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)

Increased cancer risk occurs in inflammatory bowel disease (IBD) undergoing long-term chronic inflammation. To evaluate whether inducible nitric oxide synthase (iNOS)-dependent DNA damage plays a role in the carcinogenic process triggered by IBD, we prepared a mouse model of IBD induced by transfer of CD45RBhighCD4+ T cells lacking regulatory T cells to female severe combined immunodeficiency (SCID) mice. CD45RBhighCD4+ T cells were isolated from mouse spleen after staining with fluorescein isothiocyanate (FITC)-conjugated anti-CD45RB monoclonal antibody, followed by anti-FITC-conjugated microbeads. This IBD mouse model showed that the bodyweight increased with aging to a lesser extent than non-treated controls, and that the intestine was shortened. Pathological findings of this mouse model, which showed severe inflammation in colon tissues, were similar to IBD patients. Double immunofluorescence technique revealed that both 8-nitroguanine and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) were formed mainly in epithelial cells of the IBD mouse model. 8-Nitroguanine was formed in most of 8-oxodG-immunoreactive nuclei of epithelial cells. iNOS, proliferating cell nuclear antigen and p53 protein were also expressed in the colon epithelium. These results indicate that nitrative DNA damage, as well as oxidative DNA damage, is induced in colon epithelial cells of the IBD mouse model followed by proliferation of these cells, which may contribute to colon carcinogenesis.
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PMID:Inducible nitric oxide synthase-dependent DNA damage in mouse model of inflammatory bowel disease. 1577 18

Chronic inflammation has long been recognized as a risk factor for human cancer at various sites. Examples include Helicobacter pylori-induced gastritis for gastric cancer, inflammatory bowel disease (ulcerative colitis and Crohn's disease) for colorectal cancer and chronic viral hepatitis for liver cancer. Here we review the role in carcinogenesis of nitrative damage to nucleic acids, DNA and RNA, which occurs during inflammation through the generation of reactive nitrogen species, such as peroxynitrite, nitroxyl, and nitrogen dioxide. Enhanced formation of 8-nitroguanine, representative of nitrative damage to nucleobases, has been detected in various inflammatory conditions. The biochemical nature of DNA damage mediated by reactive nitrogen species is discussed in relation to its possible involvement in mutations, genetic instability, and cell death. Better understanding of the mechanisms and role of such nitrative damage in chronic inflammation-associated human cancer is a necessary basis to develop new strategies for cancer prevention by modulating the process of inflammation.
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PMID:Nitrative DNA damage in inflammation and its possible role in carcinogenesis. 1609 98

Cancers of breast and bowel are increasingly frequent in humans. Chronic inflammation is known to be a risk factor for these malignancies, yet cellular and molecular mechanisms linking inflammation and carcinogenesis remain poorly understood. Here, we apply a widely used T-cell transfer paradigm, involving adoptive transfer of proinflammatory CD4+ CD45RB(hi) (T(E)) cells to induce inflammatory bowel disease (IBD) in mice, to investigate roles of inflammation on carcinogenesis in the Apc(Min/+) mouse model of intestinal polyposis. We find that transfer of T(E) cells significantly increases adenoma multiplicity and features of malignancy in recipient Apc(Min/+) mice. Surprisingly, we find that female Apc(Min/+) recipients of T(E) cells also rapidly develop mammary tumors. Both intestinal polyposis and mammary adenocarcinoma are abolished by cotransfer of anti-inflammatory CD4+ CD45RB(lo) regulatory lymphocytes or by neutralization of key proinflammatory cytokine tumor necrosis factor-alpha. Lastly, down-regulation of cyclooxygenase-2 and c-Myc expression is observed coincident with tumor regression. These findings define a novel mouse model of inflammation-driven mammary carcinoma and suggest that epithelial carcinogenesis can be mitigated by anti-inflammatory cells and cytokines known to regulate IBD in humans and mice.
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PMID:Proinflammatory CD4+ CD45RB(hi) lymphocytes promote mammary and intestinal carcinogenesis in Apc(Min/+) mice. 1639 16

Individuals with inflammatory bowel disease (IBD) are at increased risk of developing gastrointestinal cancer. Here, we have tested the possibility that chronic inflammation could trigger mutations. For this, we have used IL-10-deficient (IL-10-/-) mice, which spontaneously develop intestinal inflammation, in combination with a transgenic gpt gene and red/gam gene (gpt+IL-10-/-), which is a well-characterized mutation reporter locus. The total mutation frequency in the colon of gpt+IL-10-/- mice was about five times higher than that in normal gpt+IL-10+/+ mice. In the particular case of G:C to A:T transitions, the frequency of mutations in gpt+IL-10-/- mice was 4.1 times higher than that in control mice. Interestingly, the frequency of small deletions and insertions was also strikingly increased (approximately 10 times). The majority of the deletion or insertion mutations were observed in the monotonous base runs or adjacent repeats of short tandem sequences. In contrast, the frequency of large deletions, detected by loss of the Spi marker present in the red/gam transgene, was similar among the mouse strains. Finally, as a control, the mutation frequency in non-inflamed tissues, such as the liver, were similar between gpt+IL-10-/- mice and gpt+IL-10+/+ mice. Our data demonstrate that the chronic inflammatory environment in the colon promotes the generation of mutations.
Carcinogenesis 2006 May
PMID:IL-10 deficiency leads to somatic mutations in a model of IBD. 1640 68

A causal link between chronic inflammation and carcinogenesis is explored by reviewing illustrative examples of specific cancers and causal agents and mechanisms. The causal agents or pathologic conditions include microbial agents, gastroesophageal reflux, chronic cholecystitis and cholelithiasis, inflammatory bowel disease, and specific agents that cause chronic obstructive or diffuse interstitial lung disease. The proportion of total cancer deaths attributable to infectious agents is estimated to be about 20% to 25% in developing countries and 7% to 10% in more industrialized countries. Recurrent or persistent inflammation may induce, promote, or influence susceptibility to carcinogenesis by causing DNA damage, inciting tissue reparative proliferation, and/or creating a stromal "soil" that is enriched with cytokines and growth factors. Future research on the complex cascade of cellular and humoral factors participating in the chronic inflammatory process will further understanding of the pathogenesis of various cancers and potentially provide a rationale for targeted chemopreventive interventions.
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PMID:Chronic inflammation: a common and important factor in the pathogenesis of neoplasia. 1651 35

Infection and chronic inflammation are proposed to contribute to carcinogenesis through inflammation-related mechanisms. Infection with hepatitis C virus, Helicobacter pylori and the liver fluke, Opisthorchis viverrini (OV), are important risk factors for hepatocellular carcinoma (HCC), gastric cancer and cholangiocarcinoma, respectively. Inflammatory bowel diseases (IBDs) and oral diseases, such as oral lichen planus (OLP) and leukoplakia, are associated with colon carcinogenesis and oral squamous cell carcinoma (OSCC), respectively. We performed a double immunofluorescence labeling study and found that nitrative and oxidative DNA lesion products, 8-nitroguanine and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), were formed and inducible nitric oxide synthase (iNOS) was expressed in epithelial cells and inflammatory cells at the site of carcinogenesis in humans and animal models. Antibacterial, antiviral and antiparasitic drugs dramatically diminished the formation of these DNA lesion markers and iNOS expression. These results suggest that oxidative and nitrative DNA damage occurs at the sites of carcinogenesis, regardless of etiology. Therefore, it is considered that excessive amounts of reactive nitrogen species produced via iNOS during chronic inflammation may play a key role in carcinogenesis by causing DNA damage. On the basis of our results, we propose that 8-nitroguanine is a promising biomarker to evaluate the potential risk of inflammation-mediated carcinogenesis.
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PMID:Oxidative and nitrative DNA damage in animals and patients with inflammatory diseases in relation to inflammation-related carcinogenesis. 1660 33

Anemia associated with long-standing chronic inflammation and iron deficiency, and the increased risk for the development of dysplasia and carcinoma, are two of the most common complications in patients with ulcerative colitis (UC). Because of iron and nutrition deficiency, UC patients are encouraged to consume a high-protein and high-iron diet. The crucial clinical question is the effect of a high-iron diet on inflammation activity and inflammation-driven carcinogenesis. Is a high-iron diet a foe or a feat in UC and UC-associated carcinogenesis? This review updates the progress and information on (1) iron nutrition and iron-deficiency anemia in patients with UC, (2) experimental evidence of the exacerbating effect of a high-iron diet on UC and its associated carcinogenesis and the difference between a high-iron diet and parental iron supplementation, (3) the clinical efficacy of, and concerns about, oral and intravenous iron supplements in patients with inflammatory bowel disease and iron deficiency anemia, and (4) the clinical implications of long-term iron supplements and management of UC. These experimental findings from animal models provide evidence to warrant further consideration and clinical studies of iron nutrition, inflammation activity, and cancer development.
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PMID:High-iron diet: foe or feat in ulcerative colitis and ulcerative colitis-associated carcinogenesis. 1672 Dec 19

The rising incidence and poor prognosis of colorectal cancer have aroused substantial interest in novel chemopreventive strategies. Interestingly, treatment of ulcerative colitis with mesalazine, which displays few side effects during long-term treatment, is associated with a reduced incidence of colorectal cancer, but its molecular mechanism is not known. The effect of mesalazine on the Wnt/beta-catenin pathway was studied in colorectal cancer cell lines to find a molecular basis underlying its chemopreventive features. Mesalazine affects the Wnt/beta-catenin pathway in adenomatous polyposis coli mutated cells with intact beta-catenin, judged by luciferase reporter assays. Furthermore, mesalazine treatment reduced expression of nuclear beta-catenin and Wnt/beta-catenin target genes, and increased beta-catenin phosphorylation. This effect on the Wnt/beta-catenin pathway is mediated via protein phosphatase 2A (PP2A): increased phosphorylation of PP2A after mesalazine treatment is observed, which coincides with decreased PP2A enzymatic activity. The inhibition of PP2A enzymatic activity by mesalazine is essential for its effect on the Wnt/beta-catenin pathway, as shown by transient transfection with siPP2A and mutant PP2A. This study shows, using concentrations of mesalazine identical to concentrations seen in patients with inflammatory bowel disease, that mesalazine inhibits the Wnt/beta-catenin pathway via inhibition of PP2A.
Carcinogenesis 2006 Dec
PMID:Protein phosphatase 2A is required for mesalazine-dependent inhibition of Wnt/beta-catenin pathway activity. 1672 34

Recent studies have indicated a strong link between Helicobacter pylori and idiopathic thrombocytopenic purpura and iron deficiency anemia. Interesting results have also been obtained for ischemic heart disease, though most putative associations between H. pylori infection and extragastric disease remain speculative. With regard to other Helicobacter species, Helicobacter felis has been shown to play a role in gastric carcinogenesis in mouse models. An increased susceptibility to cholesterol gallstone formation has been described in animals fed a lithogenic diet and infected with Helicobacter bilis, or co-infected with Helicobacter hepaticus and Helicobacter rodentium. Finally, enterohepatic Helicobacter species have also been exploited to better understand inflammatory bowel disease.
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PMID:Extragastric manifestations of Helicobacter pylori infection--other Helicobacter species. 1692 12

Matrix metalloproteinases (MMPs) are responsible for the turnover and degradation of extracellular matrix. They play a crucial role in the growth and migration of colorectal carcinoma cells. Colorectal carcinomas are characterized by enhanced expression of MMP-2, MMP-9, MMP-7, and MMP-13. The aim of this study was to determine the expression levels of MMP-2, MMP-9, MMP-7, MMP-13, and MMP-14 and their specific inhibitor TIMP-1 in inflammatory bowel diseases and precancerous lesions of the colon, i.e., Crohn's disease and ulcerative colitis, and in adenomatous polyps (APs) for comparison. Biopsy samples of pathological and healthy tissue were obtained from 40 patients with inflammatory bowel disease (ulcerative colitis, n = 17; Crohn's disease, n = 23) and from 19 patients with APs. mRNA was measured by quantitative real-time polymerase chain reaction to study MMP and TIMP-1 gene expression in both pathological and normal mucosal specimens. For MMP-2, MMP-9, and TIMP-1, protein expression also was quantified with sandwich enzyme-linked immunosorbent assay. In biopsy specimens of Crohn's disease and ulcerative colitis, significantly increased levels of MMP-2, MMP-7, and MMP-13 mRNA were found. MMP-2 and MMP-9 showed enhanced secretion on the protein level. AP revealed an increased transcription of MMP-7 and MMP-13 genes. MMP-14 mRNA was decreased in APs. MMPs, especially MMP-7 and MMP-13, which are expressed primarily on the tumor cell surface, are elevated in inflammatory bowel disease, which may have more chance to evolve into malignancy than normal tissue. In APs, increased expression of MMP-7 and MMP-13 may serve as an early indicator for colorectal carcinogenesis.
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PMID:Enhanced expression of MMP-7 and MMP-13 in inflammatory bowel disease: a precancerous potential? 1707 43


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