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Query: UMLS:C0024623 (gastric cancer)
 36,219 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dysregulated epidermal growth factor receptor (EGFR) signaling is involved in gastric cancer (GC) cell growth. However, the mechanism that sustains EGFR signaling in GC remains unknown. Since protease-activated receptor-2 (PAR-2), a G protein-coupled receptor, has been shown to trans-activate EGFR in several cell types, we examined the role of PAR-2 in GC. We show here that in vitro activation of PAR-2 enhances the growth of two GC cell lines, AGS and MKN28. In both these cell lines, PAR-2 trans-activated EGFR and inhibition of EGFR tyrosine kinase activity by AG1478 or specific EGFR siRNA completely prevented PAR-2-driven proliferation. Antibody blockade of EGF-like ligands to EGFR did not modify EGFR signaling or cell growth induced by PAR-2 activation. In contrast, PAR-2 promoted Src activation and interaction of this kinase with EGFR. In support of this, inhibition of Src kinase activity by PP1 or siRNA blocked PAR-2-induced EGFR signaling cascade and cell growth. Finally, PAR-2 was detectable in both normal and GC specimens, but its expression was more pronounced in GC than controls and correlated with activated EGFR. These data show that PAR-2 is overexpressed in GC and suggest a role of PAR-2 in EGFR trans-activation and cell growth.
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PMID:Protease-activated receptor-2 activation in gastric cancer cells promotes epidermal growth factor receptor trans-activation and proliferation. 1681 79

The epidermal growth factor receptor (EGFR) is highly expressed in gastric cancer indicating its suitability as a target for receptor tyrosine kinase (RTK) inhibitors. In the current study we explored the role of EGFR and its potential use as a therapeutic target in gastric cancer. First we analyzed 66 gastric cancer samples of Asian and Caucasian patients for the presence of EGFR mutations. No activating EGFR mutations were found and gefitinib alone was only weakly effective in gastric cancer cell lines. However, acetylsalicylic acid (ASA) significantly enhanced the inhibitory effects of gefitinib indicating synergistic action. Whole genome expression profiling indicated significant regulation of 120 genes in the case of co-administration of gefitinib and ASA (32 induced, 88 repressed) in gastric adenocarcinoma cells. Further analyses indicated that several important signalling pathways were effectively inhibited by simultaneous exposure to gefitinib and ASA. Our findings indicate that although gastric cancer does not seem to harbour mutations which render the cancer cells constitutively susceptible to gefitinib, the co-administration of ASA can strengthen RTK inhibitor activity in adenocarcinoma cells by EGFR activation. This is the first report of effective modulation of EGFR-inhibition activity in cancer.
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PMID:Acetylsalicylic acid enhances antiproliferative effects of the EGFR inhibitor gefitinib in the absence of activating mutations in gastric cancer. 1686 77

The HER-2/neu protein is intimately involved with normal cell proliferation and tissue growth and is extensively homologous and related to the epidermal growth factor receptor. HER-2/neu protein expression has been most intensively studied in the context of breast carcinoma, in which its amplification and overexpression correlate with the overall course of disease, and with a poor prognosis, and constitute a predictive factor of poor response to chemotherapy and endocrine therapy. In this study, we investigated the relationship between the expression of HER-2/neu and the clinicopathological characteristics of tumors, including survival. This study was performed with a view toward the future introduction of Herceptin therapy for gastric cancer patients. HER-2/neu overexpression and gene amplification was examined with semiquantitative standardized immunohistochemical staining, chromogenic in situ hybridization (CISH), and fluorescence in situ hybridization (FISH) in 182 gastric cancer patients who underwent curative surgery at the Kangbuk Samsung Hospital. Twenty-nine (15.9%) of 182 patients expressed the HER-2/neu protein by immunohistochemistry. HER-2/neu gene amplification was detected in seven patients by CISH and FISH. Intestinal-type cancers exhibited higher rates of HER-2/neu amplification than did diffuse-type cancers (P < 0.05). Tumors with HER-2/neu amplification were associated with poor mean survival rates (922 vs 3243 days) and 5-year survival rates (21.4% vs 63.0%; P < 0.05). Age, TNM stage, and amplification of HER-2/neu were found to be independently related to survival by multivariate analysis. HER-2/neu amplification may constitute an independent prognostic factor in gastric cancer patients, and patients exhibiting HER-2/neu amplification might constitute potential candidates for new adjuvant therapies which involve the use of humanized monoclonal antibodies.
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PMID:HER-2/neu amplification is an independent prognostic factor in gastric cancer. 1686 27

Gastric cancer metastasised to the liver was found to overexpress HER2 at a significantly higher incidence than primary gastric cancers. The purpose of the present study was to investigate the possibility of molecular therapy targeting HER2 overexpression in gastric cancer liver metastasis. We developed three new HER2-overexpressing gastric cancer cell lines (GLM-1, GLM-2, GLM-4) without epidermal growth factor receptor (EGFR) mutations derived from such liver metastasis, two of which had HER2 gene amplifications. All these GLM series of cell lines were highly sensitive to gefitinib in vitro, a specific inhibitor of EGFR tyrosine kinase (Iressa) rather than anti-HER2 antibody trastuzumab (Herceptin), whereas most of the HER2 low-expressing counterparts were not. In these HER2-overexpressing GLM series, protein kinase B (Akt), but not extracellular signal-regulated kinase 1/2 (ERK1/2), was constitutively phosphorylated, and gefitinib efficiently inhibited this Akt phosphorylation, induced strong apoptosis in vitro and exhibited antitumour activity in tumour xenografts in nude mice. This gefitinib-mediated antitumour effect in xenograft was significantly potentiated by trastuzumab treatment. On the other hand, gefitinib-resistant cells (GLM-1R) exhibited increased EGFR expression, followed by constitutive activation of mitogen-activated protein kinase (MAPK) pathway. These results suggest that the antitumour effect of gefitinib is due to the effective inhibition of HER2-driven constitutive activation of phosphatidylinositol-3-kinase (PI3K)/Akt pathway, and that the acquired resistance to gefitinib is due to the constitutive activation of Ras/MAPK pathway in compensation for PI3K/Akt pathway. Gastric cancer liver metastasis with HER2 overexpression would be a potential molecular target for gefitinib and trastuzumab.
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PMID:Molecular basis for sensitivity and acquired resistance to gefitinib in HER2-overexpressing human gastric cancer cell lines derived from liver metastasis. 1708 2

Oncogenic signaling through activation of epidermal growth factor receptor (EGFR), HER-2, and hypoxia inducible-factor-1alpha (HIF-1alpha) has been implicated in gastric cancer growth and angiogenesis through up-regulation of vascular endothelial growth factor (VEGF). Recently, heat shock protein 90 (Hsp90) has been identified as a critical regulator of oncogenic protein stability, including EGFR, HER-2, and HIF-1alpha. We hypothesized that inhibition of Hsp90 impairs EGF- and hypoxia-mediated angiogenic signaling in gastric cancer cells and consequently inhibits angiogenesis and tumor growth. In vitro, the geldanamycin derivate 17-allylamino-17-demethoxygeldanamycin (17-AAG) led to marked reduction in constitutive and inducible activation of extracellular signal-regulated kinase 1/2, Akt, and signal transducer and activator of transcription 3 and decreased nuclear HIF-1alpha protein. In addition, EGFR and HER-2 were down-regulated after Hsp90 inhibition. With respect to regulation of angiogenic molecules, 17-AAG significantly reduced EGF-mediated VEGF secretion. Phosphorylation of focal adhesion kinase and paxillin were both abrogated by 17-AAG, which resulted in significant impairment of cancer cell motility. Interestingly, cytotoxic effects of 17-AAG in vitro were higher on cancer cells and gastric fibroblasts than on pericytes. In vivo, the water-soluble compound 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG; 25 mg/kg, thrice per week) significantly reduced s.c. xenografted tumor growth. By immunohistochemistry, 17-DMAG significantly reduced vessel area and numbers of proliferating tumor cells in sections. Furthermore, similar significant growth-inhibitory effects of 17-DMAG were achieved when administered as low-dose therapy (5 mg/kg, thrice per week). In conclusion, blocking Hsp90 disrupts multiple proangiogenic signaling pathways in gastric cancer cells and inhibits xenografted tumor growth in vivo. Hence, gastric cancer harbors attractive molecular targets for therapy with Hsp90 inhibitors, which could lead to improved efficacy of antineoplastic therapy regimens.
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PMID:Inhibition of heat shock protein 90 impairs epidermal growth factor-mediated signaling in gastric cancer cells and reduces tumor growth and vascularization in vivo. 1736 5

Evidence of Mycoplasma hyorhinis infection in human gastric cancer tissues has been found in previous work. In this study, we demonstrate that the expression of p37, a membrane lipoprotein of M. hyorhinis, in mammalian cells induces antisenescence, enhances clonogenicity in soft agar, and co-operates with human epidermal growth factor receptor-related 2 to inhibit cell adhesion. Conversely, truncated p37 protein, with the first 28 amino acids deleted from its N terminal, promotes cell senescence. Taken together, our findings suggest that p37 promotes malignant changes in mammalian cells. With the identification of this molecular component, which is responsible for mycoplasma malignancy-promoting activity, it is possible that a better understanding of the relationship between M. hyorhinis infection and human gastric cancers will lead to novel diagnostics and therapeutics.
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PMID:Mycoplasmal membrane protein p37 promotes malignant changes in mammalian cells. 1749 76

Gastric cancer associated E-cadherin germline missense mutations lead to significant functional consequences, in both the structural and signalling properties of the protein. In this study, we have characterized the effect of four E-cadherin germline missense mutations (T340A, A634V, P799R and V832M) in the interaction with the epidermal growth factor receptor (EGFR). We challenged the hypothesis that E-cadherin mutations perturb its ability to bind to EGFR, leading to constitutional activation of the EGFR, triggering activation of downstream effectors. We verified that missense mutations localized in the extracellular domain of the protein (T340A and A634V) exhibited reduced stability of the EGFR/E-cadherin heterodimers in contrast to germline mutations localized at the cytoplasmatic domain of the protein (P799R and V832M). We observed that cells expressing E-cadherin extracellular mutants displayed increased levels of phosphorylated EGFR upon ligand stimulation, when compared with cells expressing wild-type E-cadherin or intracellular mutants. We showed that upon treatment of E-cadherin extracellular mutant cells with the EGFR inhibitor, the increase of RhoA activation is abrogated and accompanied by decreased migratory behaviour, supporting the idea that Rho-like proteins are EGFR downstream effectors. Our results bring new insights into the understanding of the distinct in vitro behaviours observed for E-cadherin missense mutations localized in different domains of the protein. Furthermore, we demonstrate that E-cadherin-dependent EGFR activation contributes to enhanced cell motility, in a mechanism involving RhoA activation.
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PMID:EGFR regulates RhoA-GTP dependent cell motility in E-cadherin mutant cells. 1751 Feb 11

We recently showed that inhibition of heat shock protein 90 (Hsp90) decreases tumor growth and angiogenesis in gastric cancer through interference with oncogenic signaling pathways. However, controversy still exists about the antimetastatic potential of Hsp90 inhibitors. Moreover, in vitro studies suggested that blocking Hsp90 could overcome p53-mediated resistance of cancer cells to oxaliplatin. We therefore hypothesized that blocking oncogenic signaling with a Hsp90 inhibitor would impair metastatic behavior of colon cancer cells and also improve the efficacy of oxaliplatin in vivo. Human colon cancer cells (HCT116, HT29, and SW620) and the Hsp90 inhibitor 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG) were used for experiments. In vitro, 17-DMAG substantially inhibited phosphorylation of epidermal growth factor receptor, c-Met, and focal adhesion kinase, overall resulting in a significant decrease in cancer cell invasiveness. Importantly, 17-DMAG led to an up-regulation of the transcription factor activating transcription factor-3, a tumor suppressor and antimetastatic factor, on mRNA and protein levels. In a cell death ELISA, 17-DMAG markedly induced apoptosis in both p53-wt and p53-deficient cells. In vivo, 17-DMAG significantly reduced tumor growth and vascularization. Furthermore, blocking Hsp90 reduced hepatic tumor burden and metastatic nodules in an experimental model of hepatic colon cancer growth. Importantly, combining oxaliplatin with 17-DMAG in vivo significantly improved growth inhibitory and proapoptotic effects on p53-deficient cells, compared with either substance alone. In conclusion, inhibition of Hsp90 abrogates the invasive properties of colon cancer cells and modulates the expression of the antimetastatic factor activating transcription factor-3. Hence, targeting Hsp90 could prove valuable for treatment of advanced colorectal cancer by effectively inhibiting colon cancer growth and hepatic metastasis and improving the efficacy of oxaliplatin.
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PMID:Blocking heat shock protein-90 inhibits the invasive properties and hepatic growth of human colon cancer cells and improves the efficacy of oxaliplatin in p53-deficient colon cancer tumors in vivo. 1802 73

Gastric cancer is the seventh and oesophageal cancer the ninth most common cancer in the UK, and >50% of patients present with locally advanced or metastatic disease. The incidence of oesophageal and oesophagogastric junctional tumours is increasing, making these important disease entities to understand and research. Despite improvements in surgical and peri-operative supportive care, 3-year overall survival with surgery alone for resectable disease is still poor. Outcomes in localised oesophageal cancer are improved with pre-operative chemotherapy, and in gastric cancer with peri-operative treatment or post-operative chemoradiotherapy. Oesophageal squamous cell carcinoma can be treated with definitive chemoradiotherapy as an alternative to surgery. While survival in patients presenting with metastatic disease is improved with the addition of systemic chemotherapy, median survival remains <1 year. Patients who are otherwise fit can be offered chemotherapy and this is superior to best supportive care. Regimens including a platinum and an anthracycline agent are favoured by the results of randomised trials. No standard second-line therapy has emerged. New research into taxanes has shown promising anti-cancer activity, and novel areas of investigation include incorporation of agents targeting vascular endothelial growth factor or epidermal growth factor receptor into standard regimens. This review focuses on the clinical trial evidence that dictates the optimal management of localised and advanced oesophagogastric cancer, focusing on pharmacotherapy. We examine areas of current research and highlight future therapeutic directions.
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PMID:Pharmacotherapy for oesophagogastric cancer. 1803 90

Using laser-captured microdissection and a real-time RT-PCR assay, we quantitatively evaluated mRNA levels of the following biomarkers in paraffin-embedded gastric cancer (GC) specimens obtained by surgical resection or biopsy: excision repair cross-complementing gene 1 (ERCC1), dihydropyrimidine dehydrogenase (DPD), methylenetetrahydrofolate reductase (MTHFR), epidermal growth factor receptor (EGFR), and five other biomarkers related to anticancer drug sensitivity. The study group comprised 140 patients who received first-line chemotherapy for advanced GC. All cancer specimens were obtained before chemotherapy. In patients who received first-line S-1 monotherapy (69 patients), low MTHFR expression correlated with a higher response rate (low: 44.9% vs high: 6.3%; P=0.006). In patients given first-line cisplatin-based regimens (combined with S-1 or irinotecan) (43 patients), low ERCC1 correlated with a higher response rate (low: 55.6% vs high: 18.8%; P=0.008). Multivariate survival analysis of all patients demonstrated that high ERCC1 (hazard ratio (HR): 2.38 (95% CI: 1.55-3.67)), high DPD (HR: 2.04 (1.37-3.02)), low EGFR (HR: 0.34 (0.20-0.56)), and an elevated serum alkaline phosphatase level (HR: 1.00 (1.001-1.002)) were significant predictors of poor survival. Our results suggest that these biomarkers are useful predictors of clinical outcomes in patients with advanced GC.
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PMID:Impacts of excision repair cross-complementing gene 1 (ERCC1), dihydropyrimidine dehydrogenase, and epidermal growth factor receptor on the outcomes of patients with advanced gastric cancer. 1823 Nov 4


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