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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

DNA hypermethylation is one of major epigenetic changes. Hypermethylation of many genes has been reported to be related with carcinogenesis and tumor progression of colorectal cancer. Some genes including estrogen receptor is associated with ageing, and changes related with ageing may be accelerated in inflammatory bowel disease. Furthermore, fecal DNA methylation will be able to be used as a marker of colorectal cancer and inflammatory bowel disease. Evaluation of hypermethylation potentially contributes diagnosis of colorectal diseases.
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PMID:DNA hypermethylation in colorectal neoplasms and inflammatory bowel disease: a mini review. 1709 3

A close association between inflammatory bowel disease (IBD) and increased risk of developing adenocarcinoma exists. Moreover, chronic induction of high levels of nitric oxide (NO) produced from inducible nitric oxide synthase (iNOS) is a consistent observation in IBD. In this study we made interleukin-10/inducible nitric oxide synthase double-deficient (IL-10(-/-)/iNOS(-/-)) mice and studied the development of adenocarcinoma. Mice >6 months of age were compared with healthy wild-type (WT) controls. Inflammation was assessed using macroscopic/histological scores and myeloperoxidase activity as an indication of granulocyte infiltration. Mucosal polyps were scored macroscopically and hyperproliferation was quantified by 5-bromo-2-deoxyuridine immunohistochemistry. Dysplastic changes were assessed histologically based on cytologic and architectured atypia as well as the presence of submucosal invasion. The p53 and beta-catenin messenger RNA mRNA and protein expression were assessed using real-time polymerase chain reaction and immunohistochemistry, respectively. Inflammatory indices were significantly elevated in interleukin-10-deficient (IL-10(-/-)) over WT and not significantly different from IL-10(-/-)/iNOS(-/-) mice. The incidence of mucosal polyps was similar between IL-10(-/-) (79%) and IL-10(-/-)/iNOS(-/-) (83%) mice; however, significantly higher numbers of polyps were observed in the absence of iNOS (P < 0.05). Hyperproliferation was noted in both groups. Signs of dysplasia and submucosal invasion were significantly higher in IL-10(-/-)/iNOS(-/-) compared with IL-10(-/-) mice (P < 0.05). No significant increase in p53 and beta-catenin mRNA levels was observed in IL-10(-/-) over WT mice; however, a 2-fold (P = 0.06) and 3-fold (P < 0.05) increase, respectively, was noted in IL-10(-/-)/iNOS(-/-) mice. Our data suggest exposure to chronic NO limits abnormal p53 and beta-catenin expression and reduces incidence of adenocarcinoma in IL-10(-/-) mice.
Carcinogenesis 2007 May
PMID:Induction of inducible nitric oxide synthase: a protective mechanism in colitis-induced adenocarcinoma. 1711 28

The role of colonic mucosal ornithine decarboxylase (ODC) in inflammatory bowel disease (IBD) remains controversial. This study assessed mucosal ODC activity in IBD patients segment by segment with regard to patient characteristics, disease activity/duration, medication, degree of mucosal inflammation, and presence/absence of epithelial regeneration and guanosine triphosphate (GTP) stimulation. Mucosal ODC activity was determined in biopsy specimens from the terminal ileum, cecum/ascending, transverse, and descending colon, and the sigmoid/rectum of 35 patients with IBD (18 with Crohn's disease, 17 with ulcerative colitis) and 29 controls, using the amount of 14CO2 liberated from (carboxyl-14C)ornithine hydrochloride. GTP-stimulatable activity was expressed as the ratio of ODC activity in the presence and absence of GTP (70 micromol/L). Mucosal inflammation was assessed endoscopically/microscopically with previously described criteria. Presence/absence of mucosal regeneration also was determined by predefined criteria. Mucosal ODC-activity did not significantly differ in IBD patients and controls. There was a 4.4-fold activity gradient from the ileum to the rectum. Mucosal ODC activity was significantly higher in areas with epithelial regeneration compared to those without regeneration, and was stimulated by GTP by a factor of 1.42 in Crohn's disease and 1.19 in ulcerative colitis patients compared to controls (p < 0.004). On the other hand, there was no significant association/relationship of mucosal ODC activity with disease activity/duration and the endoscopic/histologic degree of mucosal inflammation. The observation of unchanged mucosal ODC activity in patients with IBD and the absence of a significant relationship with clinical and endoscopic/histologic disease characteristics speaks against a major role of ODC in IBD as a major disease marker. The role of the ileorectal gradient, the enhanced activity in areas with epithelial regeneration, and the GTP-stimulatable form, however, need further investigation with regard to a possible involvement in carcinogenesis in IBD.
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PMID:Colonic ornithine decarboxylase in inflammatory bowel disease: ileorectal activity gradient, guanosine triphosphate stimulation, and association with epithelial regeneration but not the degree of inflammation and clinical features. 1717 46

It is well established that cancer arises in chronically inflamed tissue, and this is particularly notable in the gastrointestinal tract. Classic examples include Helicobacter pylori-associated gastric cancer, hepatocellular carcinoma, and inflammatory bowel disease-associated colorectal cancer. Growing evidence suggests that these associations might be not casual findings. Focusing on individual cytokines has generated evidence that anti-inflammatory cytokine interleukin (IL)-10 and transforming growth factor-beta1 (TGF-beta1) may have a complex role in gastrointestinal carcinogenesis. As an example, IL-10-deficient mice develop severe atrophic gastritis and a chronic enterocolitis, developing colorectal cancer similar to human inflammatory bowel disease-associated neoplasia. TGF-beta1 is a multifunctional signaling molecule with a wide array of roles. Animal experiments suggest that TGF-beta1 plays a biphasic role in carcinogenesis by protecting against the early formation of benign epithelial growths, but promoting a significant stimulation of tumor growth invasion and metastasis during tumor progression. We assessed association of functional polymorphisms (-1082G/A; -592C/A) and TGF-beta1 (-509C/T; +869C/T) influencing the IL-10 production to colorectal cancer risk in a case-control study of 62 patients and 124 matched controls. No significant differences were observed among cancer patients and controls for IL-10 -1082G/A; -592C/A genotype frequencies. Evaluation of odds ratios (OR) for the TGF-beta1 +869C/T genotypes showed a significant increased risk for individuals bearing +869CC genotype compared to +869CT- and +869TT-positive individuals. These results suggest that the +869C allele, responsible for a Leu-->Pro substitution in the signal peptide sequence of the TGF-beta1 protein, may have a predisposing role in the development of colorectal cancer.
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PMID:Regulatory cytokine gene polymorphisms and risk of colorectal carcinoma. 1726 58

Ulcerative colitis (UC) is a chronic inflammatory bowel disease associated with intestinal inflammation and tissue damage. It is assumed that the oxidative stress that accompanies chronic inflammation contributes to the development of colorectal cancer (CRC). Thioredoxin interacting protein (TXNIP), whose expression is induced by various types of stress including oxidative stress and is downregulated in various types of human cancer including colorectal cancer, is a negative regulator of thioredoxin, which is an important regulator of redox balance. However, TXNIP expression in clinical specimens of UC remains unclear. Herein, using TaqMan RT-PCR assay, we demonstrated that TXNIP expression in UC and CRC colonic mucosa specimens was significantly lower than that in normal tissues (p=0.0007 and p<0.0001, respectively). In addition, in situ hybridization study showed that inflammatory cells expressing the TXNIP transcript were abundant in lymphoid follicles, the lamina propria and submucosa in the colonic mucosa of UC patients, but not in epithelial cells on the flat surface, whereas the TXNIP transcript was abundant in normal mucosa. Our results suggest that downregulation of TXNIP may be partly involved in the pathogenesis of UC, including inflammation and colitis-associated colon carcinogenesis.
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PMID:Decreased expression of thioredoxin interacting protein mRNA in inflamed colonic mucosa in patients with ulcerative colitis. 1767 98

The colonic epithelium is lined along its apical membrane with approximately 10(14) bacteria/g of tissue. Commensal bacteria outnumber mammalian cells in the gut severalfold. The reason for this degree of commensalism probably resides in the recent recognition of the microbiome as an important source of metabolic energy in the setting of poorly digestible nutrients. As in many themes in biology, the host may have sacrificed short-term benefit, i.e. nutritional advantages, for long-term consequences, such as chronic inflammation or colon cancer. In the present review, we examine the role of TLR (Toll-like receptor) signalling in the healthy host and the diseased host. We pay particular attention to the role of TLR signalling in idiopathic IBD (inflammatory bowel disease) and colitis-associated carcinogenesis. In general, TLR signalling in health contributes to homoeostatic functions. These include induction of antimicrobial peptides, proliferation and wound healing in the intestine. The pathogenesis of IBD, ulcerative colitis and Crohn's disease may be due to increased TLR or decreased TLR signalling respectively. Finally, we discuss the possible role of TLR signalling in colitis-associated neoplasia.
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PMID:TLR4 signalling in the intestine in health and disease. 1803 Dec 48

The cyclooxygenase (COX) is a key enzyme in the conversion of arachidonic acid to prostaglandins. COX-1 is constitutively expressed and is a critical housekeeping gene, whereas COX-2 is rapidly upregulated by growth factors and cytokines and thus responsible for inflammation. COX-2 is frequently overexpressed in colonic adenoma and carcinoma. Specific inhibitors of COX-2 have been shown to induce apoptosis in tumor cells and to inhibit tumor growth in animal models and in humans. Long-standing IBD patients have increased risk of developing colorectal cancer compared to general population. IBD-associated colorectal carcinogenesis is probably promoted by chronic inflammation and closely related to COX-2. In a recent study, powerful chemopreventive ability of selective COX-2 inhibitor was observed in colitis-related colon carcinogenesis in mouse model. But it was reported that even selective COX inhibitors aggravated the DSS-induced colonic inflammation. It is assumed that endogenous PGs are involved in the mucosal defense against DSS-induced colonic ulcerations which are produced by COX-1 at early phase and by COX-2 at late phase. Long-term use of COX-2 inhibitors for the chemoprevention of colitic cancer is needed to define their mechanism of action, that reduce side effects and have specific tumor target.
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PMID:[COX-2 inhibitors in inflammatory bowel disease: friends or foes?]. 1815 71

Mounting evidence supports the tenet that innate immune responses to luminal microbes participate in the development of gastrointestinal malignancies. The gastrointestinal tract is relatively unique in that it has evolved in the presence of diverse enteric microflora. Intestinal flora is required to develop a normal adaptive immune response in the periphery. With the characterization of the innate immune system, we have begun to understand the adaptations the intestine has made to the microbiota. The interaction between the microbiota and the intestinal mucosa through Toll-like receptors (TLRs) is required to maintain intestinal homeostasis. In particular, intestinal epithelial cells and lamina propria mononuclear cells such as antigen-presenting cells and T cells must respond to breaches in the mucosal barrier by activating TLR-dependent pathways that result in increased epithelial proliferation, wound healing and recruitment of acute inflammatory cells. In the setting of chronic inflammation such as Helicobacter pylori (H. pylori) infection in the stomach or idiopathic inflammatory bowel disease, the process of repair may eventually result in carcinogenesis. The following review highlights human and animal data that support a role for innate immune responses and TLRs specifically in promoting gastrointestinal malignancies. Candidate pathways linking TLRs to gastrointestinal malignancies include activation of nuclear factor-kappaB and cyclooxygenase-2. Studying the link between innate immune signaling and gastrointestinal malignancies offers the possibility to identify novel ways to both prevent and treat gastrointestinal cancer.
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PMID:Role of Toll-like receptors in gastrointestinal malignancies. 1817 5

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.
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PMID:Cancer in inflammatory bowel disease. 1820 Jun 60

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.
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PMID:Blocking TNF-alpha in mice reduces colorectal carcinogenesis associated with chronic colitis. 1821 90


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