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- W2560569860 abstract "Dedifferentiation induced by GI tract inflammation enhances oncogenic transformation of cells in the intestine and pancreas, and may be a rate-limiting step in tumor initiation. Colorectal cancer can arise from direct mutation of crypt stem cells, but can also arise via NF-κB mediated dedifferentiation of mature enterocytes Pancreatic ductal adenocarcinoma can arise via reprogramming of acinar cells into pancreatic intraepithelial neoplasia (PanIN) or directly from duct cells without a ‘pre-cancerous’ PanIN-like intermediate NF-κB signaling, as well as pathways crucial for endodermal development, play crucial roles in dedifferentiation and subsequent oncogenesis in the colon, pancreas, and liver. Reintroduction of acinar differentiation determinants to pancreatic cancer cells prevents proliferation and could hold promise as a therapeutic strategy. While recent studies demonstrate that cancer can arise from mutant stem cells, this hypothesis does not explain why tissues without defined stem cell populations are susceptible to inflammation-driven tumorigenesis. We propose that chronic inflammatory diseases, such as colitis and pancreatitis, predispose to gastrointestinal (GI) adenocarcinoma by reprogramming differentiated cells. Focusing on colon and pancreas, we discuss recently discovered connections between inflammation and loss of cell differentiation, and propose that dysregulation of cell fate may be a novel rate-limiting step of tumorigenesis. We review studies identifying differentiation mechanisms that limit tumor initiation and that, upon reactivation, can prevent or revert the cancer cell transformed phenotype. Together, these findings suggest that differentiation-targeted treatments hold promise as a therapeutic strategy in GI cancer. While recent studies demonstrate that cancer can arise from mutant stem cells, this hypothesis does not explain why tissues without defined stem cell populations are susceptible to inflammation-driven tumorigenesis. We propose that chronic inflammatory diseases, such as colitis and pancreatitis, predispose to gastrointestinal (GI) adenocarcinoma by reprogramming differentiated cells. Focusing on colon and pancreas, we discuss recently discovered connections between inflammation and loss of cell differentiation, and propose that dysregulation of cell fate may be a novel rate-limiting step of tumorigenesis. We review studies identifying differentiation mechanisms that limit tumor initiation and that, upon reactivation, can prevent or revert the cancer cell transformed phenotype. Together, these findings suggest that differentiation-targeted treatments hold promise as a therapeutic strategy in GI cancer. an intestinal tumor-suppressor gene that encodes a negative regulator of Wnt/β-catenin signaling. Inherited mutations in human APC cause familial CRC predisposition, while sporadic mutations often represent the first genetic ‘hits’ in sporadic CRC. the idea that CRC is initiated from a mutated crypt stem cell and propagated from the bottom of the crypt toward the lumen. oligopeptide similar to cholecystokinin (CCK); stimulates pancreatic secretion and, at supraphysiological levels, induces intrapancreatic activation of digestive enzymes and subsequent pancreatitis. longstanding inflammation of the exocrine pancreas, causing malabsorption and abdominal persistent pain, and significantly increasing the risk of PDAC. cancer originating from the epithelium of the colon or rectum. It is the most commonly diagnosed cancer of the gastrointestinal (GI) tract, with over 140 000 cases presenting each year in the USA. bacteriophage enzyme that catalyzes site-specific DNA recombination between nearby loxP sites. Commonly utilized for tissue-specific recombination in mouse genetics. putative PDAC precursor lesion that grows within pancreatic ducts and is characterized by thick fluid production. Recent studies suggest that IPMNs arise from cells of the ductal epithelium. an oncogene precursor that is mutated to an ‘active’ form in 90–95% of PDAC and 30–50% of CRC cases. Once in an active (GTP-bound) conformation, KRAS propagates growth factor signals mediated by RAF/MEK/ERK and PI3K/AKT, among other pathways. a Wnt target gene, encoding a cell-surface receptor, that is expressed exclusively in adult stem cells of the intestine, stomach, and hair follicle. from Greek, ‘change in form’, refers to the reversible change of one tissue type into another. This can occur through multiple mechanisms including transdifferentiation of mature cells, alterations to stem cells such that they produce inappropriately differentiated offspring, or the death of one tissue type and replacement by adjacent cells of another type. family of transcription factors rapidly activated by diverse mediators of injury and infection, often regulating downstream inflammatory responses. the most common cancer of the pancreas, often comprising cells with duct-like morphology. About 46 000 cases are diagnosed in the USA each year and the 5 year survival rate is ∼6%. putative precursor lesion of PDAC. Recent studies suggest PanINs arise from reprogramming of mature acinar cells. the idea that CRC initiates from a differentiated cell on the luminal surface of the colon and subsequently invades the crypt. daughter cell of a stem cell, destined to undergo a burst of proliferation followed by differentiation. Often committed to a limited range of cell fates." @default.
- W2560569860 created "2016-12-16" @default.
- W2560569860 creator A5005193747 @default.
- W2560569860 creator A5080071044 @default.
- W2560569860 date "2016-12-01" @default.
- W2560569860 modified "2023-10-02" @default.
- W2560569860 title "Differentiation and Inflammation: ‘Best Enemies’ in Gastrointestinal Carcinogenesis" @default.
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