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)

Previously, we have shown that DA-6034, a synthetic derivative of flavonoid eupatilin, inhibited NF-kappaB activation in colon epithelial cells and prevented trinitrobenzene sulfonic acid-induced rat colitis. The aim of this study was to investigate the preventive and therapeutic effect of DA-6034 on dextran sulfate sodium (DSS)-induced colitis and on inflammation-related cancer. C57BL/6 mice were given 4% DSS for 5 days with and without DA-6034 in the acute preventive model. In the acute therapeutic model, mice were given 4% DSS for 5 days followed by rectal administration of DA-6034. Colitis was quantified by body weight, disease activity index (DAI), colon length, and histology. In the inflammation-related cancer model, mice were given a single intraperitoneal injection of azoxymethane, then three cycles of 2% DSS for 5 days, then 2 weeks of free water consumption. Apoptosis was determined by in situ terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling assay, and the expression of Ki-67, phospho-kappaB kinase alpha (IKKalpha), and COX-2 were evaluated by immunohistochemistry. In both the acute preventive and acute therapeutic models, DA-6034 significantly attenuated DSS-induced weight loss, an increase in DAI, and a shortening of colon length. DA-6034-treated mice maintained crypt architecture and revealed a scanty infiltration of inflammatory cells in both the preventive and therapeutic models. In the inflammation-related cancer model, DA-6034 reduced the number of colon tumors and ameliorated weight loss and shortening of colon length. DA-6034 strongly enhanced apoptosis and inhibited the expression of COX-2 and phospho-IKKalpha in inflammation-related colon cancer models. Our results suggest that DA-6034 prevents acute murine colitis and inhibits inflammation-related colon carcinogenesis. DA-6034 could be a potential therapeutic agent for inflammatory bowel disease.
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PMID:DA-6034, a derivative of flavonoid, prevents and ameliorates dextran sulfate sodium-induced colitis and inhibits colon carcinogenesis. 1822 73

Herein, we describe the clinical, pathologic, immunohistochemical, and molecular features of 3 unique patients with long standing inflammatory bowel disease, all of whom developed numerous discrete hyperplastic/serrated colonic polyps similar to those described in the hyperplastic/serrated polyposis syndrome. The 3 patients (2 with ulcerative colitis and 1 with Crohn ileo-colitis) were evaluated for a variety of clinical, histologic (including the type, location and number of polyps in the colon), and immunohistochemical features [MLH-1, MSH-2, MGMT (O(6)-methylguanine-DNA methyltransferase), beta-catenin, and p53]. KRAS and BRAF mutation analysis was also performed on a subset of polyps from 2 patients. All patients had moderate-severe pancolitis of more than 10 years duration and had >20 colonic polyps. None had polyps in the upper gastrointestinal tract. Pathologically, a combination of conventional hyperplastic polyps and sessile serrated polyps (adenomas) were present in the 3 cases. In addition, serrated adenomas were present in 2 and conventional adenomas in 1. Two patients also had synchronous adenocarcinoma. All 3 cases showed retention of MLH-1 and MSH-2, and a membranous beta-catenin staining pattern. However, 2 cases showed loss of MGMT in several serrated polyps, and one also in adjacent colitic mucosa. KRAS mutations were detected in 5/11 serrated polyps. However, BRAF mutations were not present in any of the polyps tested. These findings suggest the possibility of a serrated pathway of carcinogenesis in inflammatory bowel disease characterized by silencing of MGMT, most likely by gene promoter methylation, KRAS mutations, and possibly other, as yet, uncharacterized molecular alterations, resulting eventually in progression to adenocarcinoma.
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PMID:Hyperplastic/serrated polyposis in inflammatory bowel disease: a case series of a previously undescribed entity. 1822 33

Regular consumption of mesalazine has been associated with a reduced risk of colorectal cancer (CRC) in patients with inflammatory bowel disease. The molecular mechanisms underlying the antineoplastic effect of 5-aminosalicylic acid remain, however, poorly characterized. In this study, we examined whether mesalazine affects cell cycle progression and analyzed specific checkpoint pathways in experimental models of CRC. Mesalazine inhibited the growth of HCT-116 and HT-29 cells, two CRC cell lines that express either a wild-type or mutated p53. Cell cycle analysis revealed that mesalazine induced cells to accumulate in S phase. This effect was associated with a sustained phosphorylation of the cyclin-dependent kinase (CDK)2 at threonine 14 and tyrosine 15 residues, an event that inactivates the CDK2-cyclin complex and blocks S-G(2) phase cell cycle transition. Consistently, mesalazine reduced the protein content of CDC25A, a phosphatase that regulates CDK2 phosphorylation status. Analysis of upstream kinases that negatively control CDC25A expression showed that mesalazine enhanced the activation of CHK1 and CHK2. However, silencing of CHK1 and CHK2 did not prevent the mesalazine-induced CDC25A protein downregulation. In contrast, CDC25A protein ubiquitination and degradation and accumulation of cells in S phase following mesalazine exposure were reverted by proteasome inhibitors. Notably, mesalazine also inhibited CDC25A in human CRC explants. Finally, we showed that mesalazine downregulated CDC25A in CT26, a murine CRC cell line, and prevented the formation of CT26-derived tumors in mice. Data show that mesalazine negatively regulates CDC25A protein expression, thus delaying CRC cell progression.
Carcinogenesis 2008 Jun
PMID:Mesalazine negatively regulates CDC25A protein expression and promotes accumulation of colon cancer cells in S phase. 1849 57

Nitric oxide production in the colon has been linked to inflammatory bowel disease (IBD) and increased risk for colon cancer. However, measurements of NO concentration in the inflamed colon have not been available and it is not known what NO levels are pathophysiological. A computational model, based on anatomical length scales and rates of NO production measured in cell cultures, was used to predict spatially varying NO concentrations within a colonic crypt under inflammatory conditions. A variety of scenarios were considered, including different spatial distributions of macrophages and a range of possible macrophage and epithelial synthesis rates for NO. Activated macrophages arranged as a monolayer at the base of the crypt elicited maximum NO concentrations of approximately 0.3 microM. The epithelial contribution to NO synthesis was calculated to be negligible. Assuming a uniform macrophage layer, NO synthesis rates greater than 20 microM/s, or more than three times that measured in vitro, would be necessary to achieve maximum NO concentrations of 1 microM in the crypt. Thus, unless NO synthesis rates in macrophages and/or epithelial cells greatly exceed those measured in cell cultures, NO concentrations will remain submicromolar in the crypt during inflammation. Additionally, the results were used to predict the range of NO concentrations (<0.3 microM) and cumulative NO dose (560 microM min) experienced by a given epithelial cell migrating from the base to the top of the crypt. These estimates of NO concentrations in inflamed crypts should facilitate efforts to elucidate the molecular biological linkage between NO exposure and carcinogenesis in IBD.
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PMID:Prediction of nitric oxide concentrations in colonic crypts during inflammation. 1850 Dec 1

Chronic inflammation increases cancer risk. While it is clear that cell signaling elicited by inflammatory cytokines promotes tumor development, the impact of DNA damage production resulting from inflammation-associated reactive oxygen and nitrogen species (RONS) on tumor development has not been directly tested. RONS induce DNA damage that can be recognized by alkyladenine DNA glycosylase (Aag) to initiate base excision repair. Using a mouse model of episodic inflammatory bowel disease by repeated administration of dextran sulfate sodium in the drinking water, we show that Aag-mediated DNA repair prevents colonic epithelial damage and reduces the severity of dextran sulfate sodium-induced colon tumorigenesis. Importantly, DNA base lesions expected to be induced by RONS and recognized by Aag accumulated to higher levels in Aag-deficient animals following stimulation of colonic inflammation. Finally, as a test of the generality of this effect we show that Aag-deficient animals display more severe gastric lesions that are precursors of gastric cancer after chronic infection with Helicobacter pylori. These data demonstrate that the repair of DNA lesions formed by RONS during chronic inflammation is important for protection against colon carcinogenesis.
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PMID:DNA damage induced by chronic inflammation contributes to colon carcinogenesis in mice. 1852 Nov 88

Chronic inflammation caused by Helicobacter pylori infection or inflammatory bowel disease (IBD) is closely linked to cancer development. Innate immune abnormalities and enhanced production of reactive oxygen species through a phagocyte NADPH oxidase (Nox2) are key issues in understanding the pathogenesis of inflammation-dependent carcinogenesis. Besides Nox2, functionally distinct homologues (Nox1, Nox3, Nox4, Nox5, Duox1, and Duox2) have been identified. Nox1 and Duox2 are highly expressed in the gastrointestinal tract. Although the functional roles of Nox/Duox in the gastrointestinal tract are still unclear, we will review their potential roles in the gastrointestinal immunopathology, particularly in H. pylori-induced inflammation, IBD, and malignancy.
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PMID:Nox enzymes and oxidative stress in the immunopathology of the gastrointestinal tract. 1852 7

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).
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PMID:Oxidative stress in ulcerative colitis-associated carcinogenesis. 1857 74

PPARbeta/delta (peroxisome-proliferator-activated receptor beta/delta) is one of three PPARs in the nuclear hormone receptor superfamily that are collectively involved in the control of lipid homoeostasis among other functions. PPARbeta/delta not only acts as a ligand-activated transcription factor, but also affects signal transduction by interacting with other transcription factors such as NF-kappaB (nuclear factor kappaB). Constitutive expression of PPARbeta/delta in the gastrointestinal tract is very high compared with other tissues and its potential physiological roles in this tissue include homoeostatic regulation of intestinal cell proliferation/differentiation and modulation of inflammation associated with inflammatory bowel disease and colon cancer. Analysis of mouse epithelial cells in the intestine and colon has clearly demonstrated that ligand activation of PPARbeta/delta induces terminal differentiation. The PPARbeta/delta target genes mediating this effect are currently unknown. Emerging evidence suggests that PPARbeta/delta can suppress inflammatory bowel disease through PPARbeta/delta-dependent and ligand-independent down-regulation of inflammatory signalling. However, the role of PPARbeta/delta in colon carcinogenesis remains controversial, as conflicting evidence suggests that ligand activation of PPARbeta/delta can either potentiate or attenuate this disease. In the present review, we summarize the role of PPARbeta/delta in gastrointestinal physiology and disease with an emphasis on findings in experimental models using both high-affinity ligands and null-mouse models.
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PMID:Role of peroxisome-proliferator-activated receptor beta/delta (PPARbeta/delta) in gastrointestinal tract function and disease. 1861 31

Patients with inflammatory bowel disease (IBD) are at increased risk of developing colorectal adenocarcinoma. The factors that result in IBD-associated carcinogenesis are not understood. We hypothesized that altered expression of intestinal epithelial tight junction proteins might contribute to neoplastic progression. Semiquantitative immunohistochemical staining of human biopsies was used to assess expression of the tight junction proteins claudin-1, claudin-2, claudin-4, and occludin in IBD, IBD-associated dysplasia, acute, self-limited colitis (ASLC), and sporadic adenomas. Claudin-1 and claudin-2 expression was elevated in active IBD, adenomas, and IBD-associated dysplasia, but not ASLC. In contrast, claudin-4 expression was elevated in both active IBD and ASLC. Occludin expression was similar to control in all cases. Importantly, in IBD, claudin-1 and claudin-2 expression correlated positively with inflammatory activity. To investigate mechanisms underlying altered claudin expression, beta-catenin activation was assessed as nuclear localization. Like claudin-1 and claudin-2, beta-catenin was markedly activated in IBD, sporadic dysplasia, and IBD-associated dysplasia, but was only slightly activated in ASLC. Taken together, these data suggest that beta-catenin transcriptional activity is elevated in chronic injury and that this may contribute to increased claudin-1 and claudin-2 expression. We speculate that increased claudin-1 and claudin-2 expression may be involved at early stages of transformation in IBD-associated neoplasia.
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PMID:Claudin-1 and claudin-2 expression is elevated in inflammatory bowel disease and may contribute to early neoplastic transformation. 1871 53

In inflammatory bowel disease (IBD), such as UC and CD, the development of colorectal carcinoma can be initiated through chronic inflammation, depending on the duration and severity of the disease. Growing evidence supports a role for various cytokines, released by epithelial and immune cells, in the pathogenesis of colitis associated cancer (CAC). For instance, TNF-alpha has been recently shown to promote tumor development in experimental colitis. Due to its role in the pathogenesis of IBD, TNF-alpha blockade has become one of the cornerstones of IBD therapy. Thus, anti-TNF-alpha strategies could also provide effective anti-tumor therapies. TGF-beta has been shown to attenuate an anti-tumor immune-response through the induction of regulatory T cells in spontaneous and inflammation associated cancer. However, IL-6 signaling promotes tumor growth in experimental CAC, and this signaling is inhibited by TGF-beta. Members of the IL-12 family, such as IL-12, IL-23, and IL-27, have been implicated in pathogenesis of colitis and IL-23 seems to be involved in inflammation associated carcinogenesis. However, a role for those cytokines in CAC remains to be shown. Whereas the above-mentioned cytokines promote tumor growth, others provide an anti tumor effect. IL-10 deficient mice develop colitis and CAC a few weeks after birth. Besides its immunosuppressive properties, IL-10 also has anti angiogenic and both tumor promoting and -inhibiting properties, which could be responsible for these observations. Since most of the above mentioned cytokines are involved in both, inflammation and carcinogenesis, it is difficult to account their contribution to the individual steps during pathogenesis of CAC. However, as already shown in IBD, cytokines may also provide promising therapeutic targets in CAC.
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PMID:Cytokines in colitis associated cancer: potential drug targets? 1878 26


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