Environmental factors, including westernised diets and alterations to the gut microbiota, are considered risk factors for inflammatory bowel diseases (IBD). The mechanisms underpinning diet-microbiota-host interactions are poorly understood in IBD. We present evidence that feeding a lard-based high-fat (HF) diet can protect mice from developing DSS-induced acute and chronic colitis and colitis-associated cancer (CAC) by significantly reducing tumour burden/incidence, immune cell infiltration, cytokine profile, and cell proliferation. We show that HF protection was associated with increased gut microbial diversity and a significant reduction in Proteobacteria and an increase in Firmicutes and Clostridium cluster XIVa abundance. Microbial functionality was modulated in terms of signalling fatty acids and bile acids (BA). Faecal secondary BAs were significantly induced to include moieties that can activate the vitamin D receptor (VDR), a nuclear receptor richly represented in the intestine and colon. Indeed, colonic VDR downstream target genes were upregulated in HF-fed mice and in combinatorial lipid-BAs-treated intestinal HT29 epithelial cells. Collectively, our data indicate that HF diet protects against colitis and CAC risk through gut microbiota and BA metabolites modulating vitamin D targeting pathways. Our data highlights the complex relationship between dietary fat-induced alterations of microbiota-host interactions in IBD/CAC pathophysiology.
This study found that patients with active UC have significantly increased colonic gene expression of cytosolic DNA sensor, inflammasome, STING, and type I IFN signaling pathways. The type I IFN, IFN-β, in combination with TNF-α induced JAK-dependent but NLRP3 and inflammasome-independent inflammatory cell death of colonic organoids. This novel inflammatory cell death phenotype is relevant to UC immunopathology and may partially explain the efficacy of the JAKinibs tofacitinib and upadacitinib in patients with UC.
Abstract Background: Esophageal cancer is an aggressive tumour which responds poorly to both chemotherapy and radiation therapy and has a poor prognosis. Approximately half of patients diagnosed with localized esophageal cancer die of metastatic disease within the first 2 years following tumour resection. Thus, a greater understanding of the biology of esophageal cancer is needed in order to identify novel therapeutic targets. Among these targets p38 MAPK isoforms are becoming increasingly important for a variety of cellular functions. A better understanding of the role(s) of p38 MAPKs may provide useful therapeutic tools for the management of human cancers. Methods: We analysed p38 MAPK isoform expression in both cancer cell lines and corresponding human normal and tumour tissue including esophageal, liver, lung, prostate, colon, renal and pancreatic. We observed that over 75% of both cell lines and human tumour tissue samples fail to express the specific isoform p38δ MAPK. To evaluate the role(s) of p38δ and active p-p38δ MAPK in esophageal cancer progression we developed a series of constructs: p38δ MAPK (pcDNA3-FLAG-p38δ MAPK), active p-p38δ MAPK (pcDNA3-MKK6b(E)-(Gly-Glu)5-FLAG-p38δ) and inactive p38δDN MAPK (pcDNA3-MKK6b(E)-(Gly-Glu)5-FLAG-p38δDN). The active p-p38δ plasmid was generated by removing the MKK6b(E) stop codon in pcDNA3-MKK6b(E). Secondly, FLAG-p38δ was amplified with a 5′(Gly-Glu)5 linker. Linear blunt-ended pcDNA3-MKK6b(E) and blunt ended (Gly-Glu)5-FLAG-p38δ were ligated. The dominant negative p-p38δ plasmid (p-p38δDN) was generated from pcDNA3-MKK6b(E)-(Gly-Glu)5-FLAG-p38δ by replacing Thr180 with Ala and Tyr182 with Phe. Stable esophageal squamous cancer cell lines expressing these plasmids were generated. Results: Re-introduction of p38δ or p-p38δ proved to be (a) anti-proliferative, (b) anti-migratory and (c) pro-apoptotic. We observed a time-dependent decrease in proliferation in esophageal cancer cells stably transfected with p38δ MAPK. This anti-proliferative effect was exacerbated with cells transfected with p-p38δ MAPK. Using a Boyden chamber and a wound healing assay we observed a decrease in cellular migration and invasion with cells transfected with p38δ or p-p38δ MAPK. Finally using Annexin V-FITC/PI double labeled flow cytometry we observed that p38δ and p-p38δ MAPK confers a greater sensitivity of esophageal cancer to certain chemotherapeutic drugs but resistance to others. Conclusion: We now provide data for the anti-tumourigenic effect of p38δ MAPK in esophageal cancer. Our research may provide a new potential target for the treatment of esophageal cancer and metastases. Interestingly, our findings are also applicable to other cancer types namely renal, prostate and pancreatic cancer which also lack p38δ MAPK isoform expression. Citation Format: Carol O'Callaghan, Liam Fanning, Aileen Houston, Orla P. Barry. New paradigms for the modulatory actions of p38δ MAPK restorative expression in esophageal squamous cancer cell growth, migration and response to chemotherapy: A possible future therapeutic target. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3993. doi:10.1158/1538-7445.AM2013-3993
Oesophageal cancer is an aggressive tumour which responds poorly to both chemotherapy and radiation therapy and has a poor prognosis. Thus, a greater understanding of the biology of oesophageal cancer is needed in order to identify novel therapeutic targets. Among these targets p38 MAPK isoforms are becoming increasingly important for a variety of cellular functions. The physiological functions of p38α and -β are now well documented in contrast to -γ and -δ which are comparatively under-studied and ill-defined. A major obstacle to deciphering the role(s) of the latter two p38 isoforms is the lack of specific chemical activators and inhibitors. In this study, we analysed p38 MAPK isoform expression in oesophageal cancer cell lines as well as human normal and tumour tissue. We observed specifically differential p38δ expression. The role(s) of p38δ and active (phosphorylated) p38δ (p-p38δ) in oesophageal squamous cell carcinoma (OESCC) was delineated using wild-type p38δ as well as active p-p38δ, generated by fusing p38δ to its upstream activator MKK6b(E) via a decapeptide (Gly-Glu)5 linker. OESCC cell lines which are p38δ-negative (KE-3 and -8) grew more quickly than cell lines (KE-6 and -10) which express endogenous p38δ. Re-introduction of p38δ resulted in a time-dependent decrease in OESCC cell proliferation which was exacerbated with p-p38δ. In addition, we observed that p38δ and p-p38δ negatively regulated OESCC cell migration in vitro. Finally both p38δ and p-p38δ altered OESCC anchorage-independent growth. Our results suggest that p38δ and p-p38δ have a role in the suppression of OESCC. Our research may provide a new potential target for the treatment of oesophageal cancer.
The IL-1 family of cytokines currently comprises of seven ligands with pro-inflammatory activity (IL-1α and IL-1β, IL-18, IL-33, IL-36α, IL-36β, IL-36γ) as well as two ligands with anti-inflammatory activity (IL-37, IL-38). These cytokines are known to play a key role in modulating both the innate and adaptive immunes response, with dysregulation linked to a variety of autoimmune and inflammatory diseases. Given the increasing appreciation of the link between inflammation and cancer, the role of several members of this family in the pathogenesis of cancer has been extensively investigated. In this review, we highlight both the pro- and anti-tumorigenic effects identified for almost all members of this family, and explore potential underlying mechanisms accounting for these divergent effects. Such dual functions need to be carefully assessed when developing therapeutic intervention strategies targeting these cytokines in cancer.
The IL-36 cytokines are a recently described subset of the IL-1 family of cytokines, shown to play a role in the pathogenesis of intestinal diseases such as Inflammatory Bowel Disease (IBD). Given the link between IBD and colitis -associated cancer, as well as the involvement of other IL-1 family members in intestinal tumorigenesis, the aim of this work was to investigate whether IL-36 cytokines play a role in the pathogenesis of colon cancer. Whilst research to date has focused on the role of IL-36 family members in augmenting the immune response to induce tumour rejection, very little remains known about IL-36R signalling in tumour cells in this context. In this study we demonstrate that expression of IL-36 family member mRNA and protein are significantly increased in colorectal cancer tissue compared to adjacent non-tumour. In vitro assays showed stimulation of colon cancer cell lines with IL-36R agonists resulted in the activation of the pro-tumorigenic phenotypes of increased cellular migration, invasion and proliferation in both 2D and 3D models. In addition, the IL-36 cytokines induced strong expression of pro-inflammatory chemokines in both human and murine cell lines. Intraperitoneal injection of IL-36Ra significantly reduced tumour burden using the subcutaneous CT26 tumour model in syngeneic Balb/mice, and this was associated with a decrease in Ki-67 expression by tumour cells in the IL-36Ra- treated group relative to untreated, suggesting the inhibition of the pro-proliferative signalling of IL-36 agonists resulted in the decreased tumour size. Moreover, colon cancer cells lacking the IL-36R also showed reduced tumour growth and reduced Ki-67 expression in vivo. Taken together, this data suggests that targeting IL-36R signalling may be a useful targeted therapy for colorectal cancer patients with IL-36R+ tumour cells.
// Grace O'Malley 1,2 , Madelon Heijltjes 3 , Aileen M. Houston 4 , Sweta Rani 1 , Thomas Ritter 1 , Laurence J. Egan 2 and Aideen E. Ryan 1,2 1 Regenerative Medicine Institute (REMEDI), National Centre for Biomedical Engineering Science (NCBES) NUI, Galway, Ireland 2 Discipline of Pharmacology and Therapeutics, Translational Research Facility, National University of Ireland, Galway, Ireland 3 Leiden University Medical Centre, Leiden, The Netherlands 4 Department of Medicine, University College Cork, Ireland Correspondence to: Aideen E. Ryan, email: // Keywords : mesenchymal stromal cells, tumour microenvironment, colorectal cancer, immunosuppression, immunomodulation Received : February 09, 2016 Accepted : July 09, 2016 Published : August 17, 2016 Abstract The tumour microenvironment (TME) is an important factor in determining the growth and metastasis of colorectal cancer, and can aid tumours by both establishing an immunosuppressive milieu, allowing the tumour avoid immune clearance, and by hampering the efficacy of various therapeutic regimens. The tumour microenvironment is composed of many cell types including tumour, stromal, endothelial and immune cell populations. It is widely accepted that cells present in the TME acquire distinct functional phenotypes that promote tumorigenesis. One such cell type is the mesenchymal stromal cell (MSC). Evidence suggests that MSCs exert effects in the colorectal tumour microenvironment including the promotion of angiogenesis, invasion and metastasis. MSCs immunomodulatory capacity may represent another largely unexplored central feature of MSCs tumour promoting capacity. There is considerable evidence to suggest that MSCs and their secreted factors can influence the innate and adaptive immune responses. MSC-immune cell interactions can skew the proliferation and functional activity of T-cells, dendritic cells, natural killer cells and macrophages, which could favour tumour growth and enable tumours to evade immune cell clearance. A better understanding of the interactions between the malignant cancer cell and stromal components of the TME is key to the development of more specific and efficacious therapies for colorectal cancer. Here, we review and explore MSC- mediated mechanisms of suppressing anti-tumour immune responses in the colon tumour microenvironment. Elucidation of the precise mechanism of immunomodulation exerted by tumour-educated MSCs is critical to inhibiting immunosuppression and immune evasion established by the TME, thus providing an opportunity for targeted and efficacious immunotherapy for colorectal cancer growth and metastasis.
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