Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0024623 (gastric cancer)
 36,219 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cigarette smoke has been shown to cause gastric cancer. Overexpression of cyclooxygenase-2 (COX-2) is a common characteristic in gastric malignancy. The present study aimed to explore the correlation between cigarette smoke and COX-2 in the promotion of tumorigenesis in human gastric cancer cells (AGS). We further studied the action of COX-2 on other proto-oncogenes on gastric tumor growth. Results showed that chloroform extract (CE) and ethanol extract (EE) from cigarette smoke dose-dependently stimulated gastric cancer cell proliferation, which was accompanied with an activation of ornithine decarboxylase (ODC) activity, COX-2, and c-myc expressions. Both antisense of c-myc and alpha-difluoromethylornithine (DFMO, specific ODC inhibitor) inhibited cell proliferation without affecting COX-2 expression in response to cigarette smoke extracts (CSE). However, selective COX-2 inhibitor (SC-236) not only blocked the proliferative activity but also the ODC activity and c-myc protein expression by CSE in gastric cancer cells. Further, supplementation of exogenous prostaglandin (PG) E(2) reversed all the inhibitory actions of SC-236. Our results underline the importance of COX-2 in the cancer-promoting effect of CSE and its modulation on its downstream growth-related genes, such as c-myc and ODC in cancer cell proliferation. These results reveal that CSE-induced gastric carcinogenesis is via the COX-2/c-myc/ODC and PGE(2)-dependent pathway. Hence, selective COX-2 inhibitor could be an effective therapeutic agent for gastric cancer in smokers.
 ...
PMID:A mechanistic study of cigarette smoke and cyclooxygenase-2 on proliferation of gastric cancer cells. 1496 10

The gastric pathogen Helicobacter pylori is associated with a progression to gastric cancer. The specific targets of H. pylori that might influence this progression are still unclear. Previous studies indicated that the gastric hormone gastrin, which may be increased in H. pylori infection, stimulates gastric expression of plasminogen activator inhibitor (PAI)-2, which is an inhibitor of the urokinase plasminogen activator and has previously been shown to be increased in gastric adenocarcinoma. Here, we report that H. pylori also increases PAI-2 expression. In gastric biopsies of H. pylori-positive subjects there was increased PAI-2, including subjects with plasma gastrin concentrations in the normal range. PAI-2 was expressed mainly in chief and mucous cells. In a gastric cancer cell line (AGS), H. pylori increased PAI-2 expression, which was associated with inhibition of H. pylori-stimulated cell invasion and apoptosis. The induction of PAI-2 by H. pylori was mediated by release of interleukin-8 and activation of cyclooxygenase-2, and interestingly, gastrin stimulated PAI-2 expression by similar paracrine pathways. The activation of NFkappaB was required for interleukin-8 and cyclooxygenase-2 activation but did not occur in cells responding to these paracrine mediators. The data suggest that induction of PAI-2 is a specific target in H. pylori infection, mediated at least partly by paracrine factors; induction of PAI-2 inhibits cell invasion and apoptosis and is a candidate for influencing the progression to gastric cancer.
 ...
PMID:Helicobacter pylori induces plasminogen activator inhibitor 2 in gastric epithelial cells through nuclear factor-kappaB and RhoA: implications for invasion and apoptosis. 1499 29

In vitro studies suggest that cyclooxygenase-2 (COX-2) induces angiogenesis by stimulating angiogenic growth factors while inhibiting apoptosis in cancer cell lines. A series of 107 gastric adenocarcinoma cases that had undergone gastrectomy was studied to determine the correlation between COX-2 expression, angiogenesis, and apoptosis in human gastric cancer tissue. COX-2, vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and Bcl-2 were stained by single and dual immunoassaying methods. Microvessel density was determined by immunostaining for CD34. Apoptosis was evaluated with the TUNEL assay. COX-2 expression was positive exclusively in cancer cells in 46 cases (43%). COX-2 expression significantly correlated with VEGF and PDGF expression. Dual staining for COX-2 and VEGF showed that colocalization of these proteins was most frequent at the advancing edge of cancer cells. Microvessel density was higher in COX-2-and VEGF-positive cases than in COX-2- and VEGF-negative cases. In addition, COX-2 expression correlated with Bcl-2 expression. The apoptotic index was lower in COX-2-positive cancer cells than in COX-2-negative cases. Multivariate analysis revealed that coexpression of COX-2 and VEGF, age, lymph node status, and serosal invasion were independent prognostic factors for overall survival in gastric cancer patients. Therefore, these data suggest that COX-2 contributes to gastric cancer development by promoting angiogenesis and inhibiting apoptosis.
 ...
PMID:Cyclooxygenase-2 expression correlates with angiogenesis and apoptosis in gastric cancer tissue. 1511 31

Early studies revealed that cigarette smoke promotes gastric cancer growth through the induction of cyclooxygenase-2 (COX-2). Nicotine, one of the active ingredients in cigarette smoke, has detrimental effects in the stomach. To date, there is no direct evidence to validate the effect of nicotine on gastric tumor growth and its carcinogenic mechanism(s). We therefore investigated whether nicotine could promote tumor growth and neovascularization in vivo, and the biological mechanism(s) in connection with the signaling cascade involving COX-2 and extracellular signal-regulated protein kinase (ERK). Athymic nude mice, with gastric cancer cells (AGS) orthotopically implanted into the gastric wall, treated with nicotine (50 or 200 microg/ml) in their drinking water for 3 months developed larger tumor areas than mice in the control group. Nicotine further increased proliferating cellular nuclear antigen (PCNA) staining and microvessel density by 70 and 30%, respectively, with concomitant activation of ERK phosphorylation, COX-2 and vascular endothelial growth factor (VEGF) expression in the tumors. Intraperitoneal administration of a selective COX-2 inhibitor (SC-236, 2 mg/kg) prevented the nicotine-induced tumor growth and neovascularization dose-dependently. Consistent with our animal model, an in vitro study also demonstrated that incubation with nicotine (50-200 microg/ml) for 5 h stimulated cell proliferation dose-dependently and increased COX-2 expression, prostaglandin E(2) (PGE(2)) and VEGF release, as well as activation of ERK phosphorylation. Pre-treatment with specific mitogen-activated protein kinase kinase (MEK) inhibitors (U0126 or PD98059) attenuated COX-2 expression and subsequent PGE(2) release by nicotine. Furthermore, the stimulatory action of nicotine on cancer cell growth and angiogenic factor VEGF production was suppressed by inhibitors of MEK (U0126) and COX-2 (SC-236). These findings reveal a direct promoting action of nicotine on the growth of gastric tumor and neovascularization through sequential activation of the ERK/COX-2/VEGF signaling pathway, which can be targeted for chemoprevention of gastric cancer, particularly in cigarette smokers.
 ...
PMID:Nicotine promotes gastric tumor growth and neovascularization by activating extracellular signal-regulated kinase and cyclooxygenase-2. 1531 99

Our previous studies indicated that cyclooxygenase-2 inhibitor or octreotide could suppress the proliferation of gastric adenocarcinoma in vitro or in vivo. The present study was aimed to find whether rofecoxib combined with octreotide could enhance the inhibitive effects on the growth of gastric cancer. The effect of rofecoxib or octreotide on proliferation of gastric cancer cell line was determined by 3H-thymidine ribotide incorporation. The TdT-mediated dUTP nick end-labeling assay was used to detect the apopotosis. To determine their synergic antineoplastic effects, the interaction between rofecoxib and octreotide on SGC-7901 cell was evaluated by the median effect plot. After orthotopical implantion of xenografts of human gastric cancer in stomach, nude mice were given rofecoxib plus octreotide for 8 weeks. Cyclooxygenase-2 in gastric cancer tissues was measured by immunohistochemistry. Combination of rofecoxib and octreotide presented synergistic effect (combination index < 1) in the majority of responses. The inhibitory rate for xenografts in nude mice was 89.7% in rofecoxib group. Combination of rofecoxib and octreotide enhanced inhibitory rate to 98.8%. The combination greatly increased the apoptotic index (78.20% +/- 6.45%) of the xenografts as compared with that of using rofecoxib alone (46.60% +/- 3.42%); the difference was very significant (p < 0.001). Rofecoxib could inhibit the activity of cyclooxygenase-2 in the tissue of gastric adenocarcinomas of nude mice. Our results indicate that combination of rofecoxib and octreotide significantly enhances the antiproliferative effect in gastric adenocarcinoma, which might have potential therapeutic value.
 ...
PMID:Enhanced inhibitive effects of combination of rofecoxib and octreotide on the growth of human gastric cancer. 1538 74

Gastric epithelial cells were incubated with a panel of clinical isolates of Helicobacter pylori, including nonulcer dyspepsia with gastritis (HS, n = 20), gastric ulcer (HU, n = 20), duodenal ulcer (HD, n = 21), and gastric cancer (HC, n = 20). HC strains induced a higher cyclooxygenase-2 (COX-2) expression than those from HS, HD, and HU. The bacterial virulence factors and the host cellular pathways were investigated. Virulence genes of iceA, vacA, babA2, cagA 3' repeat region, and hrgA failed to show any association with the disease status and COX-2 expression. Methylation-specific polymerase chain reaction revealed HC strains not affecting the methylation status of COX-2 promoter. Nuclear factor (NF)-kappaB, NF-interleukin 6, and cAMP response element were found to be involved in COX-2 induction. We explored a novel NF-kappaB activation pathway. The mutants of TLR2 and TLR9, but not TLR4, inhibited H. pylori-induced COX-2 promoter activity, and neutralizing antibodies for TLR2 and TLR9 abolished H. pylori-induced COX-2 expression. Phosphatidylinositol-specific phospholipase C (PI-PLC), protein kinase C (PKC), and Src inhibitors inhibited COX-2 induction. The dominant-negative mutants of NIK and various IkappaB kinase complexes, including IKKbeta (Y188F), IKKbeta (Y199F), and IKKbeta (FF), inhibited the COX-2 promoter activity. Phosphorylation of GST-IKKbeta (132-206) at Tyr188 and Tyr199 by c-Src was found after H. pylori infection. In summary, H. pylori induces COX-2 expression via activations of NF-kappaB, NF-interleukin 6, the cAMP response element. In NF-kappaB activation, H. pylori acts through TLR2/TLR9 to activate both the cascade of PI-PLCgamma/PKCalpha/c-Src/IKKalpha/beta and the cascade of NIK/IKKalpha/beta, resulting in the IkappaBalpha degradation and the expression of COX-2 gene. The COX-2 overexpression may contribute to the carcinogenesis in patients colonized with these strains.
 ...
PMID:Induction of cyclooxygenase-2 overexpression in human gastric epithelial cells by Helicobacter pylori involves TLR2/TLR9 and c-Src-dependent nuclear factor-kappaB activation. 1545 96

Gastric atrophy and intestinal metaplasia are generally considered to be precancerous lesions of the stomach. Chronic Helicobacter pylori infection is one the most important factors in the development of these pre-malignant gastric lesions. In addition to bacterial factors, polymorphisms in the cytokine genes of the host that modulate inflammatory responses are found to have a synergistic effect in the development of gastric cancer as well as pre-neoplastic lesions. Recently, inappropriate activation of the intestine-specific transcription factor like the homeobox gene complex CDX1 and CDX2 are found to be an important contributing factor in the induction of intestinal metaplasia in the stomach. Aberrant expression of cyclooxygenase-2 and epigenetic changes are also frequently detected in pre-neoplastic gastric lesions. One of the most important questions relating to these pre-neoplastic gastric lesions is that whether H. pylori eradication could reverse these changes. However, most controlled studies showed no or just modest improvement in intestinal metaplasia after H. pylori eradication. Further studies should evaluate the role of other chemopreventive agents, particularly cyclooxygenase-2 inhibitor, on regression of pre-neoplastic lesions.
 ...
PMID:Pathogenesis of pre-neoplastic lesions of the stomach: targets for prevention. 1581 52

Despite the decrease in incidence, gastric cancer remains the second leading cause of cancer-related death worldwide. Prevention is likely to be the most effective means of not only reducing the incidence but also mortality from this disease. The term 'chemoprevention' has been referred to the prevention of cancer using specific agents to suppress or reverse the carcinogenic process. In recent years, attention has been focused on the anticancer properties of non-steroidal anti-inflammatory drugs (NSAIDs), Helicobacter pylori eradication therapy and diet life-style. In vitro and in vivo studies show that widespread and long-term use of NSAIDs may be adopted in the healthy population for gastric chemoprevention. Albeit, enthusiasm has been thwarted by the potential toxic effects, i.e., risk of peptic ulcer disease. The new NSAIDs, selective cyclooxygenase-2 inhibitors, causing less injury to the mucosa of the upper gastrointestinal tract may be a valid alternative. However, fundamental questions such as safety, efficacy, mechanisms of actions, and optimal treatment regimens need to be defined. H. pylori triggers gastric carcinogenesis, however, cost-effect analyses suggest that only a subgroup of H. pylori-infected subjects present beneficial changes following eradication therapy. Diet plays an important role in the pathogenesis of gastric cancer either increasing the risks of or protecting against, cancer development. Thus, a reasonable suggestion for the general population is a natural chemoprevention based on life-style 'eat to live, not live to eat'.
 ...
PMID:Chemoprevention of gastric cancer: role of COX-2 inhibitors and other agents. 1581 54

Peroxisome proliferator-activated receptor delta (PPARdelta) is ligand-activated transcription factor of the nuclear receptor superfamily which is recently implicated in carcinogenesis. We examined the expression profiles of PPARdelta in human gastric cancer, normal gastric mucosa and gastric cancer cell lines by RT-PCR, Western blot and immunohistochemistry. PPARdelta mRNA and protein was found to be ubiquitously expressed in all 5 gastric cancer cell lines, 40 gastric cancer samples and 10 normal gastric mucosa from non-cancer patients. Positive immunoreactivity was detected in the nuclei of normal and malignant gastric epithelium. Treatment of gastric cell line MKN45 that overexpressed cyclooxygenase-2 (COX-2) with specific COX-2 inhibitor NS398 resulted in a time- and dose-dependent suppression of PPARdelta expression. In contrast, there was no suppression of PPARdelta in MKN28 gastric cell line with low COX-2 expression. Our results demonstrated the ubiquitous expression of PPARdelta in normal and cancer gastric epithelium. Suppression of PPARdelta may be one of the mechanisms underlying the chemopreventive effects of COX-2 inhibitor.
 ...
PMID:Expression of peroxisome proliferator-activated receptor delta in human gastric cancer and its response to specific COX-2 inhibitor. 1589 Feb 32

About 60 components in cigarette smoke are considered to be carcinogens, namely polycyclic aromatic hydrocarbons, nitrosamines, aromatic amine, trace metals, as well as nicotine. Nicotine is considered to be one of the active components in cigarette smoke, and its association with tumorigenesis is enigmatic. Nonsteroidal antiinflammatory drugs are widely accepted as antitumor agents to treat patients with cancer by inhibiting cyclooxygenase-2 activity. Stimulation of tumor growth by nicotine involves different processes of cell proliferation and angiogenesis. Study results, with the use of animal xenograft models and cell culture systems, show that nicotine stimulates the progression of tumor growth, through a cyclooxygenase-2-dependent pathway. On the basis of these findings, nicotine seems to be a potent mitogenic agent in modulating tumor cell proliferation, and selective cyclooxygenase-2 inhibitors are promising antitumor agents for gastric cancer in smokers.
 ...
PMID:Nicotine and gastric cancer. 1605 88


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>