ArticleLiterature Review

Inflammation and colorectal cancer

August 2009
Current Opinion in Pharmacology 9(4):405-10

DOI:10.1016/j.coph.2009.06.006

Source
PubMed

Authors:

Tel Aviv University

Patients with long-standing inflammatory bowel disease (IBD) have an increased risk of developing colorectal cancer (CRC). However, the underlying mechanisms are not entirely clear. A genetic basis for the increased risk of CRC in IBD patients is only a partial explanation. It is possible that high levels of inflammatory mediators that are produced in this setting may contribute to the development and progression of CRC. Growing evidence supports a role for various cytokines, released by epithelial and immune cells, in the pathogenesis of IBD-associated neoplasia. Two key genes in the inflammatory process, cyclooxygenase-2 (COX-2) and nuclear factor kappaB (NF-kappaB), provide a mechanistic link between inflammation and cancer while other factors such as, TNF-alpha and IL-6-induced signaling have been recently shown to promote tumor growth in experimental models of colitis-associated cancer. This article reviews the pathogenesis of IBD-related CRC and summarizes the molecular mechanisms underlying the development of intestinal neoplasia in the setting of chronic inflammation.

Immunological Insights on Pathogenic Connections between Hepato-Digestive Disorders and Periodontal Conditions

Chapter

Full-text available

Sep 2022

The oral cavity is an integral part of the digestive tract and thus significant diseases, including periodontitis, can have an important impact on the normal nutritional functions of the body. Certain diseases of the hepato-digestive system have an inflammatory component, such as chronic hepatitis, fatty liver disease, or gastric cancer. This inflammatory reaction is mainly driven by pro-inflammatory chemokines. This is also the case for periodontitis, a condition characterized by the inflammation of the supporting tissues of teeth. Thus, significant pathogenic connections mediated by pro-inflammatory chemokines could exist between periodontitis and diseases of the hepato-digestive system.

Chronic Inflammation: Prospective Prevention and/or Control by the Regulation of Nuclear Factor Kappa B with Natural Products as Dietary Supplements

Article

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Jan 2018

Role of melformin and probiotics in the crosstalk between inflammatory bowel disease colorectal cancer and diabetes

Thesis

Dec 2020

Sahar Al Kattar

Background : the co-occurrence of colorectal cancer (CRC), Inflammatory Bowel diseases (IBD) and diabetes mellitus along with inflammation and dysmicrobism has been frequently reported. Several studies shed light on the anti-oncogenic potential of metformin in colorectal carcinogenesis as well as the beneficial effects of probiotics on inflammatory diseases.Aims : this study aimed to demonstrate that metformin in association with probiotics act in a synergic effect in breaking the crosstalk, thus inhibiting CRC progression, improving diabetes and reducing inflammation.Methodology : ninety-six male Balb/c mice, 6-8 weeks old, were divided into 16 control and experimental groups to assess the effect of the different treatments and combinations at the clinical, histological and molecular levels. Pro-inflammatory cytokines IL-6 and TNF- levels were assessed, as well as reactive oxygen and nitrogen species. Moreover, the proliferation index of colocytes was determined by Ki-67 immunohistochemistry.Results : metformin and probiotics showed beneficial outcomes on CRC and diabetes, alone and most importantly in combination. Their effects were exerted by reversing the histopathological alterations and by inhibiting the inflammatory process whereby a downregulation of IL-6 and TNF-α as well as oxidative stress were depicted.Conclusion : the characterization of the effects of probiotics and metformin on CRC and diabetes sheds light on the role of inflammation and microbiota in this crosstalk. Deciphering more the downstream signaling pathways elicited by these compounds will help in developing new effective targeted treatment modalities.

Overdose intake of Neu5Gc triggers colorectal inflammation and alters liver metabolism

Article

Full-text available

Nov 2023

A positive correlation between massive red meat consumption with colorectal cancer had been reported. Given the complexity of meat components, we focused on investigating the role of Neu5Gc in human healthy. Two groups, either feeding with normal and overdose concentration of Neu5Gc for two weeks, to mimic the normal and overconsumption of red meat conditions in human, respectively. The colorectal transcriptomes revealed that Neu5Gc promotes intestinal immune response and identified the hub genes positively correlated with colorectal cancer such as Tnf, Cd19, Muc13, and Nso2,. The colorectal cancer patients have a 25–30% chance of developing liver metastases, thus we sequenced the liver and revealed the role of Neu5Gc in regulating cell metabolism. Moreover, we found that Neu5Gc negatively regulates the expression of Cmah. We conclude that high Neu5Gc intake promotes colorectal inflammatory responses in ApcMin/+ mice, and suppresses colorectal and hepatic metabolic and digestive processes through Cmah inhibition.

Current Treatment Strategies for Inflammatory Bowel Disease Patients at the Risk of Developing Cancer: A Comprehensive Review

Article

Full-text available

Sep 2023

Inflammatory bowel disease (IBD) is a chronic condition that affects the digestive tract and can lead to inflammation and damage to the intestinal lining. IBD patients with cancer encounter difficulties since cancer treatment weakens their immune systems. A multidisciplinary strategy that strikes a balance between the requirement to manage IBD symptoms and the potential effects of treatment on cancer is necessary for effective care of IBD in cancer patients. To reduce inflammation and avoid problems, IBD in cancer patients is often managed by closely monitoring IBD symptoms in conjunction with the necessary medication and surgical intervention. Anti-inflammatory medications, immunomodulators, and biologic therapies may be used for medical care, and surgical options may include resection of the diseased intestine or removal of the entire colon. The current study provides a paradigm for shared decision-making involving the patient, gastroenterologist, and oncologist while considering recent findings on the safety of IBD medicines, cancer, and recurrent cancer risk in individuals with IBD. We hope to summarize the pertinent research in this review and offer useful advice. Keywords: Inflammatory bowel disorder; Cancer; treatment; malignancy; Anti-TNF; therapy; risks; inflammation; immunosuppression

Carboxymethyl Cellulose as a Food Emulsifier: Are Its Days Numbered?

Article

Full-text available

May 2023

Carboxymethyl cellulose use in industry is ubiquitous. Though it is recognized as safe by the EFSA and FDA, newer works have raised concerns related to its safety, as in vivo studies showed evidence of gut dysbiosis associated with CMC’s presence. Herein lies the question, is CMC a gut pro-inflammatory compound? As no work addressed this question, we sought to understand whether CMC was pro-inflammatory through the immunomodulation of GI tract epithelial cells. The results showed that while CMC was not cytotoxic up to 25 mg/mL towards Caco-2, HT29-MTX and Hep G2 cells, it had an overall pro-inflammatory behavior. In a Caco-2 monolayer, CMC by itself increased IL-6, IL-8 and TNF-α secretion, with the latter increasing by 1924%, and with these increases being 9.7 times superior to the one obtained for the IL-1β pro-inflammation control. In co-culture models, an increase in secretion in the apical side, particularly for IL-6 (692% increase), was observed, and when RAW 264.7 was added, data showed a more complex scenario as stimulation of pro-inflammatory (IL-6, MCP-1 and TNF-α) and anti-inflammatory (IL-10 and IFN-β) cytokines in the basal side was observed. Considering these results, CMC may exert a pro-inflammatory effect in the intestinal lumen, and despite more studies being required, the incorporation of CMC in foodstuffs must be carefully considered in the future to minimize potential GI tract dysbiosis.

Incident Crohn’s Disease as a Risk Factor for Colorectal Cancer in the First 10 Years after Diagnosis: A Nationwide Population-Based Study

Article

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Oct 2021

We investigated the risk of colorectal cancer (CRC) in patients with Crohn’s disease (CD) using the claims data of the Korean National Health Insurance during 2006–2015. The data of 13,739 and 40,495 individuals with and without CD, respectively, were analyzed. Hazard ratios (HRs) were calculated using multivariate Cox proportional hazard regression tests. CRC developed in 25 patients (0.18%) and 42 patients (0.1%) of the CD and non-CD groups, respectively. The HR of CRC in the CD group was 2.07 (95% confidence interval (CI), 1.25–3.41). The HRs of CRC among men and women were 2.02 (95% CI 1.06–3.87) and 2.10 (95% CI, 0.96–4.62), respectively. The HRs of CRC in the age groups 0–19, 20–39, 40–59, and ≥60 years were 0.07, 4.86, 2.32, and 0.66, respectively. The HR of patients with late-onset CD (≥40 years) was significantly higher than that of those with early-onset CD (<40 years). CD patients were highly likely to develop CRC. Early-onset CD patients were significantly associated with an increased risk of CRC than matched individuals without CD. However, among CD patients, late-onset CD was significantly associated with an increased risk of CRC.

Advances in molecular mechanisms of inflammatory bowel disease‑associated colorectal cancer (Review)

Article

Full-text available

Apr 2024

The link between inflammation and cancer is well documented and colonic inflammation caused by inflammatory bowel disease (IBD) is thought to be a high-risk factor for the development of colorectal cancer (CRC). The complex crosstalk between epithelial and inflammatory cells is thought to underlie the progression from inflammation to cancer. The present review collates and summarises recent advances in the understanding of the pathogenesis of IBD-associated CRC (IBD-CRC), including the oncogenic mechanisms of the main inflammatory signalling pathways and genetic alterations induced by oxidative stress during colonic inflammation, and discusses the crosstalk between the tumour microenvironment, intestinal flora and host immune factors during inflammatory oncogenesis in colitis-associated CRC. In addition, the therapeutic implications of anti-inflammatory therapy for IBD-CRC were discussed, intending to provide new insight into improve clinical practice.

O-glycoprofiling of Serum Apolipoprotein C-III in Colorectal Cancer

Article

Full-text available

Jan 2024

Background: Aberrant glycosylation is a hallmark of cancer and thereby has an excellent potential for the discovery of novel biomarkers. Impairments in the glycan composition of lipoproteins impact their functional properties and can be associated with various diseases, including cancer. This research is still in its infancy; however, it can lead to the development of new diagnostic and disease stratification approaches as well as therapeutic strategies. Therefore, we aimed to evaluate anomalies in O-glycosylation of apolipoprotein C-III (apoC-III) in colorectal carcinoma (CRC) patients' sera, in comparison with sera from healthy individuals, and assess the disparities of O-glycoforms on apoC-III in CRC. Methods: The choice of patients (n = 42) was based on the same tumor type (adenocarcinoma) and tumor size (T3), without or with inconsiderable lymph node infiltration. Patients with comorbidities were excluded from the study. The control healthy individuals (n = 40) were age- and sex-matched with patients. We used an approach based on the MALDI-TOF MS in linear positive ion mode, allowing simple analysis of O-glycosylation on intact apoC-III molecules in the serum samples directly, without the need for specific protein isolation. This approach enables relatively simple and high-throughput analysis. Results: In CRC patients' sera samples, we observed significantly elevated apoC-III sialylation. Fully sialylated (disialylated) O-glycans had 1.26 times higher relative abundance in CRC samples compared to controls with a p-value of Mann-Whitney U test of 0.0021. Conclusions: We found altered O-glycosylation of apoC-III in the serum of CRC patients. However, it can be non-specific as it may be associated with another process such as ongoing inflammation. Therefore, to establish it as a potential novel non-invasive biomarker for CRC in suspected patients, further studies interrogating the changes in apoC-III O-glycosylation and the robustness of this biomarker need to be performed and evaluated.

Adenosine, bridging chronic inflammation and tumor growth

Article

Full-text available

Oct 2023

Adenosine (Ado) is a well-known immunosuppressive agent that may be released or generated extracellularly by cells, via degrading ATP by the sequential actions of the ectonucleotides CD39 and CD73. During inflammation Ado is produced by leukocytes and tissue cells by different means to initiate the healing phase. Ado downregulates the activation and the effector functions of different leukocyte (sub-) populations and stimulates proliferation of fibroblasts for re-establishment of intact tissues. Therefore, the anti-inflammatory actions of Ado are already intrinsically triggered during each episode of inflammation. These tissue-regenerating and inflammation-tempering purposes of Ado can become counterproductive. In chronic inflammation, it is possible that Ado-driven anti-inflammatory actions sustain the inflammation and prevent the final clearance of the tissues from possible pathogens. These chronic infections are characterized by increased tissue damage, remodeling and accumulating DNA damage, and are thus prone for tumor formation. Developing tumors may further enhance immunosuppressive actions by producing Ado by themselves, or by “hijacking” CD39 ⁺ /CD73 ⁺ cells that had already developed during chronic inflammation. This review describes different and mostly convergent mechanisms of how Ado-induced immune suppression, initially induced in inflammation, can lead to tumor formation and outgrowth.

Uncovering a dose-response relationship between positive fecal immunochemical test (FIT) and all-cause, cardiovascular and cancer-related mortality

Article

Sep 2023
EUR J INTERN MED

Photodynamic Therapy for Inflammatory and Cancerous Diseases of the Intestines: Molecular Mechanisms and Prospects for Application

Article

Full-text available

Sep 2023
INT J BIOL SCI

Photodynamic therapy (PDT) is a minimally invasive treatment that effectively targets cancer and inflammatory diseases. It has gained recognition for its efficacy, low toxicity, and potential for repeated use. Colorectal cancer (CRC) and inflammatory bowel diseases (IBD), including Crohn's disease (CD), and ulcerative colitis (UC), impose a significant burden on global intestinal health, with increasing incidence and prevalence rates. PDT shows promise as an emerging approach for gastrointestinal disease treatment, particularly IBD and CRC. Extensive preclinical research has demonstrated the safety and effectiveness of PDT for IBD and CRC, while clinical studies are currently underway. This review provides an overview of the underlying mechanisms responsible for the anti-inflammatory and anti-tumor effects of PDT, offering insights into the clinical application of PDT in IBD and CRC treatment. It is expected that this review will serve as a valuable reference for future research on PDT for CRC and IBD, contributing to advancements in the treatment of inflammatory and cancerous diseases of the intestines.

Systemic Neutrophil-to-Lymphocyte Ratio as a Prognostic Biomarker for Colon Cancer

Article

Jun 2023
Chirurgia

Prior research linked a high preoperative neutrophil-to-lymphocyte ratio (NLR) to a worse prognosis in individuals with a variety of malignancies. This study aimed to establish the prognostic and predictive usefulness of preoperative NLR in colorectal cancer (CRC) patients and to identify an appropriate cut-off value for the NLR. We enrolled a total of 195 patients that underwent surgery for stage II and III colorectal cancer that required adjuvant chemotherapy as well as stage IV colorectal cancer patients treated with palliative intent. The mean NLR value was 3.42 +- 2.27. We used a receiver operating characteristic curve to estimate the optimum NLR cut-off value at 3. Patients with a NLR value above 3 were classified as high-NLR, while patients with a NLR below 3 were classified as low-NLR; Results Overall survival (OS) and progression-free survival (PFS) were significantly reduced in high-NLR patients. The overall response rate (ORR) was also lower in high-NLR patients. Conclusions Preoperative NLR is an accessible measurement that seems to have prognostic and predictive value in patients with colorectal cancer.

Microbes with higher metabolic independence are enriched in human gut microbiomes under stress

Preprint

Full-text available

May 2023

A wide variety of human diseases are associated with loss of microbial diversity in the human gut, inspiring a great interest in the diagnostic or therapeutic potential of the microbiota. However, the ecological forces that drive diversity reduction in disease states remain unclear, rendering it difficult to ascertain the role of the microbiota in disease emergence or severity. One hypothesis to explain this phenomenon is that microbial diversity is diminished as disease states select for microbial populations that are more fit to survive environmental stress caused by inflammation or other host factors. Here, we tested this hypothesis on a large scale, by developing a software framework to quantify the enrichment of microbial metabolisms in complex metagenomes as a function of microbial diversity. We applied this framework to over 400 gut metagenomes from individuals who are healthy or diagnosed with inflammatory bowel disease (IBD). We found that high metabolic independence (HMI) is a distinguishing characteristic of microbial communities associated with individuals diagnosed with IBD. We trained a classifier using the normalized copy numbers of 33 HMI-associated metabolic modules. Our classifier not only distinguished states of health versus IBD, but it also tracked the recovery of the gut microbiome following antibiotic treatment, suggesting that HMI is a hallmark of microbial communities in stressed gut environments.

Antioxidative Effects of Psychrophytes Against Cold Induced Paw oedema; An In Vivo And In Vitro Approach

Article

Full-text available

May 2023

Oxidative stress ensues when disturbance occurs between body's antioxidants and reactive oxygen species ROS and this imbalance ushers in a series of ailments and other deleterious side effects. Antioxidants are cell's defense against the ROS as they can either quench their thirst of electrons or can impede the whole chain reaction. Plants possess plethora of secondary metabolites and are a renowned source of antioxidants because of the aforementioned compounds. The point of present research was to investigate the in vivo and in vitroantioxidant effects of aqueous extracts of roots and leaves of psychrophytes (plants that grow below 0°C), Bergenia ciliata, Crassula pellucida, Ruta chalapensis, Rumex nepalensis, Palhinhaea cernua, Sedum forsterianum and Pinus roxburghii obtained from Minimerg, Pakistan on Dry Ice-Induced Paw inflammation in Albino Wistar Rats. DPPH radical scavenging activity was done along with antioxidant enzymes levels which include catalase, cyclooxygenase-2 (COX-2), superoxide dismutase (SOD), interleukin-6 (IL-6) and nitric oxide (NO2). Statistically, regarding DPPH radical scavenging activity % age inhibition was maximum of 91.88% for leaves of P.cernua and minimum 29.34 % for leaves of P.roxburghii at the same concentration (100µL). % age DPPH inhibition was also observed to increase with increasing concentration. Catalase activity was maximum for leaf extracts of S.forsterianum (16.26 U/ml) and minimum for leaf extract of B.ciliata (8.27 U/ml). SOD was maximum for roots of P.roxburghii(50.26 U/ml) and minimum for roots of C.pellucida (10.47U/ml). NO2 activity was maximally inhibited by roots of B.ciliata (0.546 µmol/L) while it was minimally inhibited by roots of P.cernua and R. chalepensis (1.788 µmol/L both). Maximum COX-2 inhibition was seen in the in the leaf extracts of S. forsterianum (23.25 U/ml); while minimum COX-2 inhibition was observed in the leaf extract of C.pellucida (70.98 U/ml). As far as IL-6 is concerned, maximum inhibition of Interleukin-6 (IL-6) was demonstrated by root extracts of S.forsterianum(32.50 May 2023 | 26 pg/L), while minimum inhibition of (IL-6) was demonstrated by root extracts of C.pellucida (180.00pg/L)These crude extracts could be purified and can be a beneficial source of antioxidants.

Probiotics as a Therapeutic Approach in Colorectal Cancer

Article

Apr 2023
CURR CANCER DRUG TAR

Colorectal cancer (CRC) is a growing concern worldwide. In recent decades, the incidence of CRC has increased, and this has been attributed to changes in lifestyle. The lack of physical activity, smoking habits, and a diet high in red meat and fat and low in fiber are important aspects of these deleterious changes in lifestyle. The increase in the incidence of CRC has impelled researchers to investigate methods for preventing and treating CRC with greater efficacy and fewer complications. Probiotics are an attractive and potentially promising therapeutic approach. They have been evaluated by a large number of preclinical and clinical studies in recent years, and it has been found that they can play a role in the prevention, treatment, and management of complications of CRC. This review provides a concise summary of the mechanisms of action of probiotics. Furthermore, it focuses on the results of clinical and preclinical studies that evaluated probiotics' effects on CRC management. It also discusses the effects of different strains of probiotics and their combination in CRC treatment.

Use of Systemic Therapies for Treatment of Psoriasis in Patients with a History of Treated Solid Tumours: Inference-Based Guidance from a Multidisciplinary Expert Panel

Article

Full-text available

Mar 2023

Plain Language Summary Patients with previously treated cancer have a higher chance of cancer recurrence compared with the general population. With cancer incidence rising worldwide, doctors across medical specialities will need to treat other medical conditions, including inflammatory diseases such as psoriasis, in these patients. Effective systemic therapies for psoriasis reduce immune cell activity. Accordingly, there are concerns that treatments for psoriasis could worsen cancer recurrence/progression and infectious complications. There is not enough quality evidence to make broad recommendations for treating other inflammatory conditions in patients with a history of cancer. To guide patient and doctor discussions, we asked: what are effective and safe treatments when patients with treated solid tumours need systemic therapy (pills or injections) for their psoriasis? We focused on patients with solid tumours and excluded blood and skin cancers. Our panel of experts, including 12 dermatologists and 3 medical oncologists, reviewed direct and indirect evidence to answer this question. Considering the totality of evidence reviewed, the expert panel drafted and rated their level of support for opinion statements on important considerations in treating patients with psoriasis who have a history of solid tumours. By making inferences on systemic psoriasis therapies in this heterogeneous population, we take the onus off individual physicians to review the indirect data. This process may help answer questions in other disease populations where direct evidence is scarce or absent. To support treatment decisions, doctors should have a guided conversation with the patient and their family on a case-by-case basis about the risks and benefits of treatment.

Antitumor activity of triazine mimic antibiotics for DNA-binding implications (impressive activity in vitro against a variety of tumor types in the NCI-60 screen): NSC 710607 to fight HCT-116 human colon carcinoma cell lines in vivo using the hollow fiber assay and xenograft mouse models

Article

Full-text available

Feb 2023
J CANCER RES CLIN

Jarosław Spychała

Purpose Successful clinical applications of DNA-directed selective cytotoxic agents disrupt the vital replication/transcription processes and ultimately lead to cancer cell death. This study aimed to examine the growth screen of two lead triazine compounds in a number of cell lines and xenografts and to develop anticancer agents with noncovalent binding affinity bringing fewer side effects. Methods The NCI initial hollow fiber test was performed using an established procedure. The cytostatic and cytocidal capacities of the test compounds were assessed by evaluating cytotoxicity by simply performing a standard cellular viability assay. The nude mouse human tumor xenograft system was used as an in vivo model. Results More sensitive drug with sub-micromolar activity met the interdisciplinary criteria for testing and was referred to evaluations in subcutaneous colorectal carcinoma HCT-116 human tumor xenografted into nude mice. Principal findings of the study: total cytostasis, almost nontoxic schedules, specific working hypotheses, strong rationale for the potential use, and important general implications (relevance to human biology). NSC 710607 displayed in vivo better than Cisplatin and 5-fluorouracil abilities to significantly decrease tumor growth. Conclusion Cell proliferation can be reduced or stopped in vivo in view of the xenograft results. The mimic molecule behaves as DNA-binding antitumor antibiotics with great potential as general anticancer agents and deserves further trials. NSC 710607 represents the result of a design strategy with outstanding potential. This study also identifies the prognostic significance and is likely to translate to other species or systems.

Urinary Measurement of Epigenetic DNA Modifications and 8-oxodG as Possible Noninvasive Markers of Colon Cancer Evolution

Article

Full-text available

Nov 2022
INT J MOL SCI

The active DNA demethylation mechanism involves 5-methylcytosine (5-mCyt) enzymatic oxidation with the subsequent formation of 5-hydroxymethylcytosine (5-hmCyt), which can be further oxidized to 5-formylcytosine (5-fCyt) and 5-carboxylcytosine (5-caCyt). The products of active DNA demethylation are released into the bloodstream and eventually also appear in urine. We used online two-dimensional ultraperformance liquid chromatography with tandem mass spectrometry (2D-UPLC-MS/MS) to compare DNA methylation marks and 8-oxo-2′-deoxyguanosine (8-oxodG) in colorectal cancer and pre-cancerous condition in urine. The study included four groups of subjects: healthy controls, patients with inflammatory bowel disease (IBD), persons with adenomatous polyps (AD), and individuals with colorectal cancer (CRC). We have found that the level of 5-fCyt in urine was significantly lower for CRC and polyp groups than in the control group. The level of 5-hmCyt was significantly higher only in the CRC group compared to the control (2.3 vs. 2.1 nmol/mmol creatinine). Interestingly, we have found highly statistically significant correlation of 5-hydroxymethyluracil with 5-hydroxymethylcytosine, 5-(hydroxymethyl)-2′-deoxycytidine, 5-(hydroxymethyl)-2′-deoxyuridine, and 5-methyl-2′-deoxycytidine in the CRC patients’ group.

Interaction of Dietary Fatty Acids with Tumour Necrosis Factor Family Cytokines during Colon Inflammation and Cancer

Article

Full-text available

Apr 2014

Intestinal homeostasis is precisely regulated by a number of endogenous regulatory molecules but significantly influenced by dietary compounds. Malfunction of this system may result in chronic inflammation and cancer. Dietary essential n-3 polyunsaturated fatty acids (PUFAs) and short-chain fatty acid butyrate produced from fibre display anti-inflammatory and anticancer activities. Both compounds were shown to modulate the production and activities of TNF family cytokines. Cytokines from the TNF family (TNF-, TRAIL, and FasL) have potent inflammatory activities and can also regulate apoptosis, which plays an important role in cancer development. The results of our own research showed enhancement of apoptosis in colon cancer cells by a combination of either docosahexaenoic acid (DHA) or butyrate with TNF family cytokines, especially by promotion of the mitochondrial apoptotic pathway and modulation of NF B activity. This review is focused mainly on the interaction of dietary PUFAs and butyrate with these cytokines during colon inflammation and cancer development. We summarised recent knowledge about the cellular and molecular mechanisms involved in such effects and outcomes for intestinal cell behaviour and pathologies. Finally, the possible application for the prevention and therapy of colon inflammation and cancer is also outlined.

Pou3f1 mediates the effect of Nfatc3 on ulcerative colitis-associated colorectal cancer by regulating inflammation

Article

Full-text available

Sep 2022

Background Ulcerative colitis-associated colorectal cancer (UC-CRC) is an important complication of ulcerative colitis. Pou3f1 (POU class 3 homeobox 1) is a critical regulator for developmental events and cellular biological processes. However, the role of Pou3f1 in the development of UC-CRC is unclear. Methods In vivo, a UC-CRC mouse model was induced by azoxymethane (AOM) and dextran sulfate sodium (DSS). Body weight, colon length, mucosal damage, tumor formation, and survival rate were assessed to determine the progression of UC-CRC. Western blot, quantitative real-time PCR, ELISA, immunohistochemistry, immunofluorescence and TUNEL were performed to examine the severity of inflammation and tumorigenesis. In vitro, LPS-treated mouse bone marrow-derived macrophages (BMDMs) and RAW264.7 cells were used to study the role of Pou3f1 in inflammation. ChIP and luciferase reporter assays were used to confirm the interaction between Nfatc3 and Pou3f1. Results Pou3f1 expression was increased in the colons of UC-CRC mice, and its inhibition attenuated mucosal injury, reduced colon tumorigenesis and increased survival ratio. Knockdown of Pou3f1 suppressed cell proliferation and increased cell death in colon tumors. Both the in vivo and in vitro results showed that Pou3f1 depletion reduced the production of proinflammation mediators. In addition, ChIP and luciferase reporter assays demonstrated that Nfatc3 directly bound with the Pou3f1 promoter to induce its expression. The effect of Nfatc3 on the inflammatory response in macrophages was suppressed by Pou3f1 knockdown. Conclusion Overall, it outlines that Pou3f1 mediates the role of Nfatc3 in regulating macrophage inflammation and carcinogenesis in UC-CRC development.

Supplementation with High or Low Iron Reduces Colitis Severity in an AOM/DSS Mouse Model

Article

Full-text available

May 2022

The relationship between colitis-associated colorectal cancer (CAC) and the dysregulation of iron metabolism has been implicated. However, studies on the influence of dietary iron deficiency on the incidence of CAC are limited. This study investigated the effects of dietary iron deficiency and dietary non-heme iron on CAC development in an azoxymethane/dextran sodium sulfate (AOM/DSS) mouse model. The four-week-old mice were divided into the following groups: iron control (IC; 35 ppm iron/kg) + normal (NOR), IC + AOM/DSS, iron deficient (ID; <5 ppm iron/kg diet) + AOM/DSS, and iron overload (IOL; approximately 2000 ppm iron/kg) + AOM/DSS. The mice were fed the respective diets for 13 weeks, and the AOM/DSS model was established at week five. FTH1 expression increased in the mice’s colons in the IC + AOM/DSS group compared with that observed in the ID and IOL + AOM/DSS groups. The reduced number of colonic tumors in the ID + AOM/DSS and IOL + AOM/DSS groups was accompanied by the downregulated expression of cell proliferation regulators (PCNA, cyclin D1, and c-Myc). Iron overload inhibited the increase in the expression of NF-κB and its downstream inflammatory cytokines (IL-6, TNFα, iNOS, COX2, and IL-1β), likely due to the elevated expression of antioxidant genes (SOD1, TXN, GPX1, GPX4, CAT, HMOX1, and NQO1). ID + AOM/DSS may hinder tumor development in the AOM/DSS model by inhibiting the PI3K/AKT pathway by increasing the expression of Ndrg1. Our study suggests that ID and IOL diets suppress AOM/DSS-induced tumors and that long-term iron deficiency or overload may negate CAC progression.

Berberine as a Potential Agent for the Treatment of Colorectal Cancer

Article

Full-text available

Apr 2022

Colorectal cancer (CRC) is one of the most commonly diagnosed and deadly malignancies worldwide. The incidence of CRC has been increasing, especially in young people. Although great advances have been made in managing CRC, the prognosis is unfavorable. Numerous studies have shown that berberine (BBR) is a safe and effective agent presenting significant antitumor effects. Nevertheless, the detailed underlying mechanism in treating CRC remains indistinct. In this review, we herein offer beneficial evidence for the utilization of BBR in the management and treatment of CRC, and describe the underlying mechanism(s). The review emphasizes several therapeutic effects of BBR and confirms that BBR could suppress CRC by modulating gene expression, the cell cycle, the inflammatory response, oxidative stress, and several signaling pathways. In addition, BBR also displays antitumor effects in CRC by regulating the gut microbiota and mucosal barrier function. This review emphasizes BBR as a potentially effective and safe drug for CRC therapy.

Potential Role of Intracranial Mast Cells in Neuroinflammation and Neuropathology Associated with Food Allergy

Article

Full-text available

Feb 2022

Mast cells (MCs) are the major effector cells of allergic responses and reside throughout the body, including in the brain and meninges. Previously, we showed in a mouse model of subclinical cow’s milk allergy that brain MC numbers were elevated in sensitized mice. However, the neurophysiological consequences of intracranial MC accumulation and activation are unclear. We hypothesized that centrally recruited MCs in sensitized mice could be activated by the allergen via the IgE/FcεRI mechanism and increase the blood–brain barrier (BBB) permeability to promote neuroinflammation. Furthermore, we suspected that repeated allergen exposure could sustain MC activation. To investigate our hypothesis, we sensitized C57BL6/J mice to a bovine whey allergen, β-lactoglobulin (BLG), and subsequently placed them on a whey-containing diet for two weeks. MC activity and associated changes in the brain were examined. BLG-sensitized mice showed mobility changes and depression-like behavior with significantly increased MC numbers and histamine levels in select brain regions. IgG extravasation and perivascular astrogliosis were also evident. Importantly, myelin staining revealed cortical demyelination in the BLG-sensitized mice, suggesting a potential neural substrate for their behavioral changes. Our findings support the ability of brain MCs to release histamine and other mediators to increase BBB permeability and facilitate neuroinflammatory responses in the brain.

An Integrative Approach to Characterize the Early Phases of Dimethylhydrazine-Induced Colorectal Carcinogenesis in the Rat

Article

Full-text available

Feb 2022

This study aimed to characterize an animal model of colorectal cancer (CRC) in the early stages of disease development. Twenty-nine male Wistar rats were divided into two control groups (CTRL1 and CTRL2), receiving EDTA-saline injections and two induced groups (CRC1 and CRC2), receiving 1,2-dimethylhydrazine (DMH) injections for seven consecutive weeks. CRC1 and CTRL1 were euthanized at the 11th week, while CRC2 and CTRL2 were euthanized at the 17th week. DMH treatment decreased microhematocrit values and IL-6, ghrelin, and myostatin serum levels. Histopathological analysis of intestinal sections showed that DMH-treated rats were characterized by moderate to severe epithelial dysplasia. An adenoma was observed in one animal (CRC2 group), and the presence of inflammatory infiltrate at the intestinal level was primarily observed in DMH-treated animals. DMH also induced Ki-67 immunoexpression. The gut microbiota analysis showed a higher abundance of Firmicutes, Clostridia, Clostridiales, Peptostreptococcaceae, Blautia, Romboutsia, and Clostridium sensu stricto in CRC than CTRL rats, whereas Prevotellaceae, Prevotella, Akkermansia, and Lactobacillus levels were more prevalent in CTRL animals. Our results suggest that this model could be helpful to investigate chemoprevention in the early stages of CRC. Citation: Silva-Reis, R.; Castro Ribeiro, C.; Gonçalves, M.; Ferreira, T.; Pires, M.J.; Iglesias-Aguirre, C.E.; Cortés-Martín, A.; Selma, M.V.; Espín, J.C.; Nascimento-Gonçalves, E.; et al. An Integrative Approach to Characterize the Early Phases of Dimethylhydrazine-Induced Colorectal Carcinogenesis in the Rat.

Changing Metabolic Patterns along the Colorectal Adenoma–Carcinoma Sequence

Article

Full-text available

Jan 2022

Colorectal cancer (CRC) is a major public health burden and one of the leading causes of cancer-related deaths worldwide. Screening programs facilitate early diagnosis and can help to reduce poor outcomes. Serum metabolomics can extract vital molecular information that may increase the sensitivity and specificity of colonoscopy in combination with histopathological examination. The present study identifies serum metabolite patterns of treatment-naïve patients, diagnosed with either advanced adenoma (AA) or CRC in colonoscopy screenings, in the framework of the SAKKOPI (Salzburg Colon Cancer Prevention Initiative) program. We used a targeted flow injection analysis and liquid chromatography-tandem mass spectrometry metabolomics approach (FIA- and LC-MS/MS) to characterise the serum metabolomes of an initial screening cohort and two validation cohorts (in total 66 CRC, 76 AA and 93 controls). The lipidome was significantly perturbed, with a proportion of lipid species being downregulated in CRC patients, as compared to AA and controls. The predominant alterations observed were in the levels of lyso-lipids, glycerophosphocholines and acylcarnitines, but additionally, variations in the quantity of hydroxylated sphingolipids could be detected. Changed amino acid metabolism was restricted mainly to metabolites of the arginine/dimethylarginine/NO synthase pathway. The identified metabolic divergences observed in CRC set the foundation for mechanistic studies to characterise biochemical pathways that become deregulated during progression through the adenoma to carcinoma sequence and highlight the key importance of lipid metabolites. Biomarkers related to these pathways could improve the sensitivity and specificity of diagnosis, as well as the monitoring of therapies.

Periodontal disease as a risk factor for sporadic colorectal cancer: results from COLDENT study

Article

Full-text available

Jan 2022
CANCER CAUSE CONTROL

Colorectal cancer remains the top leading cancer worldwide. Accumulating evidence suggests periodontal pathogens are involved in colorectal carcinogenesis, indicating the need for high-quality epidemiological evidence linking periodontal disease (PD) and colorectal cancer (CRC). Thus, we conducted the first population-based case–control study that was specifically designed to investigate the association between compromised oral health and sporadic CRC. A total of 348 incident cases of colon or rectal cancer, and 310 age and sex frequency-matched controls, from the Montreal island and Laval population participated in the study. Data were collected on PD and on several CRC risk factors using validated questionnaires. A life-course approach was used to document long-term history regarding lifestyle factors. Multivariable unconditional logistic regression analysis was used to estimate the rate ratio (RR) quantifying the association between CRC and PD. Results showed that the rate of new diagnosis of CRC in persons with a positive history of PD was 1.45 times higher than in those with a negative history of PD adjusting for age, sex, BMI, education, income, diabetes, family history of CRC, regular use of non-steroidal anti-inflammatory drugs, lifetime cumulative smoking, lifetime consumption of red meats, processed meats, and alcoholic drinks, and lifetime total physical activity score (adjusted RR = 1.45; 95% CI 1.04–2.01; p = 0.026). Our results support the hypothesis of an association between PD and sporadic CRC risk.

Development and Validation of a Robust Pyroptosis-Related Signature for Predicting Prognosis and Immune Status in Patients with Colon Cancer

Article

Full-text available

Nov 2021

Background. Pyroptosis has been confirmed as a type of inflammatory programmed cell death in recent years. However, the prognostic role of pyroptosis in colon cancer (CC) remains unclear. Methods. Dataset TCGA-COAD which came from the TCGA portal was taken as the training cohort. GSE17538 from the GEO database was treated as validation cohorts. Differential expression genes (DEGs) between normal and tumor tissues were confirmed. Patients were classified into two subgroups according to the expression characteristics of pyroptosis-related DEGs. The LASSO regression analysis was used to build the best prognostic signature, and its reliability was validated using Kaplan–Meier, ROC, PCA, and t-SNE analyses. And a nomogram based on the multivariate Cox analysis was developed. The enrichment analysis was performed in the GO and KEGG to investigate the potential mechanism. In addition, we explored the difference in the abundance of infiltrating immune cells and immune microenvironment between high- and low-risk groups. And we also predicted the association of common immune checkpoints with risk scores. Finally, we verified the expression of the pyroptosis-related hub gene at the protein level by immunohistochemistry. Results. A total of 23 pyroptosis-related DEGs were identified in the TCGA cohort. Patients were classified into two molecular clusters (MC) based on DEGs. Kaplan–Meier survival analysis indicated that patients with MC1 represented significantly poorer OS than patients with MC2. 13 overall survival- (OS-) related DEGs in MCs were used to construct the prognostic signature. Patients in the high-risk group exhibited poorer OS compared to those in the low-risk group. Combined with the clinical features, the risk score was found to be an independent prognostic factor of CC patients. The above results are verified in the external dataset GSE17538. A nomogram was established and showed excellent performance. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses indicated that the varied prognostic performance between high- and low-risk groups may be related to the immune response mediated by local inflammation. Further analysis showed that the high-risk group has stronger immune cell infiltration and lower tumor purity than the low-risk group. Through the correlation between risk score and immune checkpoint expression, T-cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) was predicted as a potential therapeutic target for the high-risk group. Conclusion. The 13-gene signature was associated with OS, immune cells, tumor purity, and immune checkpoints in CC patients, and it could provide the basis for immunotherapy and predicting prognosis and help clinicians make decisions for individualized treatment. 1. Introduction Colon cancer (CC), a common malignancy arising from the digestive system of mankind, exhibited an obviously rising tendency in both morbidity and mortality [1]. Dietary habits, age, obesity, smoking, and lack of physical exercise are well-known risk factors for colon cancer. The most common subtype of colon cancer is colon adenocarcinoma (COAD) which accounts for 98% of newly diagnosed colon cancer cases with a 5-year survival rate of 40–60% [2]. For therapeutic effect, there are still significant individual differences among patients with CC. the reason is not only associated with socioeconomic factors but also associated with individual genetic heterogeneity [3]. Therefore, it is obviously a great challenge to investigate and develop new strategies for the CC early diagnosis, more precision therapy, and predicting prognosis. Currently, the tumor-node-metastasis (TNM) stage, based on anatomical information, is a common tool to evaluate the prognosis of patients. Nevertheless, the great limitation of the TNM stage is that it may not fully consider the genetic heterogeneity within individual tumors. With the development of sequencing technology, there is a deeper understanding of the transcriptomes of tumors. Assessment of KRAS and BRAF mutation status or MSI status is widely used in clinical treatments. This makes CC patients diagnosed in the middle to the late stage have more treatment opportunities than before [4]. However, because of the complexity of the molecular mechanism affecting the prognosis of CC, single gene/factor prediction models are often accompanied by low accuracy. In contrast, polygene-based models tend to show better results in predicting the prognosis of various cancers [5–7]. Therefore, we need a reliable prognostic gene signature to promote individualized therapy and help survival prediction for CC patients. Pyroptosis, also known as cell inflammatory necrosis, is a kind of programmed cell death, which is characterized by the continuous expansion of cells until the rupture of the cell membrane, leading to the release of cell contents and activating a strong inflammatory response [8]. Pyroptosis occurs when activated caspase-1 cleaves the protein gasdermin D, releasing the gasdermin N subunit, which can form a pore in the plasma membrane [9]. Pyroptosis is closely related to a variety of diseases; for tumors, it is a double-edged sword. On the one hand, as an innate immune mechanism, pyroptosis can inhibit the development of tumors, and on the other hand, as a proinflammatory cell death mode, pyroptosis, in turn, provides a suitable microenvironment for tumor growth [10]. The long-term chronic inflammatory response can lead to local tissue dysplasia and thus carcinogenesis. Especially, considering that the presence of a large number of bacteria in the intestine may increase the chance of infection with the occurrence of pyroptosis. Therefore, we hypothesized that pyroptosis might play an important role in the development of colon cancer. Although, up to now, several studies have linked pyroptosis with colon cancer [11–13], there are still few scientific and clinical studies on the correlation between CC and pyroptosis; whether pyroptosis is correlated with CC prognosis and identifies expression characteristics of the key pyroptosis-related genes (PDGs) in CC progression remains largely unknown. Despite significant progress in CC gene signatures, few have considered the use of pyroptosis-related gene characteristics to construct a prognostic signature in CC. Accordingly, we carried out a systematic study on pyroptosis-related genes to explore the expression characteristics of those in normal and tumor tissues and predict the prognosis and immune response of patients by trying to construct a prognostic signature. 2. Materials and Methods 2.1. Acquisition of Data The level 3 RNA-seq data (Workflow Type: HTSeq-FPKM) of 385 COAD patients and the corresponding clinical information were obtained from The Cancer Genome Atlas (TCGA) dataset (https://portal.gdc.cancer.gov/), in which the method of acquisition and application complied with the guidelines and policies. FPKM values were then normalized by log2 (FPKM + 1) for the subsequent analysis. The GSE17538 gene expression profiles were acquired from the Gene Expression Omnibus (GEO: https://www.ncbi.nlm.nih.gov/gds/) database, including exhaustive transcriptome information about 238 cases of colon cancer patients (Platform: GPL570). The original datasets extracted from GSE17538 were normalized with the RMA method. Both TCGA and GEO databases are publicly available; thus, ethical approval is not required for the present study. 2.2. Identification of Differentially Expressed PRGs A total of 33 pyroptosis-related genes were obtained from previous reports [14]. Among them, GSDMA is deleted because there is no annotation information about it in the GPL570 platform. The “limma” package was used to identify DEGs between tumor and adjacent normal tissues in the TCGA cohort with a value <0.05. Heatmap of DEGs was plotted by “pheatmap” package. PPI networks of DEGs were constructed using STRING v11.5 (http://string-db.org/) with default parameters (confidence = 0.4). Pearson’s correlations among DEGs were calculated using “reshape2” package (cutoff = 0.2), and the correlation networks were generated using “igraph” package. The MCODE plug-in in Cytoscape software was used to identify the hub genes of the PPI network. 2.3. PRGs-Based Classifications of CC Patients in the TCGA and GSE17538 Cohorts Unsupervised consensus clustering, an algorithm based on k-means machine learning, was utilized to explore a molecular classification of both the TCGA and GSE17538 CC cohorts based on the expression patterns of PRGs using the “ConsensusClusterPlus” package [15] in R. The optimal number of clusters is determined according to the consensus score and the relative change of the area under the CDF curve of the consensus heatmap. Then, Kaplan–Meier survival analysis was performed to evaluate the prognosis of patients in different MCs. We also performed comparisons of the clinicopathological variables and the difference of tumor immune microenvironment between different clusters of patients to further explore the associations between the PRGs-based MCs and the clinical features or local immune status of CC patients. 2.4. Development and Validation of the PRGs-Based Prognostic Risk Signature We analyzed the differences between patients with different clusters in the TCGA cohort and the GSE17538 cohort to obtain intersecting genes ( < 0.05). Then, based on the TCGA cohort, we used univariate Cox regression analysis to screen the genes related to prognosis by setting a strict significance threshold ( < 0.0001). Afterward, LASSO Cox regression analysis was performed to construct a prognostic signature with minimizing the risk of overfitting. The risk score of the patients is calculated according to the normalized expression level of each gene and corresponding regression coefficient as the following formula: Risk score = ∑ Coefi ∗ Expri. Then, patients were divided into the high-risk group and the low-risk group according to the median risk score. The survival curve was drawn between the high-risk group with the low-risk group by using the “survival” and “survminer” packages of the R software, and the accuracy of the signature is evaluated using the ROC curve. PCA and t-SNE were used for dimensionality reduction analysis to assess the ability to distinguish different risk patients of the risk signature. The stability of the risk signature is verified by the GSE17538 cohort. 2.5. Construction and Validation of a Predictive Nomogram The Cox regression analysis was performed to determine whether the risk score and relevant clinical parameters could be predictors associated with OS for CC patients. Considering the collinearity among the clinical variables, we excluded the T/N/M stage and retained the AJCC stage. Subsequently, based on the results of multivariate Cox regression analysis, a prognostic nomogram was generated to predict 1-year, 2-year, and 3‐year OS of CC patients in the TCGA cohort. The predicted OS of the nomogram against observed survival rates was plotted using the calibration curve. 2.6. Functional Enrichment and Immune Characterization Analysis The “limma” R package was used to identify DEGs between the high-risk and low-risk groups ( < 0.05). Gene Ontology (GO) including biological process (BP), cellular component (CC), and molecular function (MF), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of the DEGs were performed using the “clusterProfiler” R package. In order to compare the immune status between different groups. The “gsva” package was utilized to conduct the ssGSEA to calculate the scores of infiltrating immune cells and to evaluate the activity of immune-related pathways. Estimate, immune, and stromal scores of each patient were calculated with the ESTIMATE algorithm of the “estimate” package [16] to evaluate the difference of immune microenvironment. The correlation between the expression of common immune checkpoints and risk score was analyzed by drawing a correlation matrix diagram. 2.7. Statistical Analysis All statistical analyses were accomplished with R software (v4.0.3). Continuous variables were presented as mean ± standard deviation (SD) as appropriate. Normally and nonnormally distributed variables were analyzed using the unpaired Student’s t-test and the Wilcoxon test, respectively. A hazard ratio (HR) and a 95% confidence interval (CI) were evaluated by univariable and multivariate Cox regression models. The statistical value < 0.05 indicates that the difference is statistically significant (∗ value < 0.05, ∗∗ value < 0.01, ∗∗∗ value < 0.001). 3. Result 3.1. Identification of DEGs between Normal and Tumor Tissues Figure 1 provides an overview of the study flowchart. A total of 39 normal and 398 tumor tissues samples with gene expression were included in the analysis. We found that the majority of the pyroptosis-related genes (23/32, 72%) were significantly differentially expressed between the two groups ( < 0.001). 10 genes are upregulated (CASP8, NOD1, GPX4, CASP4, PJVK, IL6, IL1B, PLCG1, NOD2, and GSDMC) and 13 downregulated (ELANE, CASP5, NLRP7, IL18, NLRP3, NLRC4, PRKACA, NLRP1, GSDMB, CASP9, CASP3, TIRAP, and NLRP2) in tumor tissues. Figure 2(a) shows a heatmap of the expression levels of these genes. To further explore the interactions between the 23 pyroptosis-related DEGs, a PPI network was constructed (Figure 2(b)). The result shows that CASP4, CASP5, and IL18 are at the core of the network. The correlation network containing pyroptosis-related DEGs is presented in Figure 2(c). A total of 11 hub genes including NOD2, CASP4, NOD1, IL18, IL1B, NLRP1, CASP8, NLRC4, IL6, CASP5, and NLRP3 were identified by the MCODE plug-in in Cytoscape software (Figure 2(d)), and their protein levels were verified using the Human Protein Atlas (HPA) database (Figure 3).

TLR4 signaling in the development of colitis-associated cancer and its possible interplay with microRNA-155

Article

Full-text available

Dec 2021

Ulcerative colitis (UC) has closely been associated with an increased risk of colorectal cancer. However, the exact mechanisms underlying colitis-associated cancer (CAC) development remain unclear. As a classic pattern-recognition receptor, Toll like receptor (TLR)4 is a canonical receptor for lipopolysaccharide of Gram-negative bacteria (including two CAC-associated pathogens Fusobacterium nucleatum and Salmonella ), and functions as a key bridge molecule linking oncogenic infection to colonic inflammatory and malignant processes. Accumulating studies verified the overexpression of TLR4 in colitis and CAC, and the over-expressed TLR4 might promote colitis-associated tumorigenesis via facilitating cell proliferation, protecting malignant cells against apoptosis, accelerating invasion and metastasis, as well as contributing to the creation of tumor-favouring cellular microenvironment. In recent years, considerable attention has been focused on the regulation of TLR4 signaling in the context of colitis-associated tumorigenesis. MicroRNA (miR)-155 and TLR4 exhibited a similar dynamic expression change during CAC development and shared similar CAC-promoting properties. The available data demonstrated an interplay between TLR4 and miR-155 in the context of different disorders or cell lines. miR-155 could augment TLR4 signaling through targeting negative regulators SOCS1 and SHIP1; and TLR4 activation would induce miR-155 expression via transcriptional and post-transcriptional mechanisms. This possible TLR4-miR-155 positive feedback loop might result in the synergistic accelerating effect of TLR4 and miR-155 on CAC development.

Investigation of the Role of Neurokinin-1 Receptor Inhibition Using Aprepitant in the Apoptotic Cell Death through PI3K/Akt/NF-κB Signal Transduction Pathways in Colon Cancer Cells

Article

Full-text available

Aug 2021
BMRI

Background: Colorectal cancer (CRC) is recognized as one of the most common malignancies with a high mortality rate worldwide, supporting the necessity for an effective novel antitumor drug to improve current therapy's effectiveness. Substance P (SP) is the essential member of the tachykinins (TKs) family, which binds to the specific receptors, known as neurokinin-1 receptor (NK1R), exerting its multiple influences such as tumor cell proliferation, angiogenesis, and metastasis. Aprepitant, as a specific NK1R antagonist, is suggested as a novel antitumor agent, promoting apoptotic processes in tumor cells; however, the exact antitumor mechanism of aprepitant on molecular signaling in CRC is not entirely known. Method: The resazurin assay was conducted to assess the cytotoxic effects of aprepitant on the viability of the CRC cell line (SW480). The level of reactive oxygen species (ROS) was measured after 24-hour treatment with SP and aprepitant. PI/annexin V-FITC staining was conducted to assess apoptosis. Also, the expression of NF-κB antiapoptotic target genes and proapoptotic p53 target genes was measured by real-time- (RT-) PCR assay. Western blotting assay was performed to determine the expression of PI3k/AKT/NF-κB proteins. Results: We found that aprepitant stimulates apoptotic cell death and attenuates the PI3K/Akt pathway and its downstream proapoptotic target gene, including NF-κB in SW480 cells. Also, the obtained results from the quantitative RT-PCR assay showed that aprepitant could decrease the level of mRNA of NF-κB antiapoptotic target genes. Conclusion: Towards this end, this study suggests that SP/NK1R system plays a vital role in the development of CRC, and pharmaceutical targeting of NK1R using aprepitant might be a promising treatment against CRC.

DNA Methylation-Based Estimates of Circulating Leukocyte Composition for Predicting Colorectal Cancer Survival: A Prospective Cohort Study

Article

Full-text available

Jun 2021

Simple Summary Inflammation is involved in the evolution of cancer. Leukocytes, of which the proportion can be estimated using epigenome-wide methylation data, may serve as a prognostic marker in colorectal cancer (CRC). Our aim was to investigate whether DNA methylation-based estimates of circulating leukocytes is associated with all-cause and disease-specific mortality in a prospective CRC patients’ cohort. Significant associations with CRC prognosis were observed for CD4+ T cells, CD8+ T cells, B cells, NK cells, and lymphocytes, independent of age, sex, tumor stage, tumor subsite, and therapy. CD4+ T cells outperformed other leukocytes and provided added predictive value in comparison to age, sex, and tumor stage. Although cell counting is commonly used in clinical practice, DNA methylation-estimated cell proportions could be a promising tool in understanding the role of leukocytes as CRC prognostic biomarkers when using stored blood samples. Abstract Leukocytes are involved in the progression of colorectal cancer (CRC). The proportion of six major leukocyte subtypes can be estimated using epigenome-wide DNA methylation (DNAm) data from stored blood samples. Whether the composition of circulating leukocytes can be used as a prognostic factor is unclear. DNAm-based leukocyte proportions were obtained from a prospective cohort of 2206 CRC patients. Multivariate Cox regression models and survival curves were applied to assess associations between leukocyte composition and survival outcomes. A higher proportion of lymphocytes, including CD4+ T cells, CD8+ T cells, B cells, and NK cells, was associated with better survival, while a higher proportion of neutrophils was associated with poorer survival. CD4+ T cells outperformed other leukocytes in estimating the patients’ prognosis. Comparing the highest quantile to the lowest quantile of CD4+ T cells, hazard ratios (95% confidence intervals) of all-cause and CRC-specific mortality were 0.59 (0.48, 0.72) and 0.59 (0.45, 0.77), respectively. Furthermore, the association of CD4+ T cells and prognosis was stronger among patients with early or intermediate CRC or patients with colon cancer. In conclusion, the composition of circulating leukocytes estimated from DNAm, particularly the proportions of CD4+ T cells, could be used as promising independent predictors of CRC survival.

Intratumor Bacterial Presence and Serum Amyloid A in Colorectal Cancer

Preprint

Full-text available

Apr 2021

Background & Aims: The initiation, development, and progression of many cancers, including colorectal cancer (CRC), are associated with environmental factors. A significant link exists between specific bacterial infections and cancer incidence, with a strong association between chronic infection, chronic inflammation and colorectal carcinogenesis. Recently, we reported significantly increased levels of lipopolysaccharide in CRC patient blood, compared to that of healthy individuals. By analysing CRC tumors, this study aims to contribute to the identification of (novel) markers/factors associated with CRC tumorigenesis. Methods: Colorectal tumor samples from newly diagnosed (histologically confirmed) CRC patients (n = 24) and morphologically normal colon biopsies (n = 10) were collected and analysed in a cross-sectional study. Immunohistochemistry protocols and statistical signal analysis were used to detect specific bacteria and proteins of interest in human colorectal tissue. Furthermore, the presence of structural protein changes in CRC tumor tissues, compared to control tissues, was investigated using the fluorescent amyloidselective Amytracker™ 630 marker and confocal microscopy. Results: We show an intratumor bacterial presence in CRC patients, with high levels of Escherichia coli strongly associated with CRC. High levels of intratumor serum amyloid A are also strongly associated with CRC. Furthermore, Helicobacter pylori is elevated, but to a smaller degree, and only when we account for data imbalance. We also report a significantly enhanced amyloid-specific fluorescence signal in CRC tumors, compared to control tissues. Conclusions: The role that infections play in a variety of cancers, including CRC, is increasingly recognized, and we provide evidence of a bacterial presence in CRC tumors. The analysis of CRC tumors, in addition to CRC blood, offers unique opportunities to investigate factors that may fuel colorectal carcinogenesis, and to ultimately identify novel markers that are associated with CRC.

The anti-breast cancer property of physcion via oxidative stress-mediated mitochondrial apoptosis and immune response

Article

Full-text available

Jan 2021

Context Physcion (Phy) exerts several pharmacological effects including anti-inflammatory, antioxidant, and antitumor properties. Objective This study investigates the cytotoxicity and its underlying mechanisms of Phy on breast cancer. Materials and methods Human breast cancer cell MCF-7 was treated with 5–400 µM Phy for 24 h, MCF-7-xenografted BALB/c nude mice and immunosuppressive mice model induced by cyclophosphamide were intraperitoneally injected with 0.1 mL/mouse normal saline (control group) and 30 mg/kg Phy every other day for 14 or 28 days, and pathological examination, ELISA and western blot were employed to investigate the Phy anti-breast cancer property in vitro and in vivo. Results In MCF-7 cells, Phy 24 h treatment significantly reduced the cell viability at dose of 50–400 µM and 24 h, with an IC50 of 203.1 µM, and 200 µM Phy induced 56.9, 46.9, 36.9, and 46.9% increment on LDH and caspase-3, −8 and −9. In MCF-7-xenograft tumour nude mice and immunosuppressive mice, 30 mg/kg Phy treatment inhibited tumour growth from the 8th day, and reduced Bcl-2 and Bcl-xL >50%, HO-1 and SOD-1 > 70% in tumour tissues of immunosuppressive mice. In addition, Phy reduced nuclear factor erythroid 2-related factor 2 > 30% and its downstream proteins, and enhanced the phosphorylation of nuclear factor-kappa B > 110% and inhibitor of NF-кB α > 80% in the tumour tissues of BALB/c mice. Discussion and conclusions This research demonstrated that Phy has an anti-breast cancer property via the modulation of oxidative stress-mediated mitochondrial apoptosis and immune response, which provides a scientific basis for further research on its clinical applications.

A Functional Food Inhibits Azoxymethane/Dextran Sulfate Sodium-Induced Inflammatory Colorectal Cancer in Mice

Article

Full-text available

Feb 2021

Purpose: This study aimed to investigate the potential antitumor effects and mechanisms underlying the action of a functional food containing 55 different natural food ingredients. Materials and methods: Azoxymethane/dextran sulfate sodium was used to establish a mouse model of colorectal cancer. Serum levels of cytokines, diamine oxidase, D-lactate, and endotoxin were measured using enzyme-linked immunosorbent assays. Immune cells from the mouse spleen and tumor tissue were analyzed by flow cytometry. Finally, 16S rRNA gene sequencing and liquid chromatography-mass spectrometry were used to study the fecal microbiota and microbial metabolites, respectively. Results: The tumor growth was significantly lower in the FFD group than in the model group. The intestinal barrier function, fat mass, and lean body mass were significantly improved in the FFD group compared with the model group. The levels of interleukin-6 and tumor necrosis factor-α were significantly lower in the FFD group, while the proportions of total T cells, CD3+CD4+, CD3+CD8+, and interferon-γ-producing CD4+ T cells were significantly higher. Analysis of the diversity of the gut microbiota identified 60 differential bacterial genera between the FFD and model groups, with lower abundances of Desulfovibrio and unclassified Ruminococcaceae and higher abundances of the beneficial bacterial genera Bacteroides and Parasutterella in the FFD group. The fecal metabolite analysis revealed 635 differential metabolites between the FFD and model groups, with lower levels of deuteroporphyrin IX and citrulline and higher levels of acetic acid and ascorbic acid in the FFD group. Conclusion: Our results demonstrate that the functional food tested can inhibit the growth of colorectal cancer. This effect may be due to the ability of this food to improve nutritional status, enhance intestinal barrier function, and regulate the tumor microenvironment via changes in the intestinal microbiota and metabolites.

Depressive Symptoms, Systemic Inflammation, and Survival Among Patients With Head and Neck Cancer

Article

Mar 2024

Importance Patients with head and neck cancer experience high rates of depression. Depression and systemic inflammation have been found to be associated in numerous cancer types, often independently from disease status. Depression-related inflammation may elevate the risks for poor tumor response to treatment and early mortality, and comprises a mechanism by which depression is associated with survival in head and neck cancer. Objective To assess mediation pathways incorporating pretreatment depressive symptoms, pretreatment inflammation, and tumor response posttreatment on overall survival among patients with head and neck cancer. Design, Setting, and Participants This was a prospective observational cohort study of patients with head and neck cancer treated in a single multidisciplinary head and neck cancer clinic from May 10, 2013, to December 30, 2019, and followed up for 2 years. Data analysis was performed from June 29, 2022, to June 23, 2023. Exposures Patient-reported depressive symptoms using the Patient Health Questionnaire−9 item (PHQ−9) at treatment planning; pretreatment hematology workup for systemic inflammation index (SII) score; and clinical data review for tumor response (complete vs incomplete) and overall survival. Main Outcomes Two-year overall survival. Results The total study cohort included 394 patients (mean [SD] age, 62.5 [11.5] years; 277 [70.3%] males) with head and neck cancer. Among 285 patients (72.3%) who scored below the clinical cutoff for depression on the PHQ−9, depressive symptoms were significantly associated with inflammation (partial r , 0.168; 95% CI, 0.007-0.038). In addition, both depression and inflammation were associated with early mortality (PHQ−9: hazard ratio [HR], 1.04; 95% CI, 1.02-1.07; SII: HR, 1.36; 95% CI, 1.08-1.71). The depression-survival association was fully mediated by inflammation (HR, 1.28; 95% CI, 1.00-1.64). Depressive symptoms were also associated with poorer tumor response (odds ratio, 1.05; 95% CI, 1.01-1.08), and the depression-survival association was partially mediated by tumor response (HR, 9.44; 95% CI, 6.23-14.32). Systemic inflammation was not associated with tumor response. Conclusions In this cohort study, systemic inflammation emerged as a novel candidate mechanism of the association of depression with mortality. Tumor response partially mediated effects of depression on mortality, replicating prior work. Thus, depression stands out as a highly feasible target for renewed clinical attention. Even mild symptoms of depression during the treatment-planning phase may be associated with higher systemic inflammation in addition to poorer tumor response to treatment and survival outcomes; therefore, depression should be clinically addressed.

Mendelian randomization analysis using multiple biomarkers of an underlying common exposure

Article

Mar 2024
BIOSTATISTICS

Mendelian randomization (MR) analysis is increasingly popular for testing the causal effect of exposures on disease outcomes using data from genome-wide association studies. In some settings, the underlying exposure, such as systematic inflammation, may not be directly observable, but measurements can be available on multiple biomarkers or other types of traits that are co-regulated by the exposure. We propose a method for MR analysis on latent exposures (MRLE), which tests the significance for, and the direction of, the effect of a latent exposure by leveraging information from multiple related traits. The method is developed by constructing a set of estimating functions based on the second-order moments of GWAS summary association statistics for the observable traits, under a structural equation model where genetic variants are assumed to have indirect effects through the latent exposure and potentially direct effects on the traits. Simulation studies show that MRLE has well-controlled type I error rates and enhanced power compared to single-trait MR tests under various types of pleiotropy. Applications of MRLE using genetic association statistics across five inflammatory biomarkers (CRP, IL-6, IL-8, TNF-α, and MCP-1) provide evidence for potential causal effects of inflammation on increasing the risk of coronary artery disease, colorectal cancer, and rheumatoid arthritis, while standard MR analysis for individual biomarkers fails to detect consistent evidence for such effects.

Retinoid X Receptor agonists as selective modulators of the immune system for the treatment of cancer

Article

Nov 2023
PHARMACOL THERAPEUT

Rationalizing a prospective coupling effect of cannabinoids with the current pharmacotherapy for melanoma treatment

Article

Nov 2023

Melanoma is one of the leading fatal forms of cancer, yet from a treatment perspective, we have minimal control over its reoccurrence and resistance to current pharmacotherapies. The endocannabinoid system (ECS) has recently been accepted as a multifaceted homeostatic regulator, influencing various physiological processes across different biological compartments, including the skin. This review presents an overview of the pathophysiology of melanoma, current pharmacotherapy used for treatment, and the challenges associated with the different pharmacological approaches. Furthermore, it highlights the utility of cannabinoids as an additive remedy for melanoma by restoring the balance between downregulated immunomodulatory pathways and elevated inflammatory cytokines during chronic skin conditions as one of the suggested critical approaches in treating this immunogenic tumor. This article is categorized under: Cancer > Molecular and Cellular Physiology

Biology of Cancer

Chapter

Apr 2023

Today, treatment options for cancer patients typically include surgery, radiation therapy, immunotherapy, and chemotherapy. While these therapies have saved lives and reduced pain and suffering, cancer still takes millions of lives every year around the world. Researchers are now developing advanced therapeutic strategies such as immunotherapy, targeted therapy, and combination nanotechnology for drug delivery. In addition, the identification of new biomarkers will potentiate early-stage diagnosis. Molecular Targets and Cancer presents information about cancer diagnosis and therapy in a simple way. It covers several aspects of the topic with updated information on par with medical board levels. The book features contributions from experts and includes an overview of cancer from basic biology and pathology, classifications, surveillance, prevention, diagnosis, types of cancer, treatment and prognosis. The first part of this book introduces the reader to cancer epidemiology, genetic alterations in cancer, exogenous and endogenous factors in carcinogenesis, roles for growth factors in cancer progression, cell signaling in cancer, transcription factors in cancer, and cancer genetics and epigenetics. This comprehensive guide is a valuable resource for oncologists, researchers, and all medical professionals who work in cancer care and research.

Association between C-reactive protein-albumin-lymphocyte (CALLY) index and overall survival in patients with colorectal cancer: From the investigation on nutrition status and clinical outcome of common cancers study

Article

Full-text available

Mar 2023

Background Colorectal cancer (CRC) is among the most common malignant cancers worldwide, and its development is influenced by inflammation, nutrition, and the immune status. Therefore, we combined C-reactive protein (CRP), albumin, and lymphocyte, which could reflect above status, to be the CRP-albumin-lymphocyte (CALLY) index, and evaluated its association with overall survival (OS) in patients with CRC. Methods The clinicopathological and laboratory characteristics of 1260 patients with CRC were collected from the Investigation on Nutrition Status and Clinical Outcome of Common Cancers (INSCOC) study. Cox regression analysis was performed to assess the association between the CALLY index and OS. A nomogram including sex, age, the CALLY index and TNM stage was constructed. The Concordance Index (C-index) was utilized to evaluate the prognostic value of the CALLY index and classical CRC prognostic factors, such as modified Glasgow prognostic score (mGPS), neutrocyte to lymphocyte ratio (NLR), systemic immune inflammation index (SII), and platelet to lymphocyte ratio (PLR), as well as to assess the prognostic value of the nomogram and TNM stage. Results Multivariate Cox regression analyses demonstrated that the CALLY index was independently associated with OS in patients with CRC [Hazard ratio (HR) = 0.91, 95% confidence interval (CI) = 0.87-0.95, P <0.001]. The CALLY index showed the highest prognostic value (C-index = 0.666, 95% CI = 0.638-0.694, P <0.001), followed by mGPS, NLR, SII, and PLR. The nomogram demonstrated higher prognostic value (C-index = 0.784, 95% CI = 0.762-0.807, P <0.001) than the TNM stage. Conclusion The CALLY index was independently associated with OS in patients with CRC and showed higher prognostic value than classical CRC prognostic factors. The nomogram could provide more accurate prognostic prediction than TNM stage.

Das Immunsystem und Krebs

Chapter

Mar 2023

Possible role of nutrition in the prevention of Inflammatory Bowel Disease-related colorectal cancer: a focus on human studies

Article

Feb 2023
NUTRITION

Inflammatory bowel disease (IBD) patients are at substantially higher risk of colorectal cancer (CRC) and IBD-associated CRC accounts for roughly 10-15% of the annual mortality in IBD patients. IBD-related CRC also affects younger patients if compared with sporadic CRC, with a 5-year survival rate of 50%. Regardless of medical therapies, the persistent inflammation state characterizing IBD raises the risk for precancerous changes and CRC, with additional input from several elements including genetic and environmental risk factors, IBD-associated comorbidities, intestinal barrier disfunction, and gut microbiota modifications. It is well known that nutritional habits and dietary bioactive compounds can influence IBD-associated inflammation, microbiome abundance and composition, oxidative stress balance, and gut permeability. In addition, in the last years, results from broad epidemiological and experimental studies have associated certain foods or nutritional patterns with the risk of colorectal neoplasia. Here we review the possible role of nutrition in the prevention of IBD-related CRC, focusing specifically on human studies. In conclusion it emerges that nutritional interventions based on healthy, nutrient-dense dietary patterns characterized by a high intake of fiber, vegetables, fruit, Omega-3 PUFAs, and low amount of animal proteins, processed foods and alcohol, combined with probiotic supplementation have the potential of reducing IBD-activity and preventing the risk of IBD-related CRC through different mechanisms, suggesting that targeted nutritional interventions may represent a novel promising approach for the prevention and management of IBD-associated CRC.

Critical signaling pathways governing colitis-associated colorectal cancer: Signaling, therapeutic implications, and challenges

Article

Aug 2022
DIGEST LIVER DIS

Jiang Xin

Long-term colitis in people with inflammatory bowel disease (IBD) may lead to colon cancer called colitis-associated colorectal cancer (CAC). Since the advent of preclinical prototypes of CAC, various immunological messaging cascades have been identified as implicated in developing this disease. The toll-like receptor (TLR)s, Janus kinase (JAK)-signal transducer and activator of transcription (STAT), Nuclear factor-kappa B (NF-κB), mammalian target of rapamycin complex (mTOR), autophagy, and oxidative stress are only a few of the molecular mechanisms that have been recognized as major components to CAC progression. These pathways may also represent attractive medicinal candidates for the prevention and management of CAC. CAC signaling mechanisms at the molecular level and how their dysregulation may cause illness are summarized in this comprehensive overview.

The involvement of gut microbiota in the anti-tumor effect of carnosic acid via IL-17 suppression in colorectal cancer

Article

Aug 2022
CHEM-BIOL INTERACT

Colorectal cancer (CRC) is a malignant tumor that threatens human health worldwide. Disturbance of the gut microbiota caused by various external factors is one of the leading causes. Carnosic acid (CA) is a phenolic diterpene compound, mainly isolated from rosemary plants, with anti-inflammatory and anti-tumor properties. In this study, we aimed to investigate the role of CA in CRC development and its underlying mechanisms in B6/JGpt-Apcem1Cin(min)/Gpt (ApcMin/+) mice based on the analysis of gut microbiota, serum metabolomics, and tumor proteomics. Enzyme-linked immunosorbent assay (ELISA) and Western blot were performed to confirm the changes in cytokine and protein levels related to inflammation after CA administration. CA regulated the abundance of the gut microbiota, which further caused changes in the production of dl-lactic acid. CA suppressed the inflammatory response by reducing the levels of IL-1β, −6, and −17A. Overall, CA showed anti-CRC properties via modulation of gut microbiota and serum metabolites through NF-κB/STAT3 signaling to inhibit IL-17 expression in ApcMin/+ mice. These results provide experimental evidence for the future treatment of CRC with CA.

Cortex periplocae modulates the gut microbiota to restrict colitis and colitis-associated colorectal cancer via suppression of pathogenic Th17 cells

Article

Sep 2022
BIOMED PHARMACOTHER

Aberrant microbe-immune cell interaction is a predisposing factor in inflammatory bowel disease (IBD) and colitis-associated cancer (CAC). Cortex Periplocae is a famous traditional Chinese medicine with putative anti-rheumatoid arthritis and anti-dyspepsia effects. Here, we show that the Periploca sepium periplosides (PePs), a cardiac glycosides-free pregnane glycosides extract from root bark of Cortex Periplocae, alleviates colon inflammation, improves intestinal epithelial barrier function, and prevents colitis-associated tumorigenesis in mice with colitis and CAC. Mechanistically, PePs treatment modulates abnormal gut microbiota composition in model mice, especially enriches an anti-inflammatory commensal bacterium A. muciniphila BAA-835. We further demonstrate that the altered gut microbiota following PePs treatment plays an important role in modulation of intestinal Type 17 immunity in both colitis and CAC mouse model. Our results indicate that PePs may be used as a potential gut microbiota modulator to treat IBD and CAC.

Anti‐inflammatory activities of natural cyclopeptide RA‐XII in colitis‐associated colon cancer mouse model and its effect on gut microbiome

Article

May 2022

Colorectal cancer (CRC), the third most common cancer globally, is associated with intestinal inflammation that leads to poor prognosis. RA‐XII, a natural cyclopeptide, has previously been reported to possess anti‐tumor activities. Here, the anti‐inflammatory activities of RA‐XII were investigated in colitis‐associated colon cancer mice and a co‐culture in vitro model, in which colon cancer cells HCT116 and macrophages RAW264.7 were grown together to mimic the inflammatory microenvironment of CRC. Changes of inflammatory‐related molecules and protein expressions in cells were evaluated after RA‐XII incubation. Besides, azoxymethane and dextran sulfate sodium‐induced colitis‐associated colon cancer mice were treated with RA‐XII for 24 days, inflammatory parameters and gut microbiome alterations were studied. Our results showed that RA‐XII reversed the inflammatory responses of RAW264.7 cells induced by LPS and modulated the protein expressions of AKT, STAT3/p‐STAT3, P70S6K, NF‐κB and GSK3β and suppressed the expression of LC3A/B in HCT116 cells in co‐culture system. RA‐XII treatment restored the colitis damage in colon, reduced colon tumors numbers and decreased inflammatory factors (IL‐6, IL‐10 and TNF‐α). The role of RA‐XII on regulating gut microbiome was also demonstrated for the first time. In conclusion, our findings provided new scientific evidence for developing RA‐XII as a potent anti‐inflammatory agent for CRC.

Oral Delivery of Encapsulated All-Trans Retinoic Acid Ameliorates Disease in Rodent Models of Colitis

Article

Aug 2021

Background All-trans retinoic acid (ATRA) is a biologically active isomer of retinoic acid (RA). Topical ATRA (retin-a, retin-a micro, atralin, renova, and avita) is the active pharmaceutical ingredient for FDA-approved treatments for acne and skin wrinkles. Oral formulations (Vesanoid) treat acute promyelocytic leukemia, but oral dosing can induce severe side effects. Despite benefits in various rodent models of inflammatory bowel disease (IBD), toxicity and controversial clinical observations have diminished enthusiasm for ATRA IBD clinical trials. To circumvent these issues and to use ATRA’s key role in maintaining gut tolerance, we developed a poly(lactic-co-glycolic acid) (PLGA) microsphere (MS) encapsulated ATRA formulation aimed at directing ATRA delivery to immune structures of the gut, limiting systemic exposure. Initially, ATRA MS was developed as a component of a combinatorial product (TreXTAM) that also contained encapsulated transforming growth factor (TGF)-β and ATRA in a 1:2 w/w ratio. Although the combination was optimal, benefit was also observed when ATRA MS was given alone in the CD4+ CD25-T-cell adoptive transfer (ACT) colitis model. Methods We used the ACT and DSS-induced murine models of colitis to expand on the dose-dependent effects of oral ATRA MS when given alone. The DSS model was also used to compare the efficacy of ATRA MS and soluble ATRA, while healthy animals were used to compare the pharmacokinetics of the two drugs. Results In both the ACT and DSS-induced murine models of colitis, ATRA MS was observed to be effective in ameliorating disease. ATRA MS was also observed to be more effective than soluble ATRA in these models and displayed more favorable pharmacokinetics. Conclusions We suggest ATRA MS, as a standalone product, may attenuate IBD and perhaps limit fibrosis, while limiting systemic side effects.

Anti-Inflammatory Molecular Mechanism and Contribution of Drug Transport Molecules in Colorectal Cancer Cells

Chapter

Jun 2021

Colorectal cancer (CRC) is a third most common malignant neoplasm arising from the lining of colon and rectum of the large intestine. The molecular mechanisms provide some fundamental effects and activities of molecules as chemopreventive, anti-inflammatory, and antioxidative agents in CRC. The expressions and regulation of COX-2, HER-2, Oct4, Sox2, p53, MDR1/P-glycoprotein, CXCR4, VEGF-C, etc. are important to understand the anti-inflammatory molecular mechanisms and inhibitory effect on cell growth and in induction of apoptosis in colorectal cancer. Nonsteroidal anti-inflammatory drugs (NSAIDs) and several drug inhibitors can act against colorectal tumorigenesis. The present literature and experimentation provide the precise information on anti-inflammatory molecular mechanisms that regulate apoptosis in colorectal cancer cells and on proliferation and on induction of apoptosis by nonsteroidal anti-inflammatory inhibitors as transport molecules in colorectal cancer cells. The gene superfamilies that are involved in the transport of drugs are the solute carrier (SLC) family and the ATP-binding cassette (ABC) family. The effects of selective COX-2 inhibitors (COXIBs) and nonsteroidal anti-inflammatory drugs (NSAIDs) may be the most promising chemopreventive agents for CRC prevention and treatment.

The therapeutic effect of potentially probiotic Lactobacillus paracasei on dimethylhydrazine induced colorectal cancer in rats

Article

Jun 2021

This study aimed to evaluate the anti-carcinogenic and potential therapeutic effects of probiotic L. paracasei during colon carcinogenesis at the in-vivo model. 60 eight-week-old male Wistar rats were divided into five groups. The effects of L. paracasei B-14 (5 × 1010 CFU/kg/day for 7 consecutive weeks) on colorectal cancer (CRC) induced rats were studied in male Wistar rats treated with 1,2-dimethylhydrazine (30 mg/kg) for 12 weeks. The tumor incidence, number, size, and histopathological investigations, apoptosis occurrence, and cell proliferation were assessed in all groups (treated and control groups) after the end of treatment. Treatment of cancerous rats with L. paracasei decreased the symptoms of CRC like diarrhea, rectal bleeding, hair loss, and wasting. A combination of L. paracasei and 5-FU caused a significant decrease in tumor size and number and increase in total apoptotic cells (51.4%) compared to untreated control (2.1%) and DMH (5.9%) groups. Treatment with L. paracasei showed fewer dysplastic changes in the crypts, low grades of dysplasia and less proliferative and metastatic activity into deeper layers in comparison with DMH-only treated group. The lowest AgNOR counts were observed in combined L. paracasei and 5-FU treated group. Anti-apoptotic and apoptosis-inducing genes were downregulated and upregulated respectively in L. paracasei treated rats. The results of the present study suggest that L. paracasei possesses therapeutic potential for decreasing the progression of colorectal cancer and enhance the anti-tumor effects of 5-FU.

Anticancer potential of small molecule inhibitors of fatty acid amide hydrolase and monoacylglycerol lipase ‐ A mini‐review

Article

Apr 2021

Recently fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) inhibitors have come in a limelight due to their anti‐proliferative potential. Both FAAH and MAGL are the endocannabinoid degrading enzymes that hydrolyze several endogenous ligands, mainly anandamide (AEA) and 2‐arachidonic glycerol (2‐AG), which regulated the various pathophysiological condition of the body like emotion, cognition, energy balance, pain sensation, neuro‐inflammation, and cancer cell proliferation. FAAH and MAGL inhibitors block the metabolism of AEA and 2‐AG, and increases endogenous levels of fatty acid amides, and exert various therapeutic effects including chronic pain, metabolic disorders, psychoses, nausea and vomiting, depression, and anxiety disorders, etc. FAAH and MAGL are primarily neurotherapeutic targets but their contribution to various types of carcinomas are significant. Inhibitors of these enzymes either alone or multi‐target or with supra‐additive effect show the potential effect in ovarian, breast, prostate, and colorectal cancers. This review besides highlighting the role of FAAH and MAGL enzymes in cancer progression provides an update on the anti‐proliferative capabilities of known and newly discovered FAAH and MAGL inhibitors and provides further directions to develop FAAH and MAGL inhibitors as new candidates for cancer therapy.

IL-6 and Stat3 Are Required for Survival of Intestinal Epithelial Cells and Development of Colitis-Associated Cancer

Article

Full-text available

Mar 2009

Colitis-associated cancer (CAC) is the most serious complication of inflammatory bowel disease. Proinflammatory cytokines have been suggested to regulate preneoplastic growth during CAC tumorigenesis. Interleukin 6 (IL-6) is a multifunctional NF-kappaB-regulated cytokine that acts on epithelial and immune cells. Using genetic tools, we now demonstrate that IL-6 is a critical tumor promoter during early CAC tumorigenesis. In addition to enhancing proliferation of tumor-initiating cells, IL-6 produced by lamina propria myeloid cells protects normal and premalignant intestinal epithelial cells (IECs) from apoptosis. The proliferative and survival effects of IL-6 are largely mediated by the transcription factor Stat3, whose IEC-specific ablation has profound impact on CAC tumorigenesis. Thus, the NF-kappaB-IL-6-Stat3 cascade is an important regulator of the proliferation and survival of tumor-initiating IECs.

Cytokines and their relationship to the symptoms and outcome of cancer

Article

Full-text available

Nov 2008

Tumours contain immune cells and a network of pro- and anti-inflammatory cytokines, which collaborate in the development and progression of cancer. Cytokine profiles might prove to be prognostic. The systemic effects of pro-inflammatory cytokines are associated with fatigue, depression and cognitive impairment, and can affect quality of life before, during and after treatment. In people with advanced cancer, pro-inflammatory cytokines are additionally associated with anorexia and cachexia, pain, toxicity of treatment and resistance to treatment. However, physical activity might modify cytokine levels and decrease fatigue in patients with cancer, and might also improve their prognosis.

Cyclooxygenase-2 Inhibitors in Colorectal Cancer Prevention: Point

Article

Full-text available

Sep 2008

Nadir Arber

The limited success of current treatments for most advanced common malignancies highlights the importance of cancer prevention. Clinical trials on cyclooxygenase (COX) inhibitor drugs showed the potential of chemoprevention as a strategy for reducing cancer incidence, although not without associated side effects. The attractiveness of these drugs partly stems from an ability to engage multiple mechanisms of action by their potential to influence multiple components of the carcinogenesis pathway, from initiation to progression. There are two isoforms of the COX enzymes. COX-1 is constitutively expressed in normal tissues and serves as a "housekeeper" of mucosal integrity, whereas COX-2 is an immediate early response gene that is highly inducible by neoplastic and inflammatory stimuli. COX-2 is significantly overexpressed in colorectal neoplasms, making it an attractive therapeutic target. The drug market has been revolutionized by the development of preparations targeted selectively against COX-2, and a proof of concept has been achieved. Chemoprevention of colorectal cancer is already possible with celecoxib, but it is still not the ultimate drug of choice especially because of the cardiovascular risk associated with COX-2 inhibitors. Better patient selection and more effective and safer drugs are needed. Celecoxib is probably best used in a subset of individuals at moderate to high colorectal cancer risk and low risk of cardiovascular disease.

A Genetic Model for Colorectal Tumorigenesis

Article

Full-text available

Jul 1990
CELL

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Cancer in Crohn's disease: Dispelling the myths

Article

Full-text available

Dec 1994

David B Sachar

Accelerated Age-related CpG Island Methylation in Ulcerative Colitis

Article

Full-text available

May 2001

CpG island hypermethylation is a mechanism of gene silencing that can be usurped by neoplastic cells to inactivate undesirable genes. In the colon, hypermethylation often starts in normal mucosa as a function of age and is markedly increased in cancer. To test the hypothesis that subjects at increased risk of colon cancer have higher levels of methylation in their nonneoplastic mucosa, we studied methylation patterns of five genes in the normal and dysplastic mucosa of patients with ulcerative colitis (UC), a condition associated with a marked increased risk of colon cancer. One gene (Mlh1) was unmethylated in all tissues examined. All four remaining genes had low but detectable levels of methylation in the epithelium of UC patients without evidence of dysplasia, and this methylation was not different from non-UC controls. By contrast, all four genes were highly methylated in dysplastic epithelium from high-grade dysplasia (HGD)/cancer patients with UC; methylation in HGD versus controls averaged 40.0% versus 7.4% (P = 0.00003) for ER, 44.0% versus 3.0% (P < 0.00003) for MYOD, 9.4% versus 2.4% (P = 0.03) for p16 exon 1, and 57.5% versus 30.6% (P = 0.01) for CSPG2. Importantly, three of the four genes were also highly methylated in the normal appearing (nondysplastic) epithelium from these same HGD/cancer patients, indicating that methylation precedes dysplasia and is widespread in these patients. Compared with controls, methylation averaged 20.1% versus 7.2% (P = 0.07) for ER, 18.4% versus 3.0% (P < 0.008) for MYOD, and 7.9% versus 2.4% (P = 0.007) for p16 exon 1. These results are consistent with the hypothesis that age-related methylation marks (and may lead to) the field defect that reflects acquired predisposition to colorectal neoplasia. Furthermore, the data suggest that chronic inflammation is associated with high levels of methylation, perhaps as a result of increased cell turnover, and that UC can be viewed as resulting in premature aging of colorectal epithelial cells.

NF-kB in development and progression of human cancer

Article

Full-text available

Jun 2005

The nuclear factor kB (NF-kB) comprises a family of transcription factors involved in the regulation of a wide variety of biological responses. NF-kB plays a well-known function in the regulation of immune responses and inflammation, but growing evidences support a major role in oncogenesis. NF-kB regulates the expression of genes involved in many processes that play a key role in the development and progression of cancer such as proliferation, migration and apoptosis. Aberrant or constitutive NF-kB activation has been detected in many human malignancies. In recent years, numerous studies have focused on elucidating the functional consequences of NF-kB activation as well as its signaling mechanisms. NF-kB has turned out to be an interesting therapeutic target for treatment of cancer.

De Visser KE, Eichten A, Coussens LMParadoxical roles of the immune system during cancer development. Nat Rev Cancer 6(1): 24-37

Article

Full-text available

Feb 2006
NAT REV CANCER

The main function of the mammalian immune system is to monitor tissue homeostasis, to protect against invading or infectious pathogens and to eliminate damaged cells. Therefore, it is surprising that cancer occurs with such a high frequency in humans. Recent insights that have been gained from clinical studies and experimental mouse models of carcinogenesis expand our understanding of the complex relationship between immune cells and developing tumours. Here, we examine the paradoxical role of adaptive and innate leukocytes as crucial regulators of cancer development and highlight recent insights that have been gained by manipulating immune responses in mouse models of de novo and spontaneous tumorigenesis.

Nuclear IKK activity leads to dysregulated Notch-dependent gene expression in colorectal cancer

Article

Full-text available

Feb 2007

Nuclear functions for IκB kinase (IKK), including phosphorylation of histone H3 and nuclear corepressors, have been recently described. Here, we show that IKK is activated in colorectal tumors concomitant with the presence of phosphorylated SMRT (silencing mediator of retinoic acid and thyroid hormone receptor) corepressor that is aberrantly localized in the cytoplasm. In these tumors, IKKα associates to the chromatin of specific Notch targets, leading to the release of SMRT. Abrogation of IKK activity by BAY11-7082 or by expressing dominant negative IKKα restores the association of SMRT with Notch target genes, resulting in specific gene repression. Finally, BAY11-7082 significantly reduces tumor size in colorectal cancer xenografts (CRC-Xs) implanted in nude mice. • hes1 • SMRT • corepressor

Blocking TNF-?? in mice reduces colorectal carcinogenesis associated with chronic colitis

Article

Full-text available

Mar 2008

The inflammatory bowel disease ulcerative colitis (UC) frequently progresses to colon cancer. To understand the mechanisms by which UC patients develop colon carcinomas, we used a mouse model of the disease whereby administration of azoxymethane (AOM) followed by repeated dextran sulfate sodium (DSS) ingestion causes severe colonic inflammation and the subsequent development of multiple tumors. We found that treating WT mice with AOM and DSS increased TNF-alpha expression and the number of infiltrating leukocytes expressing its major receptor, p55 (TNF-Rp55), in the lamina propria and submucosal regions of the colon. This was followed by the development of multiple colonic tumors. Mice lacking TNF-Rp55 and treated with AOM and DSS showed reduced mucosal damage, reduced infiltration of macrophages and neutrophils, and attenuated subsequent tumor formation. WT mice transplanted with TNF-Rp55-deficient bone marrow also developed significantly fewer tumors after AOM and DSS treatment than either WT mice or TNF-Rp55-deficient mice transplanted with WT bone marrow. Furthermore, administration of etanercept, a specific antagonist of TNF-alpha, to WT mice after treatment with AOM and DSS markedly reduced the number and size of tumors and reduced colonic infiltration by neutrophils and macrophages. These observations identify TNF-alpha as a crucial mediator of the initiation and progression of colitis-associated colon carcinogenesis and suggest that targeting TNF-alpha may be useful in treating colon cancer in individuals with UC.

Colitis and cancer: A tale of inflammatory cells and their cytokines

Article

Full-text available

Mar 2008

Chronic inflammatory disorders are often associated with an increased cancer risk. A particularly striking example of the chronic inflammation-cancer link is seen in inflammatory bowel disease, in which chronic colitis or persistent inflammation in the colon is associated with elevated risk of colorectal cancer. Animal models exploring the mechanisms by which inflammation increases the risk of colon cancer have shown that inflammatory cells, through the effects of the cytokines they produce, have a major role in promoting neoplastic transformation. In this issue of the JCI, Popivanova and colleagues demonstrate that TNF-alpha, through its effects on the immune system, plays a critical role in promoting neoplastic transformation in this setting (see the related article beginning on page 560). Importantly, the study also provides evidence that anti-TNF-alpha therapies, which are currently in clinical use, may interrupt the process.

Sigmoidoscopic picture of chronic ulcerative colitis

Article

Crohn's diseases and cancer

Article

Jan 1973

Cicatrizing enteritis (regional enteritis) as a pathologic entity: Analysis of one hundred and twenty cases

Article

The Sigmoidoscopic Picture of Chronic Ulcerative Colitis (Non-Specific)

Article

Aug 1925
AM J MED SCI

Cancer-related inﬂammation

Article

Jul 2008
NATURE

The mediators and cellular effectors of inflammation are important constituents of the local environment of tumours. In some types of cancer, inflammatory conditions are present before a malignant change occurs. Conversely, in other types of cancer, an oncogenic change induces an inflammatory microenvironment that promotes the development of tumours. Regardless of its origin, 'smouldering' inflammation in the tumour microenvironment has many tumour-promoting effects. It aids in the proliferation and survival of malignant cells, promotes angiogenesis and metastasis, subverts adaptive immune responses, and alters responses to hormones and chemotherapeutic agents. The molecular pathways of this cancer-related inflammation are now being unravelled, resulting in the identification of new target molecules that could lead to improved diagnosis and treatment.

Cancer in inflammatory bowel disease

Article

Jan 2008
WORLD J GASTROENTERO

Steven H Itzkowitz Jianlin Xie

Patients with long-standing inflammatory bowel disease (IBD) have an increased risk of developing colorectal cancer (CRC). Many of the molecular alterations responsible for sporadic colorectal cancer, namely chromosomal instability, microsatellite instability, and hypermethylation, also play a role in colitis-associated colon carcinogenesis. Colon cancer risk in inflammatory bowel disease increases with longer duration of colitis, greater anatomic extent of colitis, the presence of primary sclerosing cholangitis, family history of CRC and degree of inflammation of the bowel. Chemoprevention includes aminosalicylates, ursodeoxycholic acid, and possibly folic acid and statins. To reduce CRC mortality in IBD, colonoscopic surveillance with random biopsies remains the major way to detect early mucosal dysplasia. When dysplasia is confirmed, proctocolectomy is considered for these patients. Patients with small intestinal Crohn’s disease are at increased risk of small bowel adenocarcinoma. Ulcerative colitis patients with total proctocolectomy and ileal pouch anal-anastomosis have a rather low risk of dysplasia in the ileal pouch, but the anal transition zone should be monitored periodically. Other extra intestinal cancers, such as hepatobiliary and hematopoietic cancer, have shown variable incidence rates. New endoscopic and molecular screening approaches may further refine our current surveillance guidelines and our understanding of the natural history of dysplasia.

Constitutive NF- B Activation in Colorectal Carcinoma Plays a Key Role in Angiogenesis, Promoting Tumor Growth

Article

May 2009

Nuclear factor kappaB (NF-kappaB) is an important transcription factor in various biological processes. Constitutive NF-kappaB activation has been noted in many tumors, including colorectal cancers. However, the precise role of this activation in colorectal cancer is unclear. Constitutive NF-kappaB activation was evaluated in colorectal cancer tissues and cell lines. To inhibit NF-kappaB activation, we established cancer cells with stable knockdown of IkappaB kinase gamma (NF-kappaB essential modulator), which is the regulatory subunit of the IkappaB kinase complex, by RNA interference. Cell growth and apoptosis were evaluated in wild-type cells (WT) and knocked-down cells (KD). Microarray and protein array analysis were also done. To determine involvement of angiogenesis, human umbilical vein endothelial cells were used. By s.c. transplantation of the cells into nude mice, tumor sizes, vascularity, and chemodrug sensitivity were analyzed. Constitutive NF-kappaB activation was observed in 40% of colorectal cancer tissues and 67% of cell lines. Cell proliferation was not different between WT and KD in vitro, whereas apoptosis mediated by tumor necrosis factor-alpha and 5-fluorouracil were increased in KD. Several angiogenic chemokines were decreased in KD. Human umbilical vein endothelial cells incubated in WT supernatant showed more branch points than in KD, suggesting that constitutive NF-kappaB activation was involved in angiogenesis. Subcutaneous tumor expansion was suppressed to 23% in KD, and vessels were also decreased. By 5-fluoruracil treatment, tumor expansion was suppressed to a greater extent in KD (to 6%) than in WT (to 50%). NF-kappaB inhibition may represent a potent treatment modality in colorectal cancer, especially in cases with constitutive NF-kappaB activation.

gp130-Mediated Stat3 Activation in Enterocytes Regulates Cell Survival and Cell-Cycle Progression during Colitis-Associated Tumorigenesis

Article

Mar 2009

Although gastrointestinal cancers are frequently associated with chronic inflammation, the underlying molecular links have not been comprehensively deciphered. Using loss- and gain-of-function mice in a colitis-associated cancer model, we establish here a link comprising the gp130/Stat3 transcription factor signaling axis. Mutagen-induced tumor growth and multiplicity are reduced following intestinal epithelial cell (IEC)-specific Stat3 ablation, while its hyperactivation promotes tumor incidence and growth. Conversely, IEC-specific Stat3 deficiency enhances susceptibility to chemically induced epithelial damage and subsequent mucosal inflammation, while excessive Stat3 activation confers resistance to colitis. Stat3 has the capacity to mediate IL-6- and IL-11-dependent IEC survival and to promote proliferation through G1 and G2/M cell-cycle progression as the common tumor cell-autonomous mechanism that bridges chronic inflammation to tumor promotion.

Bromberg, J and Wang, TC. Inflammation and cancer: IL-6 and STAT3 complete the link. Cancer Cell 15: 79-80

Article

Mar 2009

There is growing evidence that tumors are sustained and promoted by inflammatory signals from the surrounding microenvironment. Two papers by Grivennikov et al. and Bollrath et al. in this issue of Cancer Cell demonstrate the importance of the interleukin-6 family of proinflammatory cytokines and their downstream effector STAT3 in colitis-associated colon cancer.

Cicatrising enteritis (regional ileitis) as a pathologic entity: Analysis of 120 cases

Article

Jun 1948

Crohn's Disease and Cancer

Article

Dec 1973

A follow-up study of 449 patients with Crohn's enteritis, enterocolitis or colitis showed the incidence of colonorectal cancer to be 20 times greater in these cases than in a control population. Life-table methods were used for analysis, and complete follow-up observation was achieved in 442 (98.4 per cent) of the patients. (N Engl J Med 289:1099–1103, 1973)

Microsatellite Instability in Inflammatory Bowel Disease-associated Neoplastic Lesions Is Associated with Hypermethylation and Diminished Expression of the DNA Mismatch Repair Gene, hMLH1

Article

Oct 2000

Twelve to 15% of sporadic colorectal cancers display defective DNA mismatch repair (MMR), manifested as microsatellite instability (MSI). In this group of cancers, promoter hypermethylation of the MMR gene hMLH1 is strongly associated with, and believed to be the cause of, MSI. A subset of colorectal neoplastic lesions arising in inflammatory bowel disease (IBD) is also characterized by MSI. We wished to determine whether hMLH1 hypermethylation was associated with diminished hMLH1 protein expression and MSI in IBD neoplasms. We studied 148 patients with IBD neoplasms, defined as carcinoma or dysplasia occurring in patients with ulcerative colitis or Crohn's disease. MSI was evaluated using multiplex fluorescent PCR to amplify loci D2S123, BAT-25, BAT-26, D5S346, and D17S250 in all cases. Lesions were characterized as high-frequency MSI (MSI-H) if they manifested instability at two or more loci, low-frequency MSI (MSI-L) if unstable at only one locus, or MS-stable (MSS) if showing no instability at any loci. Methylation-specific PCR was performed to determine the methylation status of the hMLH1 promoter region. hMLH1 protein expression was also evaluated by immunohistochemistry. Thirteen (9%) of 148 neoplasms arising in IBD were MSI-H, comprising 11 carcinomas and 2 dysplastic lesions. Sixteen additional lesions (11%) were MSI-L, comprising 11 carcinomas and 5 dysplastic lesions. The remaining 118 neoplasms (80%) were MSS. Six (46%) of 13 MSI-H, 1 (6%) of 16 MSI-L, and 4 (15%) of 27 MSS lesions showed hMLH1 hypermethylation (P = 0.013). Diminished hMLH1 protein expression in neoplastic cell nuclei relative to surrounding normal cell nuclei was demonstrated immunohistochemically in four of four (100%) hypermethylated lesions tested. In IBD neoplasia, hMLH1 promoter hypermethylation occurs frequently in the setting of MSI, particularly MSI-H. Furthermore, hMLH1 hypermethylation and MSI are strongly associated with diminished hMLH1 protein expression in IBD neoplasms. These findings suggest that hMLH1 hypermethylation causes defective DNA MMR in at least a subset of IBD neoplasms.

Interleukin-10-deficient mice and inflammatory bowel disease associated cancer development

Article

Apr 2001

Interleukin-10-deficient mice develop colitis and colorectal cancer similar to the inflammatory bowel disease associated cancer in humans. The aim of this study was to identify possible mutations of oncogenes and tumour suppressor genes involved in tumorigenesis in Interleukin-10 (IL-10)-deficient mice. Twenty colon carcinomas from IL-10-deficient mice were screened for mutations in the K-ras and p53 genes by 'cold' single-strand-conformation polymorphism. Immunohistochemical staining was performed to detect mutations in the proteins P53, APC and MSH2, and the transforming growth factor beta type II receptor. Microsatellite instability was analysed at eight chromosomal loci and plasma levels of transforming growth factor beta1 (TGF-beta1) were also measured. At 9 weeks, 14% of the animals developed colorectal cancer, and at 10-31 weeks the incidence of carcinoma was 65%. No mutations were detected in the analysed oncogene and tumour suppressor genes. Plasma TGF-beta1 levels in IL-10-deficient mice 10-31 weeks old were higher than in wild-type littermates e.g. 45.7 +/- 4.6 ng/ml versus 19.8 +/- 4.5 ng/ml (P<0.01). No alterations in K-ras, p53, APC: and Msh2 genes suggests that other genes are involved in the development of these tumours. Elevated TGF-beta1 plasma levels correspond to the high incidence of dysplasia and cancer. Normal expression of the TGF-beta II receptors hints at genetic alterations in other members of the TGF-beta receptor signal transduction pathway.

Review article: The incidence and prevalence of colorectal cancer in inflammatory bowel disease

Article

Oct 2003

Pia Munkholm

Although colorectal cancer (CRC), complicating ulcerative colitis and Crohn's disease, only accounts for 1–2% of all cases of CRC in the general population, it is considered a serious complication of the disease and accounts for approximately 15% of all deaths in inflammatory bowel disease (IBD) patients. The magnitude of the risk was found to differ, even in population-based studies. Recent figures suggest that the risk of colon cancer for people with IBD increases by 0.5–1.0% yearly, 8–10 years after diagnosis. The magnitude of CRC risk increases with early age at IBD diagnosis, longer duration of symptoms, and extent of the disease, with pancolitis having a more severe inflammation burden and risk of the dysplasia-carcinoma cascade. Considering the chronic nature of the disease, it is remarkable that there is such a low incidence of CRC in some of the population-based studies, and possible explanations have to be investigated. One possible cancer-protective factor could be treatment with 5-aminosalicylic acid preparations (5-ASAs). Adenocarcinoma of the small bowel is extremely rare, compared with adenocarcinoma of the large bowel. Although only few small bowel cancers have been reported in Crohn's disease, the number was significantly increased in relation to the expected number.

IKK?? Links Inflammation and Tumorigenesis in a Mouse Model of Colitis-Associated Cancer

Article

Sep 2004
CELL

A link between inflammation and cancer has long been suspected, but its molecular nature remained ill defined. A key player in inflammation is transcription factor NF-kappaB whose activity is triggered in response to infectious agents and proinflammatory cytokines via the IkappaB kinase (IKK) complex. Using a colitis-associated cancer model, we show that although deletion of IKKbeta in intestinal epithelial cells does not decrease inflammation, it leads to a dramatic decrease in tumor incidence without affecting tumor size. This is linked to increased epithelial apoptosis during tumor promotion. Deleting IKKbeta in myeloid cells, however, results in a significant decrease in tumor size. This deletion diminishes expression of proinflammatory cytokines that may serve as tumor growth factors, without affecting apoptosis. Thus, specific inactivation of the IKK/NF-kappaB pathway in two different cell types can attenuate formation of inflammation-associated tumors. In addition to suppressing apoptosis in advanced tumors, IKKbeta may link inflammation to cancer.

TGF-?? Suppresses Tumor Progression in Colon Cancer by Inhibition of IL-6 trans-Signaling

Article

Nov 2004
IMMUNITY

Alterations of TGF-beta signaling have been described in colorectal cancer, although the molecular consequences are largely unknown. By using transgenic mice overexpressing TGF-beta or a dominant-negative TGF-betaRII, we demonstrate that TGF-beta signaling in tumor infiltrating T lymphocytes controls the growth of dysplastic epithelial cells in experimental colorectal cancer, as determined by histology and a novel system for high-resolution chromoendoscopy. At the molecular level, TGF-beta signaling in T cells regulated STAT-3 activation in tumor cells via IL-6. IL-6 signaling required tumor cell-derived soluble IL-6R rather than membrane bound IL-6R and suppression of such TGF-beta-dependent IL-6 trans-signaling prevented tumor progression in vivo. Taken together, our data provide novel insights into TGF-beta signaling in colorectal cancer and suggest novel therapeutic approaches for colorectal cancer based on inhibition of TGF-beta-dependent IL-6 trans-signaling.

Molecular Phenotype of Inflammatory Bowel Disease-Associated Neoplasms With Microsatellite Instability

Article

Aug 2005
GASTROENTEROLOGY

Patients with inflammatory bowel disease (IBD) are at increased risk of developing colorectal cancer (CRC). We sought to determine the frequency of high-level microsatellite instability (MSI-H) and the mutational and methylation profile of MSI-H IBD-related neoplasms (IBDNs). A total of 124 IBDNs (81 cancers, 43 dysplasias) from 78 patients were studied for the frequency of MSI-H and hypermethylation of 3 target genes: MLH1 , HPP1 , and RAB-32 . Fifteen MSI-H IBDNs were characterized according to their profile of frameshift mutations in 28 mononucleotide repeats and compared with 46 sporadic MSI-H CRCs. Nineteen of 124 IBDNs were MSI-H. The frequency of frameshift mutations in coding mononucleotide repeats was significantly lower in MSI-H IBDNs than in sporadic MSI-H CRCs for TGFBR2 (7 of 14 vs 34 of 43 samples; P = .047) and ACVR2 (3 of 14 vs 25 of 43 samples; P = .029). In contrast, ICA1 was mutated in 3 of 9 MSI-H IBDNs vs 2 of 54 sporadic MSI-H CRCs ( P = .028). HPP1 and RAB32 methylation was independent of MSI status and was observed in 4 of 59 and 0 of 64 nondysplastic mucosae, 20 of 38 and 1 of 25 dysplasias, and 28 of 61 and 20 of 60 carcinomas, respectively. The profiles of coding microsatellite mutations (instabilotypes) differ significantly between MSI-H IBDNs and MSI-H sporadic CRCs. Specifically, TGFBR2 and ACVR2 mutations are significantly rarer in MSI-H IBDNs than in MSI-H sporadic CRCs. Furthermore, HPP1 methylation occurs early, in 7% of nondysplastic and approximately half of dysplastic mucosae, whereas RAB32 methylation occurs at the transition to invasive growth, being rarer in dysplasias.

Leong, K. G. & Karsan, A. Recent insights into the role of Notch signaling in tumorigenesis. Blood 107, 2223-2233

Article

Apr 2006

Members of the Notch family of transmembrane receptors play an important role in cell fate determination. Over the past decade, a role for Notch in the pathogenesis of hematologic and solid malignancies has become apparent. Numerous cellular functions and microenvironmental cues associated with tumorigenesis are modulated by Notch signaling, including proliferation, apoptosis, adhesion, epithelial-to-mesenchymal transition, and angiogenesis. It is becoming increasingly evident that Notch signaling can be both oncogenic and tumor suppressive. This review highlights recent findings regarding the molecular and functional aspects of Notch-mediated neoplastic transformation. In addition, cellular mechanisms that potentially explain the complex role of Notch in tumorigenesis are discussed.

High-Iron Diet: Foe or Feat in Ulcerative Colitis and Ulcerative Colitis-associated Carcinogenesis

Article

May 2006

Anemia associated with long-standing chronic inflammation and iron deficiency, and the increased risk for the development of dysplasia and carcinoma, are two of the most common complications in patients with ulcerative colitis (UC). Because of iron and nutrition deficiency, UC patients are encouraged to consume a high-protein and high-iron diet. The crucial clinical question is the effect of a high-iron diet on inflammation activity and inflammation-driven carcinogenesis. Is a high-iron diet a foe or a feat in UC and UC-associated carcinogenesis? This review updates the progress and information on (1) iron nutrition and iron-deficiency anemia in patients with UC, (2) experimental evidence of the exacerbating effect of a high-iron diet on UC and its associated carcinogenesis and the difference between a high-iron diet and parental iron supplementation, (3) the clinical efficacy of, and concerns about, oral and intravenous iron supplements in patients with inflammatory bowel disease and iron deficiency anemia, and (4) the clinical implications of long-term iron supplements and management of UC. These experimental findings from animal models provide evidence to warrant further consideration and clinical studies of iron nutrition, inflammation activity, and cancer development.

Cyclooxygenase-2 (COX-2)-Independent Anticarcinogenic Effects of Selective COX-2 Inhibitors

Article

Jul 2006
J NATL CANCER I

Nonsteroidal antiinflammatory drugs (NSAIDs) appear to reduce the risk of developing cancer. One mechanism through which NSAIDs act to reduce carcinogenesis is to inhibit the activity of cyclooxygenase-2 (COX-2), an enzyme that is overexpressed in various cancer tissues. Overexpression of COX-2 increases cell proliferation and inhibits apoptosis. However, selective COX-2 inhibitors can also act through COX-independent mechanisms. In this review, we describe the COX-2-independent molecular targets of these COX-2 inhibitors and discuss how these targets may be involved in the anticarcinogenic activities of these selective COX-2 inhibitors. We also compare the concentrations of these inhibitors used in in vitro and in vivo experiments and discuss the implications of the in vitro studies for clinical management of cancer with these drugs.

Colorectal Carcinoma Development in Inducible Nitric Oxide Synthase-Deficient Mice With Dextran Sulfate Sodium-Induced Ulcerative Colitis

Article

May 2007

The overproduction of reactive oxygen and nitrogen species (RONS) may play an important role in ulcerative colitis (UC)-associated carcinogenesis. In order to study the role of nitric oxide (NO) in UC-associated colorectal carcinogenesis, the development of colorectal carcinoma was studied using the DSS-induced and iron-enhanced model of chronic UC in inducible nitric oxide synthase (iNOS)-deficient mice. Female wild-type C57BL/6 (iNOS+/+) and iNOS-/- mice were administered 1% DSS (w/v) through the drinking fluid for 15 DSS cycles and fed twofold iron-enriched diet. Colorectal inflammation and mucosal ulceration of moderate severity were observed in both iNOS+/+ and iNOS-/- mice. Similar tumor incidence and multiplicity in the colon were observed that 15 out of 23 (65.2%) iNOS+/+ mice developed colorectal tumors with a tumor multiplicity of 1.47+/-0.17 (mean+/-SE) after 15 DSS cycles, and 13 out of 19 (68.4%) iNOS-/- mice developed colorectal tumors with a tumor multiplicity of 2.08+/-0.21. Histopathologically, the tumors were confirmed to be well-differentiated adenocarcinomas. Nitrotyrosine, an indicator of peroxynitrite-caused protein modification, was detectable by immunohistochemistry in inflammatory cells and epithelial cells of the colon in iNOS+/+ and iNOS-/- mice, and no difference in staining intensity was observed between the two groups. Immunostaining for endothelial NOS (eNOS) was observed in lamina propria macrophages and colonic blood vessels, and eNOS protein levels were increased in the inflamed colon. These results show that there is no difference in UC-associated cancer development in iNOS+/+ and iNOS-/- mice, and suggest that in the absence of iNOS, other factors, such as eNOS, may play a role in nitrosative stress and UC-associated carcinogenesis in this model system.

IKKα at the Crossroads of Inflammation and Metastasis

Article

May 2007
CELL

The development of solid tumors is regulated by dynamic interactions between evolving neoplastic cells and their microenvironment. Luo et al. (2007) recently demonstrated that tumor-infiltrating immune cells expressing RANKL induce activation and nuclear localization of IKKalpha in prostatic epithelial tumor cells. This leads to repression of maspin, a critical suppressor of metastasis, and thus commits malignant prostatic epithelial cells to a metastatic fate.

Microsatellite instability and MLH1 promoter hypermethylation in colorectal cancer

Article

Apr 2007
WORLD J GASTROENTERO

Yaron Niv

Colorectal cancer (CRC) is caused by a series of genetic or epigenetic changes, and in the last decade there has been an increased awareness that there are multiple forms of colorectal cancer that develop through different pathways. Microsatellite instability is involved in the genesis of about 15% of sporadic colorectal cancers and most of hereditary nonpolyposis cancers. Tumors with a high frequency of microsatellite instability tend to be diploid, to possess a mucinous histology, and to have a surrounding lymphoid reaction. They are more prevalent in the proximal colon and have a fast pass from polyp to cancer. Nevertheless, they are associated with longer survival than stage-matched tumors with microsatellite stability. Resistance of colorectal cancers with a high frequency of microsatellite instability to 5-fluorouracil-based chemotherapy is well established. Silencing the MLH1 gene expression by its promoter methylation stops the formation of MLH1 protein, and prevents the normal activation of the DNA repair gene. This is an important cause for genomic instability and cell proliferation to the point of colorectal cancer formation. Better knowledge of this process will have a huge impact on colorectal cancer management, prevention, treatment and prognosis.

Specific Clinical and Biological Features Characterize Inflammatory Bowel Disease Associated Colorectal Cancers Showing Microsatellite Instability

Article

Oct 2007
J CLIN ONCOL

Microsatellite instability (MSI) due to mismatch repair (MMR) deficiency has been reported to occur at variable frequencies in inflammatory bowel disease-associated intestinal neoplasias (IBD-Ns). We investigated a large series of IBD-N for associations between MSI and several biologic and clinical parameters related to tumors, patients, and their treatment. A total of 277 IBD-Ns in 205 patients were screened for MSI. Biologic and clinical variables of patients with high levels of DNA microsatellite instability high (MSI-H) were collected and compared with those associated with 33 MSI-H non-IBD colorectal cancers (CRCs). A total of 27 IBD-Ns from 17 patients were found to be MSI-H. Compared with sporadic MSI-H CRCs, patients presented with a younger age at diagnosis, and there was no female predominance and no right-sided predominance. Unlike sporadic MSI-H CRCs, MSI-H IBD-Ns presented with heterogeneous mismatch repair defects involving MLH1, MSH2, MSH6, or PMS2, and a low frequency of MLH1 promoter methylation. They exhibited frequent BRAF mutations and frameshift mutations in genes containing coding repeat sequences. The mechanisms underlying MMR deficiency in MSI-H IBD-Ns are different from those in sporadic MSI-H tumors and seem to be more related to those observed in hereditary MSI-H tumors. However, BRAF mutations were observed in MSI-H IBD-Ns, similar to sporadic MSI-H tumors, but unlike hereditary MSI-H tumors. Finally, the mutational events in target genes for instability are the same in MSI-H IBD-N tumors as in non-IBD sporadic and hereditary colorectal MSI-H cancers, indicating a colon-related repertoire of target gene alterations.

Tumor Necrosis Factor-Alpha Polymorphisms in Ulcerative Colitis-Associated Colorectal Cancer

Article

Feb 2008

Ulcerative colitis (UC) is characterized by chronic recurrent mucosal inflammation. Genetic studies in UC have indicated linkage to chromosome 6 in the region of the tumor necrosis factor-alpha (TNF-alpha) gene, a potent proinflammatory cytokine. TNF-alpha production is influenced by multiple factors including the type of immune cell and its level of activation. However, several single nucleotide polymorphisms (SNP) in the promoter region of TNF-alpha have been correlated with either increased or decreased production, indicating that regulation of TNF-alpha is in part genetic. Because UC patients are at increased risk for developing colorectal cancer (CRC), we investigated if there was an association between SNPs in the promoter of the TNF-alpha gene and UC-CRC. DNA was extracted from formalin-fixed, paraffin-embedded tissue from 114 UC-CRC cases and 114 UC-no CRC controls. Controls were frequency matched on duration and extent of colitis, age, ethnicity, and gender. All 228 tissue samples were analyzed for five TNF-alpha promoter polymorphisms (-238[G-->A], -308[G-->A], -857[C-->T], -863[C-->A], and -1031[T-->C]) using PCR and sequencing. The -308(G-->A) SNP was significantly associated with UC-CRC cases at both the allele and genotype level (P < 0.0001). No other SNPs were significantly associated with UC-CRC. We report a novel finding of a strong association between the -308(G-->A) SNP and UC-CRC. Complete elucidation of the mechanism of UC-CRC carcinogenesis will require investigation of other genes involved in modulating inflammation, but our results suggest that some UC patients may have additional genetic predispositions toward developing UC-CRC.

The IkB kinase - A bridge between inflammation and cancer

Article

Apr 2008
CELL RES

Michael Karin

A potential link between inflammation and cancer has been suspected for over a century, but the exact molecular mechanisms connecting the two remained nebulous. We proposed that NF-kappaB transcription factors regulated via the IkappaB kinase (IKK) complex play a critical role in coupling inflammation and cancer and have set out to test this hypothesis in mouse models of cancer. Using mice bearing mutations in the genes coding for the IKKbeta and IKKalpha catalytic subunits we obtained evidence supporting a critical role for IKKbeta in tumor promotion and more recently identified the involvement of IKKalpha in metastatogenesis. Whereas the major pro-tumorigenic function of IKKbeta is mediated via NF-kappaB, the pro-metastatic function of IKKalpha is NF-kappaB-independent. In addition to illustrating the critical roles of the two IKK molecules in linking inflammation and cancer and providing an explanation for increased cancer risk in response to persistent infections and inflammation, these results also identify new targets for development of novel anti-cancer therapies and preventive strategies. Instead of targeting the cancer cell itself, as done by conventional anti-cancer drugs, the new therapeutics will target processes that occur within inflammatory cells that are essential for cancer development and progression. Unlike cancer cells, inflammatory cells retain a normal and stable genome and therefore are unlikely to become genetically resistant to therapeutic intervention.

Cytokines: From Gut Inflammation to Colorectal Cancer

Article

Jun 2008
CURR DRUG TARGETS

Colorectal cancer represents a life-threatening complication of inflammatory bowel diseases. Statistics indicate that the risk to develop colorectal cancer is higher in patients affected by ulcerative colitis and to a lesser extent by Crohn's disease and that such a risk is directly proportional to the number of years of active disease. These observations suggest that chronic inflammation may substantially contribute to cancer development. However the molecular mechanisms underlying this process have been only recently started to be clarified. Indeed from the initial concept that the release of free radicals during inflammation might induce the accumulation of genetic mutations thus leading to the onset of dysplastic cells, it is now becoming clear that the large amount of cytokines and growth factors released during inflammation by immune and non immune cells may influence the carcinogenesis process. IL-6 and IL-23, cytokines which play key roles in the induction and maintenance of gut inflammation during IBDs, have been recently shown to influence the development and growth of colitis associated colorectal cancer. Moreover, the activation of the nuclear factor kappa B (NF kappa B), a transcription factor activated by several cytokines released during inflammation and responsible for many of their proinflammatory effects, have been shown to promote the growth of the colon tumors in experimental models.

Kundu JK, Surh YJInflammation: gearing the journey to cancer. Mutat Res 659(1-2): 15-30

Article

Apr 2008
MUTAT RES-FUND MOL M

Chronic inflammation plays a multifaceted role in carcinogenesis. Mounting evidence from preclinical and clinical studies suggests that persistent inflammation functions as a driving force in the journey to cancer. The possible mechanisms by which inflammation can contribute to carcinogenesis include induction of genomic instability, alterations in epigenetic events and subsequent inappropriate gene expression, enhanced proliferation of initiated cells, resistance to apoptosis, aggressive tumor neovascularization, invasion through tumor-associated basement membrane and metastasis, etc. Inflammation-induced reactive oxygen and nitrogen species cause damage to important cellular components (e.g., DNA, proteins and lipids), which can directly or indirectly contribute to malignant cell transformation. Overexpression, elevated secretion, or abnormal activation of proinflammatory mediators, such as cytokines, chemokines, cyclooxygenase-2, prostaglandins, inducible nitric oxide synthase, and nitric oxide, and a distinct network of intracellular signaling molecules including upstream kinases and transcription factors facilitate tumor promotion and progression. While inflammation promotes development of cancer, components of the tumor microenvironment, such as tumor cells, stromal cells in surrounding tissue and infiltrated inflammatory/immune cells generate an intratumoral inflammatory state by aberrant expression or activation of some proinflammatory molecules. Many of proinflammatory mediators, especially cytokines, chemokines and prostaglandins, turn on the angiogenic switches mainly controlled by vascular endothelial growth factor, thereby inducing inflammatory angiogenesis and tumor cell-stroma communication. This will end up with tumor angiogenesis, metastasis and invasion. Moreover, cellular microRNAs are emerging as a potential link between inflammation and cancer. The present article highlights the role of various proinflammatory mediators in carcinogenesis and their promise as potential targets for chemoprevention of inflammation-associated carcinogenesis.

Oxidative stress in ulcerative colitis-associated carcinogenesis

Article

Feb 2008
Pathol Res Pract

Oxidative stress is defined as an imbalance between generation of reactive oxygen species (ROS) and decreased antioxidant defense systems. Oxidative stress develops particularly in inflammatory reactions because the inflammatory cells, neutrophils, and macrophages produce large amounts of ROS. It has been known for a long time that oxidative stress in inflamed tissue can pave the way for malignant tumors, and that it is a major pathogenetic factor for the well-established correlation between inflammatory diseases and cancer. Oxidative stress has long been associated with the pathogenesis of chronic inflammatory bowel disease (IBD)-related colorectal cancer. This article provides an overview of the pathology of ROS and presents recent advances concerning the role of ROS in IBD-related colorectal carcinogenesis (Fig. 1).

Risk for colorectal cancer in ulcerative colitis: Changes, causes and management strategies

Article

Aug 2008
WORLD J GASTROENTERO

The risk of colorectal cancer for any patient with ulcerative colitis is known to be elevated, and is estimated to be 2% after 10 years, 8% after 20 years and 18% after 30 years of disease. Risk factors for cancer include extent and duration of ulcerative colitis, primary sclerosing cholangitis, a family history of sporadic colorectal cancer, severity of histologic bowel inflammation, and in some studies, young age at onset of colitis. In this review, the authors discuss recent epidemiological trends and causes for the observed changes. Population-based studies published within the past 5 years suggest that this risk has decreased over time, despite the low frequency of colectomies. The crude annual incidence rate of colorectal cancer in ulcerative colitis ranges from approximately 0.06% to 0.16% with a relative risk of 1.0-2.75. The exact mechanism for this change is unknown; it may partly be explained by the more widespread use of maintenance therapy and surveillance colonoscopy.

Cancer in Crohn’s disease: dispelling the myths This review addresses the clinical and molecular features of colitis-associated CRC and also of other cancers in patients with IBD. Xie J, Itzkowitz SH: Cancer in inflammatory bowel disease

1507-1508378

Sachar

Sachar DB: Cancer in Crohn’s disease: dispelling the myths. Gut 1994, 35:1507-1508. 20. ? This review addresses the clinical and molecular features of colitis-associated CRC and also of other cancers in patients with IBD. Xie J, Itzkowitz SH: Cancer in inflammatory bowel disease. World J Gastroenterol 2008, 14:378-389.

Interleukin-10-deficient mice and inflammatory bowel disease associated cancer development 6 Cancer COPHAR-709; NO OF PAGES 6 Please cite this article in press as: Kraus S, Arber N. Inflammation and colorectal cancer

665-6711

Sturlans
G Oberhuber
Beinhauerbg
Tichyb
S Kappel
J Wang
Rogy

SturlanS,Oberhuber G,BeinhauerBG,TichyB,Kappel S,Wang J, Rogy MA: Interleukin-10-deficient mice and inflammatory bowel disease associated cancer development. Carcinogenesis 2001, 22:665-671. 6 Cancer COPHAR-709; NO OF PAGES 6 Please cite this article in press as: Kraus S, Arber N. Inflammation and colorectal cancer, Curr Opin Pharmacol (2009), doi:10.1016/j.coph.2009.06.006 Current Opinion in Pharmacology 2009, 9:1–6 www.sciencedirect.com

Inflammation: gearing the journey to cancer

Jan 2008
15-30

Kundu Jk
Surh
Yj

Kundu JK, Surh YJ: Inflammation: gearing the journey to cancer. Mutat Res 2008, 659:15-30.

Cytokines and their relationship to the symptoms and outcome of cancer This is a perspective review that discusses the role of cytokines in causing symptoms in patients with cancer and their influence in the development and progression of cancer

Jan 2008
887-899

B Seruga
H Zhang
Bernstein Lj
Tannock
If

Seruga B, Zhang H, Bernstein LJ, Tannock IF: Cytokines and their relationship to the symptoms and outcome of cancer. Nat Rev Cancer 2008, 8:887-899. This is a perspective review that discusses the role of cytokines in causing symptoms in patients with cancer and their influence in the development and progression of cancer.

Nuclear IKK activity leads to dysregulated notch-dependent gene expression in colorectal cancer This study shows that IKK plays an NF-kB independent role in CRC and suggests a role for IKK in the regulation of NF-kB-independent genes such as

Jan 2007
276-281

V Ferná
C Aguilera
A Villanueva
Robert-Moreno F A Vilardell
A Ayté
Fx
G Capella
Mw Mayo
L Espinosa

Ferná ndez-Majada V, Aguilera C, Villanueva A, Vilardell F, Robert-Moreno A, Ayté s A, Real FX, Capella G, Mayo MW, Espinosa L, Bigas A: Nuclear IKK activity leads to dysregulated notch-dependent gene expression in colorectal cancer. Proc Natl Acad Sci USA 2007, 104:276-281. This study shows that IKK plays an NF-kB independent role in CRC and suggests a role for IKK in the regulation of NF-kB-independent genes such as, Notch targets.

Blocking TNF-alpha in mice reduces colorectal carcinogenesis associated with chronic colitis This study demonstrates that TNF-a, through its effects on the immune system, plays a crucial role in promoting neoplastic transformation in the setting of chronic inflammation

Jan 2008
560-570

Popivanova Bk
K Kitamura
Y Wu
T Kondo
T Kagaya
S Kaneko
M Oshima
C Fujii
Mukaida

Popivanova BK, Kitamura K, Wu Y, Kondo T, Kagaya T, Kaneko S, Oshima M, Fujii C, Mukaida N: Blocking TNF-alpha in mice reduces colorectal carcinogenesis associated with chronic colitis. J Clin Invest 2008, 118:560-570. This study demonstrates that TNF-a, through its effects on the immune system, plays a crucial role in promoting neoplastic transformation in the setting of chronic inflammation.

IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitisassociated cancer

Jan 2004
285-296103

Fr Greten
L Eckmann
Tf Greten
Jm Park
Zw Li
Lj Egan
Mf Kagnoff
Karin M Grivennikov
S Karin
E Terzic
J Mucida
D Yu
Gy Vallabhapurapu
S Scheller
S Cheroutre
H Eckmann

Greten FR, Eckmann L, Greten TF, Park JM, Li ZW, Egan LJ, Kagnoff MF, Karin M: IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 2004, 118:285-296. 31. Grivennikov S, Karin E, Terzic J, Mucida D, Yu GY, Vallabhapurapu S, Scheller J, Rose-John S, Cheroutre H, Eckmann L, Karin M: IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitisassociated cancer. Cancer Cell 2009, 15:103-113.

Inflammation and cancer: IL-6, STAT3 complete the link

Jan 2009
79

Bromberg

Bromberg J, Wang TC: Inflammation and cancer: IL-6, STAT3 complete the link. Cancer Cell 2009, 15:79-80.

Paradoxical roles of the immune system during cancer development

Jan 2006
NAT REV CANCER
24-37

K E De Visser
A Eichten
L M Coussens

de Visser KE, Eichten A, Coussens LM: Paradoxical roles of the immune system during cancer development. Nat Rev Cancer 2006, 6:24-37.

Inflammation and colorectal cancer

Abstract

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