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

Gastric cancer is constituted by two histomorphological entities 'intestinal' and 'diffuse', however lesions with similar morphologies may differ in biological aggressiveness and response to therapy. Two distinct molecular pathways have been identified in gastric carcinogenesis: the microsatellite mutator phenotype and a phenotype associated with chromosomal and intrachromosomal instability. Mounting evidence suggests that microsatellite mutator phenotype alterations and expression of the products of cancer-related genes are early markers of cell transformation, and may serve to identify the gastric carcinoma histotypes. The lack of a clear genetic basis, lends weight to the notion that gastric cancer is not a monomorphic entity but may be affected by environmental factors. Helicobacter pylori is the most important environmental risk factor associated with sporadic gastric cancer. Exposure of gastric epithelial cells to bacterium results in the generation of reactive oxygen species and inducible nitric oxide synthase that in turn may cause genetic alterations leading to cancer in a subset of subjects. Thus, gastric cancer may be considered the result of an interplay between host genetic profile and environmental toxic agents. The new technologies of molecular analysis will help to establish an individual's risk of developing gastric cancer and will lead to novel biological therapeutic strategies.
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PMID:Review article: molecular basis of gastric carcinogenesis. 1278 17

The peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a member of the nuclear hormone receptor superfamily that is involved in the control of inflammation and carcinogenesis. We determined the effect of the specific PPAR-gamma ligand, pioglitazone (5-40 mg/kg intragastrically), on the healing of acetic-acid gastric ulcers in rats. At day 8 after ulcer induction, the ulcer area, the gastric blood flow and mucosal expression of proinflammatory cytokines such as interleukin-1beta, tumour necrosis factor alpha (TNF-alpha) and cyclooxygenase-1, cyclooxygenase-2, constitutive nitric oxide synthase (cNOS), inducible nitric oxide synthase (iNOS) and heat shock protein 70 (HSP70) was determined. Pioglitazone reduced the area of gastric ulcers and raised significantly the gastric blood flow at the ulcer margin and downregulated the mRNA for interleukin-1beta, TNF-alpha, cyclooxygenase-2 and iNOS while cyclooxygenase-1 mRNA was not affected. The expression of PPAR-gamma mRNA was increased in the ulcerated gastric mucosa. We conclude that pioglitazone accelerates the healing of preexisting gastric ulcers due to the hyperemia at ulcer margin and the anti-inflammatory action including suppression of interleukin-1beta, TNF-alpha, cyclooxygenase-2 and iNOS and by an overexpression of HSP70.
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PMID:Pioglitazone, a specific ligand of peroxisome proliferator-activated receptor-gamma, accelerates gastric ulcer healing in rat. 1287 56

Chronic inflammation induced by biological, chemical, and physical factors has been associated with increased risk of human cancer at various sites. Inflammation activates a variety of inflammatory cells, which induce and activate several oxidant-generating enzymes such as NADPH oxidase, inducible nitric oxide synthase, myeloperoxidase, and eosinophil peroxidase. These enzymes produce high concentrations of diverse free radicals and oxidants including superoxide anion, nitric oxide, nitroxyl, nitrogen dioxide, hydrogen peroxide, hypochlorous acid, and hypobromous acid, which react with each other to generate other more potent reactive oxygen and nitrogen species such as peroxynitrite. These species can damage DNA, RNA, lipids, and proteins by nitration, oxidation, chlorination, and bromination reactions, leading to increased mutations and altered functions of enzymes and proteins (e.g., activation of oncogene products and/or inhibition of tumor-suppressor proteins) and thus contributing to the multistage carcinogenesis process. Appropriate treatment of inflammation should be explored further for chemoprevention of human cancers.
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PMID:Chemical basis of inflammation-induced carcinogenesis. 1292 73

While a great deal of clinical evidence has been found regarding anti-acids for the treatment of gastric disorders including peptic ulcers, not all disorders can be explained only by the hyperfunction of acid secretion. Especially in the Asian region, glandular atrophy is more prominent than in Western countries, therefore low acid output is often observed in these patients. Improvement of mucosal protection is rational therapy for these patients; this is the reason for use of these agents in Asian countries. Rebamipide has many biological activities for gastric mucosa such as increasing the blood flow and biosynthesis prostaglandins and the decrease of oxygen radicals. These suggest the possible efficacy of rebamipide in the prevention of both Helicobacter pylori-related and nonsteroidal anti-inflammatory drug (NSAID)-induced gastric injury, which has been proved by human studies. Rebamipide is the only mucosal-protective drug which can improve the histological gastritis in vivo, whereas anti-acids have a lesser effect in influencing gastritis. Improvement of gastritis is expressed not only in quantity but also in quality of gastritis, which is shown as the reduction of iNOS expression in the gastric mucosa. Clinically, it is suggested that rebamipide has the potential to prevent gastric carcinogenesis by improvement of histological gastritis.
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PMID:Review article: clinical significance of mucosal-protective agents: acid, inflammation, carcinogenesis and rebamipide. 1292 54

The molecular messenger nitric oxide (NO) is synthesized endogenously from L-arginine by three isoforms of the enzyme NO synthase. The isoform most consistently associated with neoplasia is the inducible form, inducible nitric oxide synthase (iNOS). However, the role played by the NO/iNOS system in tumor development is complex, and both promoting and inhibitory effects on neoplasia have been reported. This review attempts to clarify the role of iNOS in carcinogenesis, with particular emphasis on the early stages of tumor development, offers possible explanations for the confused picture presented in the literature regarding the association of the NO/iNOS pathway with neoplasia, and identifies selective iNOS inhibitors that may have chemopreventive potential.
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PMID:Is inducible nitric oxide synthase a target for chemoprevention? 1293 72

Folate depletion and aging are risk factors for colorectal cancer. We investigated the effects of folate status and aging on gene expression in the rat colon. Young (weanling) and older (12 month) rats were fed folic acid depleted (0 mg/kg) and supplemented (8 mg/kg) diets for 20 weeks. Gene expression was measured in colonic mucosal scrapings (n = 3 per group) using oligonucleotide arrays (Affymetrix U34A). Folate depletion induced the up-regulation of immune-related genes, urokinase and inducible nitric oxide synthase and the down-regulation of adhesion molecules (protocadherin-4, nidogen and integrin alphaV) and vascular endothelial growth factor in young rats. The abbreviated response to depletion in old rats (62 changes versus 136 in the young) included up-regulation of caspase-2 and deleted in colon cancer. Gene expression changes due to aging were more abundant in folate depleted than supplemented rats (38 versus 119 genes, respectively). In folate-deficient rats, aging induced the down-regulation of immune-related genes, urokinase, p53, insulin-like growth factor binding protein-3 and vav-1 oncogene. In folate supplemented rats, aging induced the down-regulation of vascular endothelial growth factor and caspase-2. Lower expression of adhesion molecules and higher expression of urokinase with folate depletion in young rats may indicate that cell detachment and migration, cancer-related processes, may be modulated by folate status. An age-related decline in p53 and IGF-BP3 expression was only observed in folate depleted animals, indicating that folate supplementation may reduce the risk for age-associated cancers by suppressing deleterious changes in the expression of certain genes.
Carcinogenesis 2004 Jan
PMID:Effects of dietary folate and aging on gene expression in the colonic mucosa of rats: implications for carcinogenesis. 1297 65

There is extensive evidence that cyclooxygenase-2 (COX-2) plays a significant role in the process of carcinogenesis in different tumors. Although most of these evidences derive from studies in colorectal cancer, data obtained from recent studies strongly suggest that COX-2 might play an important role in the neoplastic transformation of esophageal epithelium. NSAIDs use is associated with a reduction of the risk of developing esophageal cancer, including adenocarcinoma. Up-regulation of COX-2 has been reported in different stages of the carcinogenic sequence leading to esophageal adenocarcinoma. Treatment with selective COX-2 inhibitors has been shown to reduce the damage induced by acid and pepsin in the esophageal mucosa of rabbits, the incidence of tumors in an animal model of esophageal adenocarcinoma and to decrease proliferation and induce apoptosis in both Barrett's epithelial and adenocarcinoma cells. The first clinical study has shown that selective inhibition of COX-2 is followed by a significant decrease of cell proliferation in human Barrett's metaplasia. Clinical trials have begun in order to assess the efficacy of selective COX-2 inhibitors to prevent the progression of Barrett's esophagus to adenocarcinoma. Bile salts and acid are likely to early induce COX-2 in this sequence, although other factors, such as proinflammatory cytokines, inducible nitric oxide synthase and growth factors such as TGF-beta, are potential COX-2 inducers in the esophagus. Further studies are necessary in order to better understand factors involved in COX-2 up-regulation and mechanisms of COX-2 associated tumorigenesis in the esophagus.
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PMID:COX-2 inhibition in esophagitis, Barrett's esophagus and esophageal cancer. 1455 27

The overexpression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) has been previously reported in head and neck squamous cell carcinoma (HNSCC), as well as in many cancers. We hypothesized that endogenous nitric oxide (NO) might increase the expression of COX-2 in cancer cells. Therefore, we investigated the cross-talk between NO and the prostaglandin (PG) pathways in HNSCC cell lines. We found that COX-2 and iNOS expressions were elevated simultaneously. On adding the NO donor, SNAP, the PGE2 level was increased 2-20 times due to increased COX-2 expression. This increase of COX-2 expression by SNAP or PMA (potent inducer of both iNOS and COX-2) was blocked to various degrees by NO scavengers and NOS inhibitors (L-NAME and 1400W). Also, the expression of COX-2 in resting cells was inhibited by NOS inhibitors. Moreover, COX-2 expression, induced by SNAP, was inhibited by ODQ, a soluble guanylate cyclase (sGC) inhibitor. The effect of dibutyryl-cGMP on COX-2 expression was similar to that of SNAP. These results imply that endogenous or exogenous NO activates sGC and that the resulting increase of cGMP induces a signaling that upregulates the expression of COX-2 in HNSCC cell lines. We also observed that NO increased COX-2 expression in different cancer cell lines, including cervic and gastric cancer cell lines. These findings further support the notion that NO can be associated with carcinogenesis through the upregulation of COX-2, and that NOS inhibitor may be also useful for cancer prevention.
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PMID:The effect of nitric oxide on cyclooxygenase-2 (COX-2) overexpression in head and neck cancer cell lines. 1456 22

The objective of this study is to determine if treatment with the angiogenesis inhibitor TNP-470 results in impairment of oxidative stress, inhibition of nuclear factor kappa B (NF-kappaB) activation and decrease of nitric oxide production in an experimental model of rat hepatocarcinogenesis. Tumour was induced by diethylnitrosamine and promoted by two-thirds hepatectomy plus acetaminofluorene administration. Experiments were carried out at 28 weeks after initiating the treatment. TNP-470 was administered at 30mg/kg, three times per week from 20 to 28 weeks. Carcinomatous tissue growing outside dysplastic nodules and a marked expression of placental glutathione S-transferase were detected in rats with induced carcinogenesis. Liver concentrations of thiobarbituric acid reactive substances, reduced glutathione (GSH) and glutathione disulfide (GSSG) were significantly higher than those of controls and there was a significant increase in the GSSG/GSH ratio. Tumour growth was accompanied by augmented expression of inducible nitric oxide synthase, activation of (NF-kappaB) and proteolysis of IkappaB. All these effects were absent in animals receiving TNP-470. Our results indicate that TNP-470 inhibits oxidative stress, nitric oxide production and NF-kappaB activation induced by experimental hepatocarcinogenesis. These changes would contribute to the beneficial effects of TNP-470 in cancer treatment.
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PMID:TNP-470 inhibits oxidative stress, nitric oxide production and nuclear factor kappa B activation in a rat model of hepatocellular carcinoma. 1456 44

Activating mutations of K-ras are frequent in colon tumors and aberrant crypt foci, and may play important roles in colon carcinogenesis. Here, we investigated the effects of a K-ras codon 12 mutation on inducible nitric oxide synthase (iNOS) expression. When rat intestinal epithelial cells (IEC-6) were transfected with K-rasAsp12 cDNA, the iNOS expression linked to interleukin-1beta (IL-1beta) or lipopolysaccharide (LPS) treatment was markedly increased and prolonged. In contrast, it was only very faint and transient in cells transfected with the control vector or K-rasWT. Electrophoretic mobility-shift assays demonstrated that NF-kappaB binding activity induced by IL-1beta or LPS was also increased in K-rasAsp12-transfected cells, along with the binding of CREB-1, CREM-1, ATF-1, ATF-2, and Jun D to a cAMP-responsive element (CRE)-like site and the binding of C/EBPbeta to a C/EBP-binding consensus site. Furthermore, the anchorage-independent growth of K-rasAsp12-transfected cells was markedly increased by IL-1beta or LPS treatment, and decreased by ONO-1714, an iNOS inhibitor. In addition, tumor growth in nude mice injected with K-rasAsp12-transfected cells was significantly suppressed by NOS inhibition with 50 p.p.m. ONO-1714 or 100 p.p.m. L-NG-nitroarginine methyl ester. These results suggest that an activating mutation of K-ras can markedly enhance the iNOS expression mediated by IL-1beta or LPS, through the activation of promoters on NF-kappaB, C/EBP, and CRE-like sites, and that nitric oxide contributes to the colony formation and tumor growth of K-ras-transformed cells.
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PMID:Transfection of K-rasAsp12 cDNA markedly elevates IL-1beta- and lipopolysaccharide-mediated inducible nitric oxide synthase expression in rat intestinal epithelial cells. 1457 30


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