ROS), glutathione (GSH) and nicotinamide adenine dinucleotide phosphate (NADPH) were detected to assess redox balance. The transcriptional regulatory role of signal transducer and activator of transcription 1 (STAT1) on ENO2 was validated through Dual-Luciferase Reporter Gene Assay. Explore the impact of ENO2 expression on the formation of lung metastases in nude mice. Results We found that the glycolysis process was activated in detached ATC cells. Several genes in the glycolysis process, particularly ENO2, a member of the enolase superfamily was upregulated in ATC cells cultured in suspension. The upregulation of ENO2 enabled the maintenance of redox balance by supplying GSH and NADPH, thereby preventing cells from undergoing anoikis. In terms of mechanism, the expression of STAT1 was enhanced in anoikis resistance cells, which in turn positively regulated the expression of ENO2. In vivo, ENO2-suppressed ATC cells resulted in a significantly lower rate of lung colonization compared to control ATC cells. Conclusions Stable expression of ENO2 and the maintenance of redox balance played a pivotal role in facilitating anoikis resistance of ATC.
Article
Full-text available
In the realm of cancer research, the tumor microenvironment (TME) plays a crucial role in tumor initiation and progression, shaped by complex interactions between cancer cells and surrounding non-cancerous cells. Cytokines, as essential immunomodulatory agents, are secreted by various cellular constituents within the TME, including immune cells, cancer-associated fibroblasts, and cancer cells themselves. These cytokines facilitate intricate communication networks that significantly influence tumor initiation, progression, metastasis, and immune suppression. Pyroptosis contributes to TME remodeling by promoting the release of pro-inflammatory cytokines and sustaining chronic inflammation, impacting processes such as immune escape and angiogenesis. However, challenges remain due to the complex interplay among cytokines, pyroptosis, and the TME, along with the dual effects of pyroptosis on cancer progression and therapy-related complications like cytokine release syndrome. Unraveling these complexities could facilitate strategies that balance inflammatory responses while minimizing tissue damage during therapy. This review delves into the complex crosstalk between cytokines, pyroptosis, and the TME, elucidating their contribution to tumor progression and metastasis. By synthesizing emerging therapeutic targets and innovative technologies concerning TME, this review aims to provide novel insights that could enhance treatment outcomes for cancer patients.
Article
Full-text available
Cancer is a leading cause of global morbidity and mortality. Tumor cells grow in a complex microenvironment, comprising immune cells, stromal cells, and vascular cells, collaborating to support tumor growth and facilitate metastasis. Transforming growth factor-beta (TGF-β) is a multipotent factor that can not only affect fibrosis promotion but also assume distinct roles in the early and late stages of the tumor. Matrix metalloproteinases (MMPs) primarily function to degrade the extracellular matrix, a pivotal cellular player in tumor progression. Moreover, endothelial-to-mesenchymal transition (EndMT), similar to epithelial-to-mesenchymal transition, is associated with cancer progression by promoting angiogenesis, disrupting the endothelial barrier, and leading to cancer-associated fibroblasts. Recent studies have underscored the pivotal roles of TGF-β and MMPs in EndMT. This review delves into the contributions of TGF-β and MMPs, as well as their regulatory mechanisms, within the tumor microenvironment. This collective understanding offers fresh insights into the potential for combined targeted therapies in the fight against cancer.
Article
Parecoxib, a well‐recognized nonsteroidal anti‐inflammatory drug, has been reported to possess anticancer properties in various tumor types. In this work, we aimed to investigate the potential anticancer effects of parecoxib on hepatocellular carcinoma (HCC) cells. To assess the impact of parecoxib on HCC cell proliferation, we employed Cell Counting Kit‐8, colony formation, and 5‐ethynyl‐2′‐deoxyuridine assays. Hoechst/propidium iodide (PI) double staining and flow cytometry were performed to evaluate apoptosis and cell cycle analysis. Wound healing and transwell assays were utilized to assess cell migration and invasion. Tube formation assay was employed to analyze angiogenesis. Protein levels were determined using western blotting, and mRNA expression levels were assessed using quantitative real‐time polymerase chain reaction (PCR). A xenograft mouse model was used to confirm the antitumor effects of parecoxib on HCC tumors in vivo. Our data demonstrated that parecoxib effectively inhibited the proliferation of HCC cells in a dose‐ and time‐dependent manner. In addition, parecoxib induced cell cycle arrest in the G2 phase and promoted apoptosis. Moreover, parecoxib hindered tumor migration and invasion by impeding the epithelial–mesenchymal transition process. Further investigation showed that parecoxib could significantly suppress angiogenesis through the inhibition of extracellular signal‐regulated kinase (ERK)–vascular endothelial growth factor (VEGF) axis. Notably, treatment with the ERK activator phorbol myristate acetate upregulated the expression of matrix metalloproteinase (MMP)‐2, MMP‐9, and VEGF and reversed the function of parecoxib in HCC cells. Besides, parecoxib displayed its antitumor efficacy in vivo. Collectively, our results suggest that parecoxib ameliorates HCC progression by regulating proliferation, cell cycle, apoptosis, migration, invasion, and angiogenesis through the ERK–VEGF/MMPs signaling pathway.
Article
The Homeobox (HOX) gene family is essential to regulating cellular processes because it maintains the exact coordination required for tissue homeostasis, cellular differentiation, and embryonic development. The most distinctive feature of this class of genes is the presence of the highly conserved DNA region known as the homeobox, which is essential for controlling their regulatory activities. Important players in the intricate process of genetic regulation are the HOX genes. Many diseases, especially in the area of cancer, are linked to their aberrant functioning. Due to their distinctive functions in biomedical research—particularly in the complex process of tumor advancement—HOXA9 and HOXB9 have drawn particular attention. HOXA9 and HOXB9 are more significant than what is usually connected with HOX genes since they have roles in the intricate field of cancer and beyond embryonic processes. The framework for a focused study of the different effects of HOXA9 and HOXB9 in the context of tumor biology is established in this study.
Article
Full-text available
It is well known that solid hypoxic tumour cells oxidise glucose through glycolysis, and the end product of this pathway is fermented into lactate which accumulates in the tumour microenvironment (TME). Initially, it was proclaimed that cancer cells cannot use lactate; therefore, they dump it into the TME and subsequently augment the acidity of the tumour milieu. Furthermore, the TME acts as a lactate sink with stope variable amount of lactate in different pathophysiological condition. Regardless of the amount of lactate pumped out within TME, it disappears immediately which still remains an unresolved puzzle. Recent findings have paved a pathway in exploring the main role of lactate acidosis in TME. Cancer cells utilize lactate in the de novo fatty acid synthesis pathway to initiate angiogenesis and invasiveness, and lactate also plays a crucial role in the suppression of immunity. Furthermore, lactate re-programmed the lipid biosynthetic pathway to develop a metabolic symbiosis in normoxic, moderately hypoxic, and severely hypoxic cancer cells. For instance: severely hypoxic cancer cells enable to synthesize polyunsaturated fatty acids (PUFA) in oxygen scarcity and secrete an excess of lactate in TME. Lactate from TME is taken up by the normoxic cancer cells whereas it is converted back to PUFAs after a sequence of reactions and then liberated in the TME to be utilized in the severely hypoxic cancer cells. Although much is known about the role of lactate in these biological processes, the exact molecular pathways that are involved remain unclear. This review attempts to understand the molecular pathways exploited by lactate to initiate angiogenesis, invasiveness, suppression of immunity and cause re-programming of lipid synthesis. This review will help the researchers to develop proper understanding of lactate-associated bimodal regulations of TME.is, and suppression of immunity.
Article
Full-text available
β-thalassemia is characterized by the faulty generation of hemoglobin resulting in an elevated α/β globin ratio; this led to several patients needing red blood cell (RBC) transfusions for the rest of their lives. Luspatercept is an erythroid maturation test for treating various types of anemia, including β-thalassemia. It inhibits the Smad2/3 cascade and treats β-thalassemia by downregulating the transforming growth factor-beta (TGF-β) pathway. Luspatercept was evaluated in randomized controlled trials (RCTs). However, there is still limited data. Therefore, the study aims to review the current literature to assess the efficacy of luspatercept in cure β-thalassemia and its safety. From 2015 to 2022, searches were undertaken in PubMed, Google Scholar, and Cochrane. Only RCTs published in English were eligible for inclusion. The Cochrane Collaboration tool for bias assessment was used to analyze the quality of the publications. Our search strategy revealed 94 publications, of which 12 full-text papers were read and five were chosen for this review.All five trials included 1161 participants. Of whom, 153 (13.18%) entered phase 2, and 1008 (86.82%) entered phase 3. Two articles included 153 participants, of whom 70 (45.75%) were transfusion-dependent beta-thalassemia (TD) and 83 (54.25%) were non-transfusion-dependent beta-thalassemia (NTD) of phase 2. Three articles included 1008 participants, of whom 672 (66.67%) were given luspatercept and 336 (33.33%) were given a placebo. All participants in RCTs were 18 years of age or older. In phase 2, 0.2 to 1.25 mg/kg of luspatercept was given, and in phase 3, 1.0 to 1.25 mg/kg of luspatercept was given once every three weeks. In beta-thalassemia patients, luspatercept was more effective than a placebo and well tolerated. The high dose has shown promising results in the erythroid response, measured by a drop in blood transfusions or an average rise in hemoglobin levels. Luspatercept might make patients less likely to need RBC transfusions, improve their clinical results, and improve their quality of life. Adverse events were hyperuricemia, arthralgia, dizziness, influenza hypertension, and bone pain, but they were manageable.
Article
Full-text available
Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease, and the molecular mechanisms remain poorly understood. Our findings demonstrated that pyruvate kinase M2 (PKM2) promoted fibrosis progression by directly interacting with Smad7 and reinforcing transforming growth factor-β1 (TGF-β1) signaling. Total PKM2 expression and the portion of the tetrameric form elevated in lungs and fibroblasts were derived from mice with bleomycin (BLM)-induced pulmonary fibrosis. Pkm2 deletion markedly alleviated BLM-induced fibrosis progression, myofibroblast differentiation, and TGF-β1 signaling activation. Further study showed that PKM2 tetramer enhanced TGF-β1 signaling by directly binding with Smad7 on its MH2 domain, and thus interfered with the interaction between Smad7 and TGF-β type I receptor (TβR1), decreased TβR1 ubiquitination, and stabilized TβR1. Pharmacologically enhanced PKM2 tetramer by TEPP-46 promoted BLM-induced pulmonary fibrosis, while tetramer disruption by compound 3k alleviated fibrosis progression. Our results demonstrate how PKM2 regulates TGF-β1 signaling and is a key factor in fibrosis progression.
Article
Full-text available
Transforming growth factor-β (TGF-β) signaling has a paradoxical role in cancer progression, and it acts as a tumor suppressor in the early stages but a tumor promoter in the late stages of cancer. Once cancer cells are generated, TGF-β signaling is responsible for the orchestration of the immunosuppressive tumor microenvironment (TME) and supports cancer growth, invasion, metastasis, recurrence, and therapy resistance. These progressive behaviors are driven by an “engine” of the metabolic reprogramming in cancer. Recent studies have revealed that TGF-β signaling regulates cancer metabolic reprogramming and is a metabolic driver in the tumor metabolic microenvironment (TMME). Intriguingly, TGF-β ligands act as an “endocrine” cytokine and influence host metabolism. Therefore, having insight into the role of TGF-β signaling in the TMME is instrumental for acknowledging its wide range of effects and designing new cancer treatment strategies. Herein, we try to illustrate the concise definition of TMME based on the published literature. Then, we review the metabolic reprogramming in the TMME and elaborate on the contribution of TGF-β to metabolic rewiring at the cellular (intracellular), tissular (intercellular), and organismal (cancer-host) levels. Furthermore, we propose three potential applications of targeting TGF-β-dependent mechanism reprogramming, paving the way for TGF-β-related antitumor therapy from the perspective of metabolism.
Article
Full-text available
Objectives: Homeobox B9 (HOXB9), a homeodomain-containing transcription factor, may play a role in hepatocellular carcinoma (HCC) progression. However, the exact mechanisms underlying its action remain unclear. Materials and methods. Immunohistochemistry was used to investigate the expression of HOBX9 and its prognostic values in HCC patients. HCC cells were transfected with pBabe-HOXB9 and shHOXB9 plasmids, and MTT assay, Transwell assays, and xenograft mouse models were employed to determine the effects of HOXB9 on HCC cell proliferation, migration, and invasion in vitro and in vivo. The biological mechanisms involved in the role of HOXB9 were determined with Western blot and RT-qPCR methods. Results: HOXB9 expression was significantly increased in HCC tissues and cell lines. Patients with higher HOXB9 levels were associated with poor prognosis. Overexpression of HOXB9 in BEL-7405 cells promoted proliferation, migration, and invasion, whereas knockdown of HOXB9 in HepG2 cells significantly reduced cell proliferation, migration, and invasion abilities. Mechanically, a positive correlation was found between HOXB9 expression and transforming growth factor-β1 (TGF-β1) and extracellular signal-regulated kinase (ERK)1/2 pathway in HCC tissues. HOXB9 overexpression stimulated TGF-β1/Smads signaling pathway in BEL-7405 cells. In contrast, HOXB9 knockdown inhibited the TGF-β1/Smads signaling pathway in HepG2 cells. In addition, the treatment with TGF-β1 inhibitor, LY364947, significantly reserved HOXB9 overexpression-induced cell proliferation, migration, and invasion abilities. Conclusions: These findings validated that HOXB9 promoted proliferation, migration, and invasion in HCC cells by stimulating the TGF-β1/Smads and ERK1/2 signaling pathway. HOXB9 could be a promising prognostic biomarker and a potential therapeutic target in HCC.
Article
Full-text available
The tumour microenvironment (TME) imposes a major obstacle to infiltrating T-lymphocytes and suppresses their function. Several immune checkpoint proteins that interfere with ligand/receptor interactions and impede T-cell anti-tumour responses have been identified. Immunotherapies that block immune checkpoints have revolutionized the treatment paradigm for many patients with advanced-stage tumours. However, metabolic constraints and soluble factors that exist within the TME exacerbate the functional exhaustion of tumour-infiltrating T-cells. Here we review these multifactorial constraints and mechanisms – elevated immunosuppressive metabolites and enzymes, nutrient insufficiency, hypoxia, increased acidity, immense amounts of extracellular ATP and adenosine, dysregulated bioenergetic and purinergic signalling, and ionic imbalance - that operate in the TME and collectively suppress T-cell function. We discuss how scientific advances could help overcome the complex TME obstacles for tumour-infiltrating T-lymphocytes, aiming to stimulate further research for developing new therapeutic strategies by harnessing the full potential of the immune system in combating cancer.
Article
Full-text available
Background Gemogenovatucel-T (Vigil) is a triple-function autologous tumor cell immunotherapy which expresses granulocyte-macrophage colony-stimulating factor and decreases expression of furin and downstream TGF-β1 and TGF-β2. Vigil has suggested survival benefit in frontline maintenance ovarian cancer patients who are BRCA-wt. In addition, Vigil demonstrates relapse-free and overall survival advantage in homologous recombination-proficient patients with OC. Further evidence of clinical benefit and safety has been demonstrated in combination with atezolizumab. Methods In this pilot study (NCT02725489), the concurrent combination of the programmed death-ligand 1 (PD-L1) inhibitor durvalumab and Vigil was explored in advanced BRCA-wt relapsed triple-negative breast cancer (TNBC) patients and stage III-IV recurrent/refractory OC patients. Patients received the combination regimen of Vigil (1 × 10e6-10e7 cells/dose intradermally, up to 12 doses) and durvalumab (1500 mg/dose intravenous infusion, up to 12 months) once every 4 weeks. The primary objective was to evaluate safety of this combination. The study included 13 BRCA-wt patients (TNBC, n = 8; OC, n = 5). Results The most common treatment-emergent adverse events (⩾20%) in all patients included injection-site reaction (92.3%), myalgia (38.5%), bruise at injection site (23.1%), and pruritus (23.1%). Three grade 3 treatment-related adverse events were observed and related to durvalumab. There were no grade 4/5 treatment-related adverse events. Median progression-free survival was 7.1 months and the median overall survival was not reached. Prolonged progression-free survival was improved in patients with PD-L1+ tumors (n = 8, hazard ratio = 0.304, 95% confidence interval, 0.0593-1.56, 1-sided P = .04715) compared with those with PD-L1− tumors. Conclusions Vigil plus durvalumab was well tolerated and showed promising clinical activity in advanced BRCA-wt TNBC and stage III-IV recurrent/refractory OC patients.
Article
Full-text available
Myeloid-derived suppressor cells (MDSCs) are a class of heterogeneous myeloid cells, which play an important role in immunosuppression. We intended to find an effective method that can produce MDSCs with significantly better efficiency and promote immune tolerance for transplant rejection through cell therapy. It has been reported that granulocyte and macrophage colony-stimulating factor (GM-CSF) could induce MDSCs in vitro to cause immunosuppression. In the present study, transforming growth factor β (TGF-β) was added to the induction system, and flow cytometry analysis was used to detect the phenotypes of induced MDSCs. Their potential immunosuppressive function and mechanisms were determined by co-culturing MDSCs with stimulated T cells in vitro and transferring MDSCs to the skin grafted C57BL/6J mouse models in vivo. It was found that the addition of TGF-β could effectively cause bone marrow cells to differentiate into a group of cells with stronger immunosuppressive functions, thereby inhibiting the proliferation of stimulated T cells. The population of CD11b⁺Gr-1⁺ MDSCs also increased significantly as compared with GM-CSF alone treatment. While detecting for immunosuppressive effectors, we found that expression of arginase 1 (Arg-1) was significantly upregulated in these MDSCs, and inhibitor of Arg-1 significantly suppressed their immunosuppressive capabilities. Moreover, an adoptive transfer of these cells significantly prolonged survival of allo-skin and improved immune tolerance in vivo. These findings indicated that TGF-β + GM-CSF could serve as an effective and feasible method to induce powerful immunosuppressive MDSCs in vitro. Thus, TGF-β + GM-CSF–induced MDSCs may have a promising role in prevention of the graft rejection.
Article
Full-text available
Since TGF-β was recognized as an essential secreted cytokine in embryogenesis and adult tissue homeostasis a decade ago, our knowledge of the role of TGF-β in mammalian development and disease, particularly cancer, has constantly been updated. Mounting evidence has confirmed that TGF-β is the principal regulator of the immune system, as deprivation of TGF-β signaling completely abrogates adaptive immunity. However, enhancing TGF-β signaling constrains the immune response through multiple mechanisms, including boosting Treg cell differentiation and inducing CD8⁺ T-cell apoptosis in the disease context. The love-hate relationship between TGF-β signaling and the immune system makes it challenging to develop effective monotherapies targeting TGF-β, especially for cancer treatment. Nonetheless, recent work on combination therapies of TGF-β inhibition and immunotherapy have provide insights into the development of TGF-β-targeted therapies, with favorable outcomes in patients with advanced cancer. Hence, we summarize the entanglement between TGF-β and the immune system in the developmental and tumor contexts and recent progress on hijacking crucial TGF-β signaling pathways as an emerging area of cancer therapy.
Article
Full-text available
Complexity in mechanisms that drive cancer development and progression is exemplified by the transforming growth factor β (TGF-β) signaling pathway, which suppresses early-stage hyperplasia, yet assists aggressive tumors to achieve metastasis. Of note, several molecules, including mRNAs, non-coding RNAs, and proteins known to be associated with the TGF-β pathway have been reported as constituents in the cargo of extracellular vesicles (EVs). EVs are secreted vesicles delimited by a lipid bilayer and play critical functions in intercellular communication, including regulation of the tumor microenvironment and cancer development. Thus, this review aims at summarizing the impact of EVs on TGF-β signaling by focusing on mechanisms by which EV cargo can influence tumorigenesis, metastatic spread, immune evasion and response to anti-cancer treatment. Moreover, we emphasize the potential of TGF-β-related molecules present in circulating EVs as useful biomarkers of prognosis, diagnosis, and prediction of response to treatment in cancer patients.
Article
Full-text available
Acetyl-CoA carboxylases (ACCs) are enzymes that catalyze the carboxylation of acetyl-CoA to produce malonyl-CoA. In mammals, ACC1 and ACC2 are two members of ACCs. ACC1 localizes in the cytosol and acts as the first and rate-limiting enzyme in the de novo fatty acid synthesis pathway. ACC2 localizes on the outer membrane of mitochondria and produces malonyl-CoA to regulate the activity of carnitine palmitoyltransferase 1 (CPT1) that involves in the β-oxidation of fatty acid. Fatty acid synthesis is central in a myriad of physiological and pathological conditions. ACC1 is the major member of ACCs in mammalian, mountains of documents record the roles of ACC1 in various diseases, such as cancer, diabetes, obesity. Besides, acetyl-CoA and malonyl-CoA are cofactors in protein acetylation and malonylation, respectively, so that the manipulation of acetyl-CoA and malonyl-CoA by ACC1 can also markedly influence the profile of protein post-translational modifications, resulting in alternated biological processes in mammalian cells. In the review, we summarize our understandings of ACCs, including their structural features, regulatory mechanisms, and roles in diseases. ACC1 has emerged as a promising target for diseases treatment, so that the specific inhibitors of ACC1 for diseases treatment are also discussed.
Article
Full-text available
Fortilin is a 172-amino acid multifunctional protein present in both intra- and extracellular spaces. Although fortilin binds and regulates various cellular proteins, the biological role of extracellular fortilin remains unknown. Here we report that fortilin specifically interacts with TGF-β1 and prevents it from activating the TGF-β1 signaling pathway. In a standard immunoprecipitation-western blot assay, fortilin co-immunoprecipitates TGF-β1 and its isoforms. The modified ELISA assay shows that TGF-β1 remains complexed with fortilin in human serum. Both bio-layer interferometry and surface plasmon resonance (SPR) reveal that fortilin directly bind TGF-β1. The SPR analysis also reveals that fortilin and the TGF-β receptor II (TGFβRII) compete for TGF-β1. Both luciferase and secreted alkaline phosphatase reporter assays show that fortilin prevents TGF-β1 from activating Smad3 binding to Smad-binding element. Fortilin inhibits the phosphorylation of Smad3 in both quantitative western blot assays and ELISA. Finally, fortilin inhibits TGFβ-1-induced differentiation of C3H10T1/2 mesenchymal progenitor cells to smooth muscle cells. A computer-assisted virtual docking reveals that fortilin occupies the pocket of TGF-β1 that is normally occupied by TGFβRII and that TGF-β1 can bind either fortilin or TGFβRII at any given time. These data support the role of extracellular fortilin as a negative regulator of the TGF-β1 signaling pathway. Fortilin prevents the activation of the TGF-β1 receptor by occupying the pocket of TGF-β1 and competing with TGF-βRII to bind with TGF-β1. This inhibits Smad3 phosphorylation and the differentiation of C3H10T1/2 mesenchymal progenitor cells to smooth muscle cells.
Article
Full-text available
The current study investigated the role of combination therapy with voacamine and vincristine in preventing mammary gland carcinoma through prolyl hydroxylase-2 activation. Prolyl hydroxylase-2 activation leads to the downregulation of hypoxia-inducible factor-1α and fatty acid synthase. Overexpression of hypoxia-inducible factor-1α and fatty acid synthase has been previously reported in solid tumors of the mammary gland. After screening a battery of natural compounds similar to vincristine, voacamine was selected as a possible prolyl hydroxylase-2 activator, and its activity was evaluated using a 7,12-dimethylbenz[a]anthracene-induced rat model. The combination therapy was evaluated for cardiac toxicity using a hemodynamic profile. Angiogenic markers were evaluated by carmine staining. Monotherapy and combination therapy were also evaluated for liver and kidney toxicity using hematoxylin and eosin staining. The antioxidant potential was delineated using oxidative stress markers. The serum metabolomic profile was studied using NMR spectroscopy, and the disruption of fatty acids was evaluated using gas chromatography. Western blotting of proteins involved in hypoxic pathways was performed to decipher the action of therapy at the molecular level. Immunoblotting analysis validated that combination therapy has potential toss with prolyl hydroxylase-2 activity and thus initiates proteolytic degradation of hypoxia-inducible factor-1α and its consequent effects. Combination therapy also stimulated programmed cell death (apoptosis) in rapidly dividing cancer cells. The present study explored the role of voacamine inactivation of prolyl hydroxylase-2, which can decrease the overexpression of hypoxia-inducible factor-1α and fatty acid synthase in mammary gland carcinoma cells.
Article
Full-text available
Cell state transitions control the functional behavior of cancer cells. Epithelial-to-mesenchymal transition (EMT) confers cancer stem cell-like properties, enhanced tumorigenicity and drug resistance to tumor cells, while mesenchymal-epithelial transition (MET) reverses these phenotypes. Using high-throughput chemical library screens, retinoids are found to be potent promoters of MET that inhibit tumorigenicity in basal-like breast cancer. Cell state transitions are defined by reprogramming of lipid metabolism. Retinoids bind cognate nuclear receptors, which target lipid metabolism genes, thereby redirecting fatty acids for β-oxidation in the mesenchymal cell state towards lipid storage in the epithelial cell state. Disruptions of key metabolic enzymes mediating this flux inhibit MET. Conversely, perturbations to fatty acid oxidation (FAO) rechannel fatty acid flux and promote a more epithelial cell phenotype, blocking EMT-driven breast cancer metastasis in animal models. FAO impinges on the epigenetic control of EMT through acetyl-CoA-dependent regulation of histone acetylation on EMT genes, thus determining cell states.
Article
Full-text available
Background Diffuse-type gastric cancer (GC) is known to be more aggressive and relatively resistant to conventional chemotherapy. Hence, more optimized treatment strategy is urgently needed in diffuse-type GC. Methods Using a panel of 10 GC cell lines and 3 GC patient-derived cells (PDCs), we identified cell lines with high EMTness which is a distinct feature for diffuse-type GC. We treated GC cells with high EMTness with ramucirumab alone, TGF-β receptor kinase inhibitor (TEW-7197) alone, or in combination to investigate the drug's effects on invasiveness, spheroid formation, EMT marker expression, and tumor-induced angiogenesis using a spheroid-on-a-chip model. Results Both TEW-7197 and ramucirumab treatments profoundly decreased invasiveness of EMT-high cell lines and PDCs. With a 3D tumor spheroid-on-a-chip, we identified versatile influence of co-treatment on cancer cell-induced blood vessel formation as well as on EMT progression in tumor spheroids. The 3D tumor spheroid-on-a-chip demonstrated that TEW-7197 + ramucirumab combination significantly decreased PDC-induced vessel formation. Conclusions In this study, we showed TEW-7197 and ramucirumab considerably decreased invasiveness, thus EMTness in a panel of diffuse-type GC cell lines including GC PDCs. Taken together, we confirmed that combination of TEW-7197 and ramucirumab reduced tumor spheroid and GC PDC-induced blood vessel formation concomitantly in the spheroid-on-a-chip model.
Article
Full-text available
Particular dramatic macromolecule proteins are responsible for various cellular events in our body system. Lipids have recently recognized a lot more attention of scientists for understanding the relationship between lipid and cellular function and human health However, a biological membrane is formed with a lipid bilayer, which is called a P-L-P design. Our body system is balanced through various communicative signaling pathways derived from biological membrane proteins and lipids. In the case of any fatal disease such as cancer, the biological membrane compositions are altered. To repair the biological membrane composition and prevent cancer, dietary fatty acids, such as omega-3 polyunsaturated fatty acids, are essential in human health but are not directly synthesized in our body system. In this review, we will discuss the alteration of the biological membrane composition in breast cancer. We will highlight the role of dietary fatty acids in altering cellular composition in the P-L-P bilayer. We will also address the importance of omega-3 polyun-saturated fatty acids to regulate the membrane fluidity of cancer cells.
Article
Full-text available
Cancer associated fibroblasts (CAF) play a key role in cancer progression and metastasis. Diminished TGFβ response on CAF correlates with poor outcome and recurrence in cancer patients. Mechanisms behind lost TGFβ signaling on CAF are poorly understood, but, utilizing MMTV-PyMT mouse model, we have previously demonstrated that in tumor microenvironment myeloid cells, producing adenosine, contribute to downregulated TGFβ signaling on CAFs. In the current work, we performed serial in vitro studies to investigate the role of adenosine/TGFβ axis in mouse mammary fibroblast functions, i.e., proliferation, protein expression, migration, and contractility. We found that adenosine analog NECA diminished TGFβ-induced CCL5 and MMP9 expression. Additionally, we discovered that NECA completely inhibited effect of TGFβ to upregulate αSMA, key protein of cytoskeletal rearrangements, necessary for migration and contractility of fibroblasts. Our results show that TGFβ increases contractility of mouse mammary fibroblasts and human fibroblast cell lines, and NECA attenuates theses effects. Using pharmacological approach and genetically modified animals, we determined that NECA effects on TGFβ pathway occur via A2A/A2B adenosine receptor—AC—PKA dependent manner. Using isolated CD11b⁺ cells from tumor tissue of CD73-KO and CD39-KO animals in co-culture experiments with ATP and AMP, we confirmed that myeloid cells can affect functions of mammary fibroblasts through adenosine signaling. Our data suggest a novel mechanism of interaction between adenosine and TGFβ signaling pathways that can impact phenotype of fibroblasts in a tumor microenvironment.
Article
Full-text available
Immune checkpoint inhibitors have demonstrated, over the recent years, impressive clinical response in cancer patients, but some patients do not respond at all to checkpoint blockade, exhibiting primary resistance. Primary resistance to PD-1 blockade is reported to occur under conditions of immunosuppressive tumor environment, a condition caused by myeloid derived suppressor cells (MDSCs), and by T cells exclusion, due to increased level of T regulatory cells (Tregs). Since TGF-β activates Tregs, TGF-β inhibitor may overcome primary resistance to anti-PD-1. Indeed, recent mice experiments show that combining anti-PD-1 with anti-TGF-β yields significant therapeutic improvements compared to anti-TGF-β alone. The present paper introduces two cancer-specific parameters and, correspondingly, develops a mathematical model which explains how primary resistance to PD-1 blockade occurs, in terms of the two cancer-specific parameters, and how, in combination with anti-TGF-β, anti-PD-1 provides significant benefits. The model is represented by a system of partial differential equations and the simulations are in agreement with the recent mice experiments. In some cancer patients, treatment with anti-PD-1 results in rapid progression of the disease, known as hyperprogression disease (HPD). The mathematical model can also explain how this situation arises, and it predicts that HPD may be reversed by combining anti-TGF-β to anti-PD-1. The model is used to demonstrate how the two cancer-specific parameters may serve as biomarkers in predicting the efficacy of combination therapy with PD-1 and TGF-β inhibitors.
Article
Full-text available
(1) Background: The transforming growth factor (TGF)-β plays a dual role in liver carcinogenesis. At early stages, it inhibits cell growth and induces apoptosis. However, TGF-β expression is high in advanced stages of hepatocellular carcinoma (HCC) and cells become resistant to TGF-β induced suppressor effects, responding to this cytokine undergoing epithelial–mesenchymal transition (EMT), which contributes to cell migration and invasion. Metabolic reprogramming has been established as a key hallmark of cancer. However, to consider metabolism as a therapeutic target in HCC, it is necessary to obtain a better understanding of how reprogramming occurs, which are the factors that regulate it, and how to identify the situation in a patient. Accordingly, in this work we aimed to analyze whether a process of full EMT induced by TGF-β in HCC cells induces metabolic reprogramming. (2) Methods: In vitro analysis in HCC cell lines, metabolomics and transcriptomics. (3) Results: Our findings indicate a differential metabolic switch in response to TGF-β when the HCC cells undergo a full EMT, which would favor lipolysis, increased transport and utilization of free fatty acids (FFA), decreased aerobic glycolysis and an increase in mitochondrial oxidative metabolism. (4) Conclusions: EMT induced by TGF-β in HCC cells reprograms lipid metabolism to facilitate the utilization of FFA and the entry of acetyl-CoA into the TCA cycle, to sustain the elevated requirements of energy linked to this process.
Article
Full-text available
Cancer, a disease of inappropriate cell proliferation, is strongly interconnected with the cell cycle. All cancers consist of an abnormal accumulation of neoplastic cells, which are propagated toward uncontrolled cell division and proliferation in response to mitogenic signals. Mitogenic stimuli include genetic and epigenetic changes in cell cycle regulatory genes and other genes which regulate the cell cycle. This suggests that multiple, distinct pathways of genetic alterations lead to cancer development. Products of both oncogenes (including cyclin-dependent kinase (CDKs) and cyclins) and tumor suppressor genes (including cyclin-dependent kinase inhibitors) regulate cell cycle machinery and promote or suppress cell cycle progression, respectively. The identification of cyclins and CDKs help to explain and understand the molecular mechanisms of cell cycle machinery. During breast cancer tumorigenesis, cyclins A, B, C, D1, and E; cyclin-dependent kinase (CDKs); and CDK-inhibitor proteins p16, p21, p27, and p53 are known to play significant roles in cell cycle control and are tightly regulated in normal breast epithelial cells. Following mitogenic stimuli, these components are deregulated, which promotes neoplastic transformation of breast epithelial cells. Multiple studies implicate the roles of both types of components—oncogenic CDKs and cyclins, along with tumor-suppressing cyclin-dependent inhibitors—in breast cancer initiation and progression. Numerous clinical studies have confirmed that there is a prognostic significance for screening for these described components, regarding patient outcomes and their responses to therapy. The aim of this review article is to summarize the roles of oncogenic and tumor-suppressive components of the cell cycle in breast cancer progression and prognosis.
Article
Full-text available
Vigil® is a personalized vaccine that enhances tumor neoantigen expression. We investigated for the first time safety and efficacy of Vigil in combination with atezolizumab in relapsed ovarian cancer (OC) patients. This is a randomized, Phase 1 study of Vigil, an autologous tumor tissue transfected vaccine encoding for GMCSF and bi-shRNA-furin thereby creating enhanced immune activation and TGFβ expression control. Part 1 is a safety assessment of Vigil (1 × 10e7 cells/mL/21 days) plus atezolizumab (1200 mg/21 days). Part 2 is a randomized study of Vigil first (Vigil-1st) or atezolizumab first (Atezo-1st) for two cycles followed by the combination of both agents. The primary endpoint of the study was the determination of safety. Twenty-four patients were enrolled in the study; three patients to Part 1 and 21 to Part 2. Patients in Part 1 completed combination therapy without dose-limiting toxicity justifying expansion to Part 2. Twenty-one patients were randomized (1:1) to Part 2 to Vigil-1st (n = 11) or Atezo-1st (n = 10). Grade 3/4 treatment-related adverse events of Atezo-1st vs. Vigil-1st were 17.2% vs. 5.1%. Median overall survival (OS) was not reached (NR) (Vigil-1st) vs. 10.8 months (Atezo-1st) (hazard ratio [HR] 0.33). The exploratory subset analysis of BRCAwt suggested improved OS benefit [NR in Vigil-1st vs. 5.2 months in Atezo-1st, HR 0.16, p 0.027]. The Vigil-1st combination therapy with atezolizumab was safe and results in support continued investigation in BRCAwt patients.
Article
Full-text available
Checkpoint inhibitors offer a promising immunotherapy strategy for cancer treatment; however, due to primary or acquired resistance, many patients do not achieve lasting clinical responses. Recently, the transforming growth factor-β (TGFβ) signaling pathway has been identified as a potential target to overcome primary resistance, although the nonselective inhibition of multiple TGFβ isoforms has led to dose-limiting cardiotoxicities. SRK-181 is a high-affinity, fully human antibody that selectively binds to latent TGFβ1 and inhibits its activation. To support SRK-181 clinical development, we present here a comprehensive preclinical assessment of its pharmacology, pharmacokinetics, and safety across multiple species. In vitro studies showed that SRK-181 has no effect on human platelet function and does not induce cytokine release in human peripheral blood. Four-week toxicology studies with SRK-181 showed that weekly intravenous administration achieved sustained serum exposure and was well tolerated in rats and monkeys, with no treatment-related adverse findings. The no-observed-adverse-effect levels levels were 200 mg/kg in rats and 300 mg/kg in monkeys, the highest doses tested, and provide a nonclinical safety factor of up to 813-fold (based on C max ) above the phase 1 starting dose of 80 mg every 3 weeks. In summary, the nonclinical pharmacology, pharmacokinetic, and toxicology data demonstrate that SRK-181 is a selective inhibitor of latent TGFβ1 that does not produce the nonclinical toxicities associated with nonselective TGFβ inhibition. These data support the initiation and safe conduct of a phase 1 trial with SRK-181 in patients with advanced cancer.
Article
Full-text available
Simple Summary Metabolic reprogramming is an emerging hallmark in cancer. Beside the malignant compartment, the tumor microenvironment also undergoes to a metabolic skewing, contributing to the neoplastic progression and metastasizing process. Growing evidence pointed out a central role for Transforming Growth Factor Beta (TGF-β) as a driver of these metabolic changes in multiple cellular targets in cancer. This review deals with very recent discoveries on TGF-β-mediated metabolic reprogramming of stromal and immune cell population within the tumor microenvironment. In particular, we scrutinized current literature to highlight relevant metabolic checkpoints in the TGF-β cascade that sustain tolerogenic programs in tumors. Abstract Overcoming tumor immunosuppression still represents one ambitious achievement for cancer immunotherapy. Of note, the cytokine TGF-β contributes to immune evasion in multiple cancer types, by feeding the establishment of a tolerogenic environment in the host. Indeed, it fosters the expansion and accumulation of immunosuppressive regulatory cell populations within the tumor microenvironment (TME), where it also activates resident stromal cells and enhances angiogenesis programs. More recently, TGF-β has also turned out as a key metabolic adjuster in tumors orchestrating metabolic pathways in the TME. In this review, we will scrutinize TGF-β-mediated immune and stromal cell crosstalk within the TME, with a primary focus on metabolic programs.
Article
Full-text available
Transforming growth factor-β (TGFβ) family members are structurally and functionally related cytokines that have diverse effects on the regulation of cell fate during embryonic development and in the maintenance of adult tissue homeostasis. Dysregulation of TGFβ family signaling can lead to a plethora of developmental disorders and diseases, including cancer, immune dysfunction, and fibrosis. In this review, we focus on TGFβ, a well-characterized family member that has a dichotomous role in cancer progression, acting in early stages as a tumor suppressor and in late stages as a tumor promoter. The functions of TGFβ are not limited to the regulation of proliferation, differentiation, apoptosis, epithelial–mesenchymal transition, and metastasis of cancer cells. Recent reports have related TGFβ to effects on cells that are present in the tumor microenvironment through the stimulation of extracellular matrix deposition, promotion of angiogenesis, and suppression of the anti-tumor immune reaction. The pro-oncogenic roles of TGFβ have attracted considerable attention because their intervention provides a therapeutic approach for cancer patients. However, the critical function of TGFβ in maintaining tissue homeostasis makes targeting TGFβ a challenge. Here, we review the pleiotropic functions of TGFβ in cancer initiation and progression, summarize the recent clinical advancements regarding TGFβ signaling interventions for cancer treatment, and discuss the remaining challenges and opportunities related to targeting this pathway. We provide a perspective on synergistic therapies that combine anti-TGFβ therapy with cytotoxic chemotherapy, targeted therapy, radiotherapy, or immunotherapy.
Article
Full-text available
Objective: Colorectal cancer (CRC) is the fourth leading cause of death worldwide and there is a need for more specific therapeutic targets and biomarkers for the disease. Transforming growth factor β1-induced transcript 1 (TGFΒ1I1) was reported to be downregulated in CRC tissues; however, the precise roles of TGFΒ1I1 in CRC remain unclear. Patients and methods: The expression of TGFΒ1I1 in CRC cell lines and tissues was assessed by quantitative Polymerase Chain Reaction (qPCR). TGFΒ1I1 was overexpressed in SW620 and RKO cells. Cell viability was analyzed by a CCK-8 assay. The proportion of apoptotic cells was analyzed by flow cytometry. The EdU cell proliferation assay of SW620 and RKO cells after transfection was performed via flow cytometry. The migration potency of SW620 and RKO cells was analyzed using a cell migration assay. A wound healing assay was performed to assess the migration potency of SW620 and RKO cells. The invasion potency of SW620 and RKO cells after TGFΒ1I1 overexpression was analyzed. The protein levels of VEGF, TGF-β, MMP9, p-Smad2/3, N-cadherin, and E-cadherin were analyzed by Western blot. Results: Decreased expression of TGFΒ1I1 was found in CRC tissues and cell lines. Overexpression of TGFΒ1I1 inhibited the proliferation and induced the apoptosis of CRC cells. The overexpression of TGFΒ1I1 inhibited the migration and invasion of CRC cells. We also found that the overexpression of TGFΒ1I1 in CRC cells inhibited the TGF-β pathway and epithelial-mesenchymal transition (EMT) progress. Conclusions: TGFΒ1I1 suppressed cell migration and invasion in CRC by inhibiting the TGF-β pathway and EMT progress.
Article
Full-text available
TGF-β is a multifunctional cytokine that plays an important role in both physiologic and pathologic processes, including cancer. Importantly, TGF-β has a dual role in tumorigenesis, acting as a tumor suppressor or a tumor promoter, depending on the stage of tumor development. The aberrantly upregulated production of TGF-β has been strongly implicated in tumor progression, angiogenesis, and metastasis, as well as immune evasion. Therefore, hyperactivated TGF-β signaling is considered a potential therapeutic target for cancer therapy. Numerous inhibitors of overactivated TGF-β signaling have been developed, and some of them are currently in clinical trials. This review focuses on the TGF-β signaling that contributes to tumor progression and immune evasion in the tumor microenvironment and presents recent achievements on TGF-β signaling inhibition as a single or combined therapeutic approach in cancer therapy.
Article
Full-text available
Transforming growth factor-β (TGF-β) is a multifunctional cytokine that is involved in proliferation, metastasis, and many other important processes in malignancy. Inhibitors targeting TGF-β have been considered by pharmaceutical companies for cancer therapy, and some of them are in clinical trial now. Unfortunately, several of these programs have recently been relinquished, and most companies that remain in the contest are progressing slowly and cautiously. This review summarizes the TGF-β signal transduction pathway, its roles in oncogenesis and fibrotic diseases, and advancements in antibodies and small-molecule inhibitors of TGF-β.
Article
Full-text available
Galectin-9 is one of the key proteins employed by a variety of human malignancies to suppress anti-cancer activities of cytotoxic lymphoid cells and thus escape immune surveillance. Human cancer cells in most cases express higher levels of galectin-9 compared to non-transformed cells. However, the biochemical mechanisms underlying this phenomenon remain unclear. Here we report for the first time that in human cancer as well as embryonic cells, the transcription factors hypoxia-inducible factor 1 (HIF-1) and activator protein 1 (AP-1) are involved in upregulation of transforming growth factor beta 1 (TGF-β1) expression, leading to activation of the transcription factor Smad3 through autocrine action. This process triggers upregulation of galectin-9 expression in both malignant (mainly in breast and colorectal cancer as well as acute myeloid leukaemia (AML)) and embryonic cells. The effect, however, was not observed in mature non-transformed human cells. TGF-β1-activated Smad3 therefore displays differential behaviour in human cancer and embryonic vs non-malignant cells. This study uncovered a self-supporting biochemical mechanism underlying high levels of galectin-9 expression operated by the human cancer and embryonic cells employed in our investigations. Our results suggest the possibility of using the TGF-β1 signalling pathway as a potential highly efficient target for cancer immunotherapy.
Article
Full-text available
Tissues are dynamically shaped by bidirectional communication between resident cells and the extracellular matrix (ECM) through cell-matrix interactions and ECM remodelling. Tumours leverage ECM remodelling to create a microenvironment that promotes tumourigenesis and metastasis. In this review, we focus on how tumour and tumour-associated stromal cells deposit, biochemically and biophysically modify, and degrade tumour-associated ECM. These tumour-driven changes support tumour growth, increase migration of tumour cells, and remodel the ECM in distant organs to allow for metastatic progression. A better understanding of the underlying mechanisms of tumourigenic ECM remodelling is crucial for developing therapeutic treatments for patients.
Article
Full-text available
The immune system uses two distinct defence strategies against infections: microbe-directed pathogen destruction characterized by type 1 immunity¹, and host-directed pathogen containment exemplified by type 2 immunity in induction of tissue repair². Similar to infectious diseases, cancer progresses with self-propagating cancer cells inflicting host-tissue damage. The immunological mechanisms of cancer cell destruction are well defined3–5, but whether immune-mediated cancer cell containment can be induced remains poorly understood. Here we show that depletion of transforming growth factor-β receptor 2 (TGFBR2) in CD4⁺ T cells, but not CD8⁺ T cells, halts cancer progression as a result of tissue healing and remodelling of the blood vasculature, causing cancer cell hypoxia and death in distant avascular regions. Notably, the host-directed protective response is dependent on the T helper 2 cytokine interleukin-4 (IL-4), but not the T helper 1 cytokine interferon-γ (IFN-γ). Thus, type 2 immunity can be mobilized as an effective tissue-level defence mechanism against cancer.
Article
Full-text available
Oncogenic transformation alters lipid metabolism to sustain tumor growth. We define a mechanism by which cholesterol metabolism controls the development and differentiation of pancreatic ductal adenocarcinoma (PDAC). Disruption of distal cholesterol biosynthesis by conditional inactivation of the rate-limiting enzyme Nsdhl or treatment with cholesterol-lowering statins switches glandular pancreatic carcinomas to a basal (mesenchymal) phenotype in mouse models driven by KrasG12D expression and homozygous Trp53 loss. Consistently, PDACs in patients receiving statins show enhanced mesenchymal features. Mechanistically, statins and NSDHL loss induce SREBP1 activation, which promotes the expression of Tgfb1, enabling epithelial-mesenchymal transition. Evidence from patient samples in this study suggests that activation of transforming growth factor β signaling and epithelial-mesenchymal transition by cholesterol-lowering statins may promote the basal type of PDAC, conferring poor outcomes in patients.
Article
Full-text available
Circulating natural killer (NK) cells have been shown to adopt a type 1 innate lymphoid cell (ILC1)-like phenotype in response to TGF-β and secrete VEGF-A when exposed to hypoxia. Although these changes are often considered to be linked attributes of tissue residency, it has yet to be determined if TGF-β and hypoxia work in concert to coordinate NK cellular phenotype and angiogenic potential. Examination of human circulating NK cells treated with TGF-β demonstrated heterogeneity in their potential to adopt an ILC1-like phenotype, as indicated by the upregulation of CD9 and CD103 on only a subset of cells in culture. Culturing NK cells in chronic hypoxia did not induce a similar ILC1-like conversion and did not enhance the degree of conversion for cells exposed to TGF-β. Similarly, hypoxic culture of circulating NK cells induced VEGF-A secretion, but this production was not enhanced by TGF-β. Fluorescent in-situ hybridization flow cytometry demonstrated that hypoxia-induced VEGF-A production was uniform across all NK cells in culture and was not a selective feature of the cellular subset that adopted an ILC1-like phenotype in response to TGF-β. Examination of VEGF-A isoforms demonstrated that hypoxia induces the production of pro-angiogenic VEGF-A isoforms, including VEGF-A165 and VEGF-A121, and does not stimulate any meaningful production of anti-angiogenic isoforms, such as VEGF-Ab transcriptional variants or VEGF-Ax. In summary, TGF-β-mediated ILC1-like conversion and hypoxia-induced VEGF-A production are discrete processes in NK cells and are not part of a linked cellular program associated with tissue residency.
Article
Full-text available
Smad ubiquitin regulatory factor 2 (Smurf2), an essential negative regulator of TGF-β signaling, ubiquitinates TGF-β receptors (TβRs) and Smad proteins, inducing their proteasomal degradation. Smurf2 plays crucial roles in regulating TGF-β signaling and maintaining normal cellular functions and tissue homeostasis; dysfunction of Smurf2 triggers abnormal TGF-β signaling in pathological states. Smurf2 has been reported as a potentially strong candidate for targeting therapies for related diseases. Recent work has begun to focus on the regulation of Smurf2 itself, and emerging evidence indicates that Smurf2 is regulated by post-translational modifications (PTMs) mechanisms. These mechanisms predominantly regulate the expression level and E3 ligase activity of Smurf2, strongly suggesting that this protein contributes to complicated roles under multiple pathophysiological conditions. In this review, we cover some significant and novel mechanisms of the PTMs that potentially control Smurf2 participation in TGF-β signaling, including ubiquitylation, SUMOylation, neddylation, phosphorylation, and methylation in order to provide a broad view of the depth and sophistication of Smurf2 function in TGF-β regulation, as well as perspectives for future therapeutic directions for its associated diseases.
Article
Full-text available
Tumor progression is governed by various growth factors and cytokines in the tumor microenvironment (TME). Among these, transforming growth factor-β (TGF-β) is secreted by various cell types residing in the TME and promotes tumor progression by inducing the epithelial-to-mesenchymal transition (EMT) of cancer cells and tumor angiogenesis. TGF-β comprises three isoforms, TGF-β1, -β2, and -β3, and transduces intracellular signals via TGF-β type I receptor (TβRI) and TGF-β type II receptor (TβRII). For the purpose of designing ligand traps that reduce oncogenic signaling in the TME, chimeric proteins comprising the ligand-interacting ectodomains of receptors fused with the Fc portion of immunoglobulin are often used. For example, chimeric soluble TβRII (TβRII-Fc) has been developed as an effective therapeutic strategy for targeting TGF-β ligands, but several lines of evidence indicate that TβRII-Fc more effectively traps TGF-β1 and TGF-β3 than TGF-β2, whose expression is elevated in multiple cancer types. In the present study, we developed a chimeric TGF-β receptor containing both TβRI and TβRII (TβRI-TβRII-Fc) and found that TβRI-TβRII-Fc trapped all TGF-β isoforms, leading to inhibition of both the TGF-β signal and of TGF-β–induced EMT of oral cancer cells, whereas TβRII-Fc failed to trap TGF-β2. Furthermore, we found that TβRI-TβRII-Fc suppresses tumor growth and angiogenesis more effectively than TβRII-Fc in a subcutaneous xenograft model of oral cancer cells with high TGF-β expression. These results suggest that TβRI-TβRII-Fc may be a promising tool for targeting all TGF-β isoforms in the TME.
Article
Full-text available
Transforming growth factor-β1 (TGF-β1) is highly expressed in the tumor microenvironment and known to play a multifunctional role in cancer progression. In addition, TGF-β1 promotes metastasis by inducing epithelial–mesenchymal transition (EMT) in a variety of tumors. Thus, inhibition of TGF-β1 is considered an important strategy in the treatment of cancer. In most tumors, TGF-β1 signal transduction exhibits modified or non-functional characteristics, and TGF-β1 inhibitors have various inhibitory effects on cancer cells. Currently, many studies are being conducted to develop TGF-β1 inhibitors from non-toxic natural compounds. We aimed to develop a new TGF-β1 inhibitor to suppress EMT in cancer cells. As a result, improved chalcone-like chain CTI-82 was identified, and its effect was confirmed in vitro. We showed that CTI-82 blocked TGF-β1-induced EMT by inhibiting the cell migration and metastasis of A549 lung cancer cells. In addition, CTI-82 reduced the TGF-β1-induced phosphorylation of SMAD2/3 and inhibited the expression of various EMT markers. Our results suggest that CTI-82 inhibits tumor growth, migration, and metastasis.
Article
Full-text available
For poorly immunogenic tumors such as mesothelioma there is an imperious need to understand why antigen-presenting cells such as dendritic cells (DCs) are not prone to supporting the anticancer T cell response. The tumor microenvironment (TME) is thought to be a major contributor to this DC dysfunction. We have reported that the acidic TME component promotes lipid droplet (LD) formation together with epithelial-to-mesenchymal transition in cancer cells through autocrine transforming growth factor-β2 (TGF-β2) signaling. Since TGF-β is also a master regulator of immune tolerance, we have here examined whether acidosis can impede immunostimulatory DC activity. We have found that exposure of mesothelioma cells to acidosis promotes TGF-β2 secretion, which in turn leads to LD accumulation and profound metabolic rewiring in DCs. We have further documented how DCs exposed to the mesothelioma acidic milieu make the anticancer vaccine less efficient in vivo, with a reduced extent of both DC migratory potential and T cell activation. Interestingly, inhibition of TGF-β2 signaling and diacylglycerol O-acyltransferase (DGAT), the last enzyme involved in triglyceride synthesis, led to a significant restoration of DC activity and anticancer immune response. In conclusion, our study has identified that acidic mesothelioma milieu drives DC dysfunction and altered T cell response through pharmacologically reversible TGF-β2-dependent mechanisms.
Article
Full-text available
Transforming growth factor-β (TGF-β) represents an evolutionarily conserved family of secreted polypeptide factors that regulate many aspects of physiological embryogenesis and adult tissue homeostasis. The TGF-β family members are also involved in pathophysiological mechanisms that underlie many diseases. Although the family comprises many factors, which exhibit cell type-specific and developmental stage-dependent biological actions, they all signal via conserved signaling pathways. The signaling mechanisms of the TGF-β family are controlled at the extracellular level, where ligand secretion, deposition to the extracellular matrix and activation prior to signaling play important roles. At the plasma membrane level, TGF-βs associate with receptor kinases that mediate phosphorylation-dependent signaling to downstream mediators, mainly the SMAD proteins, and mediate oligomerization-dependent signaling to ubiquitin ligases and intracellular protein kinases. The interplay between SMADs and other signaling proteins mediate regulatory signals that control expression of target genes, RNA processing at multiple levels, mRNA translation and nuclear or cytoplasmic protein regulation. This article emphasizes signaling mechanisms and the importance of biochemical control in executing biological functions by the prototype member of the family, TGF-β.
Article
Full-text available
Metastasis is the hallmark of cancer that is responsible for the greatest number of cancer-related deaths. Yet, it remains poorly understood. The continuous evolution of cancer biology research and the emergence of new paradigms in the study of metastasis have revealed some of the molecular underpinnings of this dissemination process. The invading tumor cell, on its way to the target site, interacts with other proteins and cells. Recognition of these interactions improved the understanding of some of the biological principles of the metastatic cell that govern its mobility and plasticity. Communication with the tumor microenvironment allows invading cancer cells to overcome stromal challenges, settle, and colonize. These characteristics of cancer cells are driven by genetic and epigenetic modifications within the tumor cell itself and its microenvironment. Establishing the biological mechanisms of the metastatic process is crucial in finding open therapeutic windows for successful interventions. In this review, the authors explore the recent advancements in the field of metastasis and highlight the latest insights that contribute to shaping this hallmark of cancer.
Article
Full-text available
Immunosuppressive entities in the tumor microenvironment (TME) remain a major impediment to immunotherapeutic approaches for a majority of patients with cancer. While the immunosuppressive role of transforming growth factor-β (TGF-β) in the TME is well known, clinical studies to date with anti-TGF-β agents have led to limited success. The bifunctional agent bintrafusp alfa (previously designated M7824) has been developed in an attempt to address this issue. Bintrafusp alfa consists of an IgG 1 targeting programmed death ligand 1 (PD-L1) moiety fused via peptide linkers to the extracellular domain of two TGF-β receptor II molecules designed to ‘trap’ TGF-β in the TME. This agent is able to bring the TGF-β trap to the TME via its anti-PD-L1 component, thus simultaneously attacking both the immunosuppressive PD-L1 and TGF-β entities. A number of preclinical studies have shown bintrafusp alfa capable of (1) preventing or reverting TGF-β-induced epithelial-mesenchymal transition in human carcinoma cells; this alteration in tumor cell plasticity was shown to render human tumor cells more susceptible to immune-mediated attack as well as to several chemotherapeutic agents; (2) altering the phenotype of natural killer and T cells, thus enhancing their cytolytic ability against tumor cells; (3) mediating enhanced lysis of human tumor cells via the antibody-dependent cell-mediated cytotoxicity mechanism; (4) reducing the suppressive activity of T reg cells; (5) mediating antitumor activity in numerous preclinical models and (6) enhancing antitumor activity in combination with radiation, chemotherapy and several other immunotherapeutic agents. A phase I clinical trial demonstrated a safety profile similar to other programmed cell death protein 1 (PD-1)/PD-L1 checkpoint inhibitors, with objective and durable clinical responses. We summarize here preclinical and emerging clinical data in the use of this bispecific and potentially multifunctional agent.
Article
Full-text available
In recent years, CAR-T cell therapy has proven to be a promising approach against cancer. Nonetheless, this approach still faces multiple challenges in eliminating solid tumors, one of which being the immunosuppressive tumor microenvironment (TME). Here we demonstrated that knocking out the endogenous TGFβ receptor II (TGFBR2) in CAR-T cells with CRISPR/Cas9 technology could reduce the induced regulatory T-cell (iTreg) conversion and prevent the exhaustion of CAR-T cells. Meanwhile, TGFBR2 edited CAR-T cells had better in vivo tumor elimination efficacy, both in cell line derived xenograft (CDX) and patient derived xenograft (PDX) solid tumor models, whether administered locally or systemically. In addition, the TGFBR2 edited CAR-T cells could eliminate contralaterally re-inoculated xenografts in mice effectively with an increased proportion of central memory and effector memory subsets. In conclusion, we greatly improved the in vitro and in vivo function of CAR-T cells in TGFβ-rich tumor environments by knocking out endogenous TGFBR2, proposing a new method to improve the efficacy of CAR-T cell therapy for treating solid tumors.
Article
Full-text available
Acidosis, a common characteristic of the tumor microenvironment, is associated with alterations in metabolic preferences of cancer cells and progression of the disease. Here we identify the TGF-β2 isoform at the interface between these observations. We document that acidic pH promotes autocrine TGF-β2 signaling, which in turn favors the formation of lipid droplets (LD) that represent energy stores readily available to support anoikis resistance and cancer cell invasiveness. We find that, in cancer cells of various origins, acidosis-induced TGF-β2 activation promotes both partial epithelial-to-mesenchymal transition (EMT) and fatty acid metabolism, the latter supporting Smad2 acetylation. We show that upon TGF-β2 stimulation, PKC-zeta-mediated translocation of CD36 facilitates the uptake of fatty acids that are either stored as triglycerides in LD through DGAT1 or oxidized to generate ATP to fulfill immediate cellular needs. We also address how, by preventing fatty acid mobilization from LD, distant metastatic spreading may be inhibited. The tumour microenvironment is known to have an acidic pH but how this influences cancer cell phenotype is unclear. Here, the authors show that tumour cells upregulate TGF-β2 under acidosis, which leads to the increased formation of lipid droplets allowing for invasiveness and metastases.
Article
Full-text available
Lactate is a ubiquitous molecule in cancer. In this exploratory study, our aim was to test the hypothesis that lactate could function as an oncometabolite by evaluating whether lactate exposure modifies the expression of oncogenes, or genes encoding transcription factors, cell division, and cell proliferation in MCF7 cells, a human breast cancer cell line. Gene transcription was compared between MCF7 cells incubated in (a) glucose/glutamine-free media (control), (b) glucose-containing media to stimulate endogenous lactate production (replicating some of the original Warburg studies), and (c) glucose-containing media supplemented with L-lactate (10 and 20 mM). We found that both endogenous, glucose-derived lactate and exogenous, lactate supplementation significantly affected the transcription of key oncogenes (MYC, RAS, and PI3KCA), transcription factors (HIF1A and E2F1), tumor suppressors (BRCA1, BRCA2) as well as cell cycle and proliferation genes involved in breast cancer (AKT1, ATM, CCND1, CDK4, CDKN1A, CDK2B) (0.001 < p < 0.05 for all genes). Our findings support the hypothesis that lactate acts as an oncometabolite in MCF7 cells. Further research is necessary on other cell lines and biopsy cultures to show generality of the findings and reveal the mechanisms by which dysregulated lactate metabolism could act as an oncometabolite in carcinogenesis.
Article
Full-text available
A common feature of cancer cells is their ability to rewire their metabolism to sustain the production of ATP and macromolecules needed for cell growth, division and survival. In particular, the importance of altered fatty acid metabolism in cancer has received renewed interest as, aside their principal role as structural components of the membrane matrix, they are important secondary messengers, and can also serve as fuel sources for energy production. In this review, we will examine the mechanisms through which cancer cells rewire their fatty acid metabolism with a focus on four main areas of research. (1) The role of de novo synthesis and exogenous uptake in the cellular pool of fatty acids. (2) The mechanisms through which molecular heterogeneity and oncogenic signal transduction pathways, such as PI3K–AKT–mTOR signalling, regulate fatty acid metabolism. (3) The role of fatty acids as essential mediators of cancer progression and metastasis, through remodelling of the tumour microenvironment. (4) Therapeutic strategies and considerations for successfully targeting fatty acid metabolism in cancer. Further research focusing on the complex interplay between oncogenic signalling and dysregulated fatty acid metabolism holds great promise to uncover novel metabolic vulnerabilities and improve the efficacy of targeted therapies.
Article
Full-text available
High T-cell infiltration in colorectal cancer (CRC) correlates with a favorable disease outcome and immunotherapy response. This, however, is only observed in a small subset of CRC patients. A better understanding of the factors influencing tumor T-cell responses in CRC could inspire novel therapeutic approaches to achieve broader immunotherapy responsiveness. Here, we investigated T cell-suppressive properties of different myeloid cell types in an inducible colon tumor mouse model. The most potent inhibitors of T-cell activity were tumor-infiltrating neutrophils. Gene expression analysis and combined in vitro and in vivo tests indicated that T-cell suppression is mediated by neutrophil-secreted metalloproteinase activation of latent TGFβ. CRC patient neutrophils similarly suppressed T cells via TGFβ in vitro, and public gene expression datasets suggested that T-cell activity is lowest in CRCs with combined neutrophil infiltration and TGFβ activation. Thus, the interaction of neutrophils with a TGFβ-rich tumor microenvironment may represent a conserved immunosuppressive mechanism in CRC.
Article
After several decades, therapeutic cancer vaccines now show signs of efficacy and potential to help patients resistant to other standard-of-care immunotherapies, but they have yet to realize their full potential and expand the oncologic armamentarium. Here, we classify cancer vaccines by what is known of the included antigens, which tumors express those antigens and where the antigens colocalize with antigen-presenting cells, thus delineating predefined vaccines (shared or personalized) and anonymous vaccines (ex vivo or in situ). To expedite clinical development, we highlight the need for accurate immune monitoring of early trials to acknowledge failures and advance the most promising vaccines. Brody and colleagues discuss the current status and potential of cancer vaccines, highlighting challenges and opportunities to advance promising candidates to the clinic.
Article
Immune checkpoint blockade (ICB) has become well-known in cancer therapy, strengthening the body’s anti-tumor immune response rather than directly targeting cancer cells. Therapies targeting immune inhibitory checkpoints, such as PD-1, PD-L1, and CTLA-4, have resulted in impressive clinical responses across different types of solid tumors. However, as with other types of cancer treatments, ICB-based immunotherapy is hampered by both innate and acquired drug resistance. We previously reported the enrichment of gene signatures associated with the wound healing, epithelial-to-mesenchymal, and angiogenesis processes in the tumors of patients with innate resistance to PD-1 checkpoint antibody therapy; we termed these the Innate Anti-PD-1 Resistance (IPRES) signatures. Based on gene signatures, the TGF-β and VEGFA pathways emerge as the dominant drivers of IPRES-associated processes. Here, we review these pathways’ functions, their roles in immunosuppression, and the currently available therapies that target them. We also discuss recent developments in the targeting of TGF-β using a specific antibody class called the trap antibody. The application of trap antibodies opens the promise of localized targeting of the TGF-β and VEGFA pathways within the tumor microenvironment. Such specificity may offer an enhanced therapeutic window that allows suppression of the IPRES processes in the tumor while sparing the normal homeostatic functions of the TGF-β and VEGFA in normal tissues.
Article
Background Gemogenovatucel-T is an autologous tumour cell vaccine manufactured from harvested tumour tissue, which specifically reduces expression of furin and downstream TGF-β1 and TGF-β2. The aim of this study was to determine the safety and efficacy of gemogenovatucel-T in front-line ovarian cancer maintenance. Methods This randomised, double-blind, placebo-controlled, phase 2b trial involved 25 hospitals in the USA. Women aged 18 years and older with stage III/IV high-grade serous, endometrioid, or clear cell ovarian cancer in clinical complete response after a combination of surgery and five to eight cycles of chemotherapy involving carboplatin and paclitaxel, and an Eastern Cooperative Oncology Group status of 0 or 1 were eligible for inclusion in the study. Patients were randomly assigned (1:1) to gemogenovatucel-T or placebo by an independent third party interactive response system after successful screening using randomly permuted block sizes of two and four and stratified by extent of surgical cytoreduction and neoadjuvant versus adjuvant chemotherapy. Gemogenovatucel-T (1 × 10⁷ cells per injection) or placebo was administered intradermally (one per month) for a minimum of four and up to 12 doses. Patients, investigators, and clinical staff were masked to patient allocation until after statistical analysis. The primary endpoint was recurrence-free survival, analysed in the per-protocol population. All patients who received at least one dose of gemogenovatucel-T were included in the safety analysis. The study is registered with ClinicalTrials.gov, NCT02346747. Findings Between Feb 11, 2015, and March 2, 2017, 310 patients consented to the study at 22 sites. 217 were excluded. 91 patients received gemogenovatucel-T (n=47) or placebo (n=44) and were analysed for safety and efficacy. The median follow-up from first dose of gemogenovatucel-T was 40·0 months (IQR 35·0–44·8) and from first dose of placebo was 39·8 months (35·5–44·6). Recurrence-free survival was 11·5 months (95% CI 7·5–not reached) for patients assigned to gemogenovatucel-T versus 8·4 months (7·9–15·5) for patients assigned to placebo (HR 0·69, 90% CI 0·44–1·07; one-sided p=0·078). Gemogenovatucel-T resulted in no grade 3 or 4 toxic effects. Two patients in the placebo group had five grade 3 toxic events, including arthralgia, bone pain, generalised muscle weakness, syncope, and dyspnea. Seven patients (four in the placebo group and three in the gemogenovatucel-T group) had 11 serious adverse events. No treatment-related deaths were reported in either of the groups. Interpretation Front-line use of gemogenovatucel-T immunotherapy as maintenance was well tolerated but the primary endpoint was not met. Further investigation of gemogenovatucel-T in patients stratified by BRCA mutation status is warranted. Funding Gradalis.
Article
Reprogramming of biochemical pathways is a hallmark of cancer cells, and generation of lactic acid from glucose/glutamine represents one of the consequences of such metabolic alterations. Cancer cells export lactic acid out to prevent intracellular acidification, not only increasing lactate levels but also creating an acidic pH in extracellular milieu. Lactate and protons in tumor microenvironment are not innocuous bystander metabolites but have special roles in promoting tumor-cell proliferation and growth. Lactate functions as a signaling molecule by serving as an agonist for the G-protein-coupled receptor GPR81, involving both autocrine and paracrine mechanisms. In the autocrine pathway, cancer cell-generated lactate activates GPR81 on cancer cells; in the paracrine pathway, cancer cell-generated lactate activates GPR81 on immune cells, endothelial cells, and adipocytes present in tumor stroma. The end result of GPR81 activation is promotion of angiogenesis, immune evasion, and chemoresistance. The acidic pH creates an inwardly directed proton gradient across the cancer-cell plasma membrane, which provides driving force for proton-coupled transporters in cancer cells to enhance supply of selective nutrients. There are several molecular targets in the pathways involved in the generation of lactic acid by cancer cells and its role in tumor promotion for potential development of novel anticancer therapeutics.