Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Patients with long-standing ulcerative colitis and Crohn's disease have an increased risk of developing colorectal cancer and patients with small intestinal Crohn's disease are at increased risk of small bowel adenocarcinoma. Colorectal cancer appearing on the ground of inflammatory bowel disease is the result of a process which is believed to begin from no dysplasia progressing to indefinite dysplasia, low-grade dysplasia, high-grade dysplasia and finally to invasive adenocarcinoma, although colorectal cancer can arise without proceeding through each of these steps. Ulcerative colitis patients with total proctocolectomy and ileal pouch anal-anastomosis have a rather low risk of dysplasia in the ileal pouch, although the anal transition zone should be monitored periodically, especially if chronic pouchitis is present with associated severe villous atrophy. Concerning the risk factors predisposing to colorectal cancer in the setting of ulcerative colitis or Crohn's disease, it seems that the risk increases with longer duration and greater anatomic extent of colitis, the degree of inflammation, and the presence of primary sclerosing cholangitis and family history of colorectal cancer. Concerning the mechanisms of carcinogenesis, it is now well established that the molecular alterations responsible for sporadic colorectal cancer, namely chromosomal instability, microsatellite instability and hypermethylation, also play a role in colitis-associated colon carcinogenesis. Chemoprevention strategies include the administration of agents such as aminosalicylates, ursodeoxycholic acid, and possibly folic acid and statins, the exact role of which remains to be further elucitated.
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PMID:Colorectal cancer and inflammatory bowel disease: epidemiology, risk factors, mechanisms of carcinogenesis and prevention strategies. 1959 53

Chronic inflammation predisposes to a variety of human cancers. Affected tissues slowly accumulate mutations, some of which affect growth regulation and drive successive waves of clonal evolution, whereas a far greater number are functionally neutral and serve only to passively mark expanding clones. Ulcerative colitis (UC) is an inflammatory bowel disease, in which up to 10% of patients eventually develop colon cancer. Here we have mapped mutations in hypermutable intergenic and intronic polyguanine tracts in patients with UC to delineate the extent of clonal expansions associated with carcinogenesis. We genotyped colon biopsies for length altering mutations at 28 different polyguanine markers. In eight patients without neoplasia, we detected only two mutations in a single individual from among 37 total biopsies. In contrast, for 11 UC patients with neoplasia elsewhere in the colon, we identified 63 mutations in 51 nondysplastic biopsies, and every patient possessed at least one mutant clone. A subset of clones were large and extended over many square centimeters of colon. Of these, some occurred as isolated populations in nondysplastic tissue, considerably distant from neoplastic lesions. Other large clones included regions of cancer, suggesting that the tumor arose within a preexisting clonal field. Our results demonstrate that neutral mutations in polyguanine tracts serve as a unique tool for identifying fields of clonal expansions, which may prove clinically useful for distinguishing a subset of UC patients who are at risk for developing cancer.
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PMID:Clonal expansions in ulcerative colitis identify patients with neoplasia. 1992 51

Colorectal cancer (CRC) is one of the most serious complications of inflammatory bowel disease. Tumor necrosis factor-alpha (Tnfalpha) is a major mediator of inflammation and there is increasing evidence that Tnfalpha/Tnf-receptor-1 (Tnfr1) signaling may act as an endogenous tumor promoter for colon carcinogenesis. In fact, a previous study revealed that mice lacking Tnfr1 develop significantly fewer colonic tumors in the inflammation-related CRC model. In addition, antibodies against Tnfalpha have been shown to inhibit the development of inflammation-related CRC. In the present study, Apc Min/+; Tnfalpha -/- mice were treated with 2% dextran sodium sulfate (DSS) and the tumor development was compared with Apc Min/+; Tnfalpha +/+ control mice in order to investigate the role of Tnfalpha by itself in the inflammation-related CRC. Surprisingly, there were no detectable differences in either the severity of colonic inflammation or the expression of DSS-induced chemokines and cytokines (Ccl2, Cxcl1, Tnfbeta, Il1beta, Il6, and Cox-2) that relate to the colonic inflammation and tumorigenesis between these two groups. Furthermore, the genetic ablation of Tnfalpha did not suppress the colon tumorigenesis in comparison to the wild-type mice. Our observations suggest that intricate inflammatory responses promote the inflammation-related mouse colon tumorigenesis.
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PMID:Genetic ablation of Tnfalpha demonstrates no detectable suppressive effect on inflammation-related mouse colon tumorigenesis. 2007 48

Patients with chronic colitis (ulcerative colitis or colonic Crohn's disease) have an increased risk of colorectal cancer (CRC). Although most of the molecular alterations reported in sporadic CRC have also been observed in colitis-associated CRC, they do not occur at the same timing and frequency, indicating a different pathophysiology. In particular, recent work highlighted the importance of chronic mucosal inflammation as a key factor favouring colorectal carcinogenesis in these patients. This may also be one of the reasons explaining the role of 5-aminosalicylates as chemopreventive agents for CRC in inflammatory bowel disease (IBD) patients with colonic involvement. Beside chemoprevention, colonoscopic screening and surveillance have been shown to be the cornerstone for CRC prevention and early detection in this particular patients' population. Periodic surveillance colonoscopy to detect dysplasia has been shown to decrease the mortality attributed to CRC. More recently, progress in imaging techniques increased our ability to identify dysplasia, and should probably now be considered to be an integral part of surveillance colonoscopy. In the future, further improvement of our knowledge of CRC biology, refinement of imaging techniques, as well as molecular discovery (e.g. identification of specific mutations in stool DNA extracts), might lead to develop more accurate diagnostic strategies to reduce the morbidity and mortality related to CRC in patients with ulcerative colitis or colonic Crohn's disease.
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PMID:Colon cancer in inflammatory bowel disease: recent trends, questions and answers. 2011 42

Survival and proliferation signals are two processes closely interrelated and finely controlled in most cell types, whose deregulation may lead to carcinogenesis. In the last decade, different studies have suggested that both cellular functions are also intimately associated with other cellular activities such as differentiation and cellular activation, especially in immune cells. The aim of this study was to evaluate the effects of the short-chain fatty acid (SCFA) butyrate on the proliferation and activation state of different cell types involved in inflammatory bowel disease. We focused on intestinal epithelial cells, macrophages and T-lymphocytes, using both primary non-transformed cultures and established cell lines. The results showed that low concentrations of butyrate inhibited the proliferation of all the immune cell types tested in this work, whereas it only induced apoptosis in activated T-lymphocytes, non-differentiated epithelial cells and macrophage cell lines, but not in differentiated epithelial cells or primary macrophages. Butyrate apoptosis induction was mediated by caspase-3/7 activation. This SCFA was only able to modify cell activation, measured as expression of inflammatory cytokines, in those cell types in which apoptosis was induced. In conclusion, our results suggest a cell type-specificity of the immune-modulatory effects of butyrate based on the proliferation/activation characteristic physiology of these processes in different cells types.
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PMID:Butyrate in vitro immune-modulatory effects might be mediated through a proliferation-related induction of apoptosis. 2014 75

Patients with ulcerative colitis and Crohn's disease are at increased risk of developing intestinal cancers via mechanisms that remain incompletely understood. However, chronic inflammation and repeated events of inflammatory relapse in inflammatory bowel disease (IBD) expose these patients to a number of signals known to have tumorigenic effects including persistent activation of the nuclear factor-kappaB and cyclooxygenase-2/prostaglandin pathways, release of proinflammatory mediators such as tumor necrosis factor-alpha and interleukin-6, and enhanced local levels of reactive oxygen and nitrogen species. These inflammatory signals can contribute to carcinogenesis via 3 major processes: 1) by increasing oxidative stress, which promotes DNA mutagenesis thus contributing to tumor initiation; 2) by activating prosurvival and antiapoptotic pathways in epithelial cells, thereby contributing to tumor promotion; and 3) by creating an environment that supports sustained growth, angiogenesis, migration, and invasion of tumor cells, thus supporting tumor progression and metastasis. The present review integrates clinical and basic research observations in an attempt to provide a comprehensive understanding of how inflammatory processes may contribute to intestinal cancer development in IBD patients.
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PMID:Mechanisms by which inflammation may increase intestinal cancer risk in inflammatory bowel disease. 2015 48

Many chronic inflammatory diseases are associated with increased risk of developing cancer. In the colon, strong support for a link between chronic inflammation and cancer extends, in part, from population-based studies of persons with inflammatory bowel disease (IBD). Patients with IBD are at increased risk of developing colorectal cancer (CRC). The general consensus is that IBD results from the combined effects of genetics and environment factors known to affect the immune system. Vitamin D, an important regulator of the immune system, has been linked to IBD. Despite the strong potential reported for 1,25-dihydroxyvitamin D (1,25-OH)2D), its effects on calcium metabolism limits its application. Recently, less active vitamin D metabolites, cholecalciferol and 25-hydroxyvitamin D (25(OH)D), have gained considerable attention as promising agents against IBD-related colon cancer. Yet, their anti-proliferative properties and mechanism of action remain to be better defined. We present several signaling pathways commonly regulated by vitamin D compounds and highlight their regulation on TLR4. The efficacy of 25(OH)D and 1alpha-hydroxyviatmin D5 are evaluated using the azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced IBD-related colon carcinogenesis model. In summary, vitamin D supplementation may provide a cost-effective approach to reduce IBD related colon cancer.
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PMID:Actions of vitamin D are mediated by the TLR4 pathway in inflammation-induced colon cancer. 2021 86

This perspective on the report by Beatty et al. in this issue of the journal (beginning on page 438) discusses the prevention of cancer through vaccination strategies that target antigens associated with tumor promotion and progression. Such approaches were first developed for treating cancer. We address cancer vaccination in the context of a mouse model of inflammatory bowel disease expressing MUC1, an epithelial mucin aberrantly expressed during chronic inflammation and in colorectal carcinogenesis, and in a broader context that includes the potential of targeting the tumor microenvironment for immunoprevention in humans. Obstacles in developing effective cancer vaccines, including antigen selection, immunoediting, and tumor-mediated immunosuppression, are also discussed.
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PMID:Vaccine prevention of cancer: can endogenous antigens be targeted? 2033 1

Epithelial-mesenchymal interactions regulate normal gut epithelial homeostasis and have a putative role in inflammatory bowel disease and colon cancer pathogenesis. Epimorphin is a mesenchymal and myofibroblast protein with antiproliferative, promorphogenic effects in intestinal epithelium. We previously showed that deletion of epimorphin partially protects mice from acute colitis, associated with an increase in crypt cell proliferation. Here we explored the potential therapeutic utility of modulating epimorphin expression by examining the effects of epimorphin deletion on chronic inflammation-associated colon carcinogenesis using the azoxymethane/dextran sodium sulfate (AOM/DSS) model. We found that mice in which epimorphin expression was absent had a marked reduction in incidence and extent of colonic dysplasia. Furthermore, epimorphin deletion in myofibroblasts altered the morphology and growth of cocultured epithelial cells. Loss of epimorphin affected secretion of soluble mesenchymal regulators of the stem cell niche such as Chordin. Importantly, IL-6 secretion from LPS-treated epimorphin-deficient myofibroblasts was completely inhibited, and stromal IL-6 expression was reduced in vivo. Taken together, these data show that epimorphin deletion inhibits chronic inflammation-associated colon carcinogenesis in mice, likely as a result of increased epithelial repair, decreased myofibroblast IL-6 secretion, and diminished IL-6-induced inflammation. Furthermore, we believe that modulation of epimorphin expression may have therapeutic benefits in appropriate clinical settings.
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PMID:Epimorphin deletion protects mice from inflammation-induced colon carcinogenesis and alters stem cell niche myofibroblast secretion. 2045 44

Colorectal cancer is respectively the third and second most common cancer among men and women in France. Interest in chemoprevention for colorectal cancer has increased over the last two decades. Beside non-steroidal anti-inflammatory drugs, ursodeoxycholic acid (UDCA) may have chemopreventive action in colorectal cancer with a likely better tolerance. In high-risk populations such as patients with inflammatory bowel disease or prior colorectal adenoma or carcinoma, retrospective and prospective studies have suggested a beneficial effect of UDCA. In azoxymethane model, UDCA inhibits tumor development by countering the tumor-promoting effects of secondary bile acids, such as deoxycholic acid (DCA). The opposing effects of UDCA and DCA on lipid raft composition may be central to their effects on colonic tumorigenesis. Differential effects of DCA and UDCA on growth factor and inflammatory signals involved in colorectal carcinogenesis, such as epidermal growth factor receptors (EGFR) signaling and Cox-2 expression, likely mediate their opposing effects on colonic tumor promotion and tumor inhibition, respectively.
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PMID:Ursodeoxycholic acid and chemoprevention of colorectal cancer. 2060 43


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