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

Both the availability of multiple treatment modalities and novel therapeutic targets make the correct prognostic stratification and the identification of truly predictive factors an issue of major debate in gastric cancer. Along with "classic" prognostic factors such as those related to the diffusion of the tumour at diagnosis (i.e., depth of gastric wall infiltration, locoregional lymph nodes or distant metastases) or those concerning the pathologic characteristics of the tumour, other, innovative, factors should be considered if a better definition of the characteristics of the tumour is to be given. These biological factors are often derived from the genetic process, which is thought to represent a crucial step to gastric cancer (DNA copy number changes, microsatellite instability, thymidilate synthase, E-cadherin, beta-catenin, mucin antigen, p53, c-erb B-2, COX-2, matrix metalloproteinases, VEGFR and EGFR). Some of those putative prognostic indicators can also be considered predictive of response to therapy as they are a molecular target either to chemotherapeutics (i.e., thymidilate synthase that is targeted by 5FU) or to a new class of antineoplastic molecules (i.e., c-erb B-2 targeted by trastuzumab, COX-2 by NSAIDs, matrix metalloproteinases, EGFR and VEGFR by specific inhibitors).
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PMID:Molecular biology of sporadic gastric cancer: prognostic indicators and novel therapeutic approaches. 1524 77

Vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF) have been strongly implicated in the growth and metastasis of gastric cancer. The purpose of this study was to examine the effects of ZD6474, an inhibitor of inhibitor of VEGF receptor (VEGFR) tyrosine kinase with additional activity against EGF receptor (EGFR), on tumor growth and angiogenesis in an orthotopic model of gastric cancer. In vitro, ZD6474 inhibited human umbilical vascular endothelial cell and TMK-1 human gastric tumor cell proliferation in a dose-dependent fashion. EGF-mediated activation of EGFR and Erk-1/2 was decreased in tumor cells after ZD6474 treatment. In addition, VEGF-mediated activation of VEGFR2 and Erk-1/2 was decreased in human umbilical vascular endothelial cells. TMK-1 human gastric adenocarcinoma cells were injected into the gastric wall of nude mice. ZD6474 therapy was initiated on day 10. Mice (n = 14 per group) were treated p.o. with (a) 1% Tween 80 (control), (b) 50 mg/kg/d ZD6474, or (c) 100 mg/kg/d ZD6474. Mice were sacrificed on day 33. Tumors from each group were stained for markers of blood vessels, pericytes, proliferation, and apoptosis. ZD6474 at both 50 and 100 mg/kg/d led to marked inhibition of tumor growth (P < 0.05). ZD6474 reduced tumor cell proliferation by 48% in the 50 mg/kg/d group and 65% in the 100 mg/kg/d group (P < 0.03) and increased tumor cell apoptosis (P < 0.001) in vivo. ZD6474 led to a 69% decrease in microvessel density in the 50 mg/kg/d group (P < 0.001) and a 62% decrease in the 100 mg/kg/d group (P < 0.001). Although microvessel density was decreased by ZD6474, the remaining vessels showed a relatively higher percentage of pericyte coverage (3-fold increase; P < 0.001), perhaps reflecting selective loss of uncovered vessels in the ZD6474 group. In conclusion, therapies such as ZD6474 that target two distinct aspects of tumor growth, angiogenesis and tumor cell proliferation, warrant further investigation.
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PMID:ZD6474, a vascular endothelial growth factor receptor tyrosine kinase inhibitor with additional activity against epidermal growth factor receptor tyrosine kinase, inhibits orthotopic growth and angiogenesis of gastric cancer. 1536 98

Angiogenesis inhibitors have been used to treat some cancers, but the therapeutic potential of these agents for gastric cancer has remained unclear. To investigate their therapeutic potential, we examined the effect of ZD6474, an agent that selectively targets vascular endothelial growth factor receptor-2 (VEGFR-2; KDR) tyrosine kinase and epidermal growth factor receptor (EGFR) tyrosine kinase, in a highly metastatic orthotopic model using an undifferentiated gastric cancer cell line, 58As1. ZD6474 (100 mg/kg/day, p.o., 2 weeks) significantly inhibited tumor growth (p < 0.05 vs. control) and reduced tumor dissemination into the peritoneal cavity (p < 0.05 vs. control). In addition, to identify putative tumor biomarkers that would reflect the effects of ZD6474 treatment in clinical settings, we examined the gene expression profiles of implanted gastric tumors treated with ZD6474 in vivo. Twenty-eight candidate genes were identified, including IGFBP-3, ADM, ANGPTL4, PLOD2, DSIPI, NDRG1, ENO2, HIG2 and BNIP3L, which are known to be hypoxia-inducible genes. These genes and gene products may be useful biomarkers for monitoring the effects of ZD6474 treatment. ZD6474 also improved the survival of mice with implanted another undifferentiated gastric cancer cell line, 44As3. In conclusion, our results suggest that ZD6474 may have clinical activity against gastric cancer, particularly undifferentiated gastric cancer with peritoneal dissemination. We also identified putative biomarkers for monitoring the pharmacodynamic effects of ZD6474 by gene expression profiling.
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PMID:ZD6474 inhibits tumor growth and intraperitoneal dissemination in a highly metastatic orthotopic gastric cancer model. 1605 30

Blockade of angiogenesis is a promising strategy to suppress tumor growth, invasion, and metastasis. Vascular endothelial growth factor (VEGF), which binds to tyrosine kinase receptors [VEGF receptors (VEGFR) 1 and 2], is the mediator of angiogenesis and mitogen for endothelial cells. Cyclooxygenase-2 (COX-2) plays an important role in the promoting action of nicotine on gastric cancer growth. However, the action of nicotine and the relationship between COX-2 and VEGF/VEGFR system in tumorigenesis remain undefined. In this study, the effects of nicotine in tumor angiogenesis, invasiveness, and metastasis were studied with sponge implantation and Matrigel membrane models. Nicotine (200 microg/mL) stimulated gastric cancer cell proliferation, which was blocked by SC-236 (a highly selective COX-2 inhibitor) and CBO-P11 (a VEGFR inhibitor). This was associated with decreased VEGF levels as well as VEGFR-2 but not VEGFR-1 expression. Topical injection of nicotine enhanced tumor-associated vascularization, with a concomitant increase in VEGF levels in sponge implants. Again, application of SC-236 (2 mg/kg) and CBO-P11 (0.4 mg/kg) partially attenuated vascularization by approximately 30%. Furthermore, nicotine enhanced tumor cell invasion through the Matrigel membrane by 4-fold and promoted migration of human umbilical vein endothelial cells in a cocultured system with gastric cancer cells. The activity of matrix metalloproteinases 2 and 9 and protein expressions of plasminogen activators (urokinase-type plasminogen activator and its receptor), which are the indicators of invasion and migration processes, were increased by nicotine but blocked by COX-2 and VEGFR inhibitors. Taken together, our results reveal that the promoting action of nicotine on angiogenesis, tumor invasion, and metastasis is COX-2/VEGF/VEGFR dependent.
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PMID:Nicotine induces cyclooxygenase-2 and vascular endothelial growth factor receptor-2 in association with tumor-associated invasion and angiogenesis in gastric cancer. 1631 86

Prognostic criteria of the patients with gastric cancer are of critical importance in their management and follow-up. Angiogenesis is essential for the growth and metastasis of solid tumors. Tumor angiogenesis is a multi-step interactive process, and vascular endothelial growth factor (VEGF) and its receptors have a major role in tumor angiogenesis. Thus, we investigated the effects of VEGF and VEGF receptor-2 (VEGFR-2, KDR) on survival in patients with gastric cancer. We analyzed 51 patients who had undergone total or subtotal gastric resection. The patients were divided into two subgroups according to their VEGF and VEGFR-2 (KDR) expression in resected specimens. There was no significant difference between sex, surgical method, lymph node metastasis, serosal invasion, hematogenous metastasis, chemotherapy status of the two subgroups. Mean follow-up time was 24.22 +/- 15.38 months. We found the survival rates of the patients with VEGF positive tumors to be significantly shorter than those of the patients with VEGF negative tumors. There was no significant difference between the survival rates of VEGFR-2 (KDR) positive and negative patients. It was established that the presence of VEGF expression was significantly associated with the short survival rates in patients with gastric cancer. Analysis of VEGF expression in resected specimens may provide additional guidance in determining the prognosis of such patients. If more extensive studies confirm the significance of VEGF and its receptors in gastric cancer, new therapeutic approaches targeting VEGF and its receptors may be considered in gastric cancer management.
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PMID:The effects of VEGF and VEGFR-2 on survival in patients with gastric cancer. 1676 23

Gastric cancer is the second commonest cause of cancer-associated death in the world. Its molecular markers can be useful not only for diagnostic, but also prognostic purposes. The aim of the study was to assess the usefulness of soluble angiogenesis markers such as endoglin and VEGFR2 in gastric cancer patients and to compare these results with those of VEGF levels. As a secondary objective, we compared the concentrations of all three soluble markers in plasma and serum. The study was performed on 26 patients with gastric cancer (17 intestinal-type and 9 diffuse-type), and additionally in 2 patients with B cell lymphoma and 2 with gastro-intestinal stromal tumor. In summary, we showed increases in circulating VEGF-A in patients with both types of gastric cancer. The levels of VEGFR2 did not change significantly in patients with gastric cancer as compared to healthy subjects. Interestingly, after the operation greater levels of VEGFR2 were observed in patients without metastases. Both VEGF and VEGFR2 circulating levels were greater in patients with lymphoma, when compared to both gastric cancer patients and the control group. However, because of small number of patients, this requires further studies. Presented data suggests that endoglin does not seem to be a valuable tool in the assessment of gastric cancer invasion and spread.
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PMID:Soluble angiogenesis markers in gastric tumor patients. 1941 43

The receptor tyrosine kinases (RTKs), epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor 1-3 (VEGFR1-3), are frequently expressed in gastric cancer and are putative therapeutic targets in this disease. We have investigated the anti-proliferative and chemosensitizing properties of the multitargeted small-molecule RTK inhibitors sunitinib and vandetanib in a panel of 4 human gastric and esophageal cancer cell lines. In the 1st instance, the expression of potential targets of these small-molecule inhibitors was examined by reverse transcriptase-polymerase chain reaction, western blotting, and flow cytometry. EGFR mRNA and protein was detected in all cases, with VEGFR2 expression noted in all but 1 line. Both EGF and VEGF were shown to stimulate tumor cell growth, and both sunitinib and vandetanib were found to be associated with significant dose-dependent inhibition of proliferation and an enhancement of apoptosis, as determined by MTT and propidium iodide/Annexin V labeling assays, respectively. The addition of sunitinib to VEGF-stimulated NCI-N87 cells was associated with a reduction in MAPK phosphorylation (pMAPK) but not Akt phosphorylation (pAkt), whereas the addition of vandetanib was associated with reductions in both VEGF- and EGF-mediated VEGFR2 phosphorylation, pMAPK and pAkt. Co-administration of sunitinib significantly enhanced the sensitivity of MKN-45 cells to cisplatin and irinotecan. In addition, vandetanib synergistically enhanced the sunitinib-associated inhibition of gastric cancer cell growth. In conclusion, these preliminary data confirm the importance of EGFR and VEGFR signaling in gastric cancer and suggest that the simultaneous inhibition of RTK-pathways through sunitinib and vandetanib may provide therapeutic benefit in this disease.
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PMID:Analysis of anti-proliferative and chemosensitizing effects of sunitinib on human esophagogastric cancer cells: Synergistic interaction with vandetanib via inhibition of multi-receptor tyrosine kinase pathways. 2003 26

Aurora-A, encoding serine/threonine kinases with a key role in mitosis has been demonstrated to be involved in tumor progression. Hematogenous and lymphatic metastasis are also involved in cancer progression. Vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) have been implicated in tumor-related angiogenesis and lymphagenesis. The purpose of this study was to analyze the expression and prognostic significance of Aurora-A, VEGFs and VEGFRs in gastric cancer. The expression profiles of Aurora-A, VEGF-A and VEGF-D in gastric cancer cell lines were detected employing real-time reverse transcription polymerase chain reaction and Western blot analysis. The expression levels of Aurora-A, VEGF-A/VEGFR-2, VEGF-D/VEGFR-3 and clinicopathological characteristics were analyzed in 89 gastric cancer patients treated with curative surgery. Univariate analysis demonstrated that histological grade (P=0.052), TNM stage (P<0.001), lymphovascular involvement (P<0.001), Aurora-A (P<0.001) and VEGF-D (P=0.048) were prognostic factors. The presence of Aurora-A was correlated with tumor progression (P=0.053) and shorter survival (P=0.001). Cox multivariate regression analysis demonstrated that Aurora-A positive expression, stage III-IV and lymphovascular involvement were independent unfavorable prognostic factors in gastric cancer. Aurora-A positive expression was predictive for worse outcome in patients without lymph node metastasis (P<0.05) and in patients with stage III-IV (P<0.001). Aurora-A could serve as an independent prognostic marker in gastric cancer and could identify patients with worse outcome even in a relatively early and local disease, thus offering valuable information for administering individualized treatment and/or surveillance for these patients.
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PMID:Aurora-A as an independent molecular prognostic marker in gastric cancer. 2147 65

The anti-VEGF receptor 2 antibody IMC-1121B is a promising antiangiogenic drug being tested for treatment of breast and gastric cancer. We have determined the structure of the 1121B Fab fragment in complex with domain 3 of VEGFR2, as well as the structure of a different neutralizing anti-VEGFR2 antibody, 6.64, also in complex with VEGFR2 domain 3. The two Fab fragments bind at opposite ends of VEGFR2 domain 3; 1121B directly blocks VEGF binding, whereas 6.64 may prevent receptor dimerization by perturbing the domain 3:domain 4 interface. Mutagenesis reveals that residues essential for VEGF, 1121B, and 6.64 binding are nonoverlapping among the three contact patches.
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PMID:The structural basis for the function of two anti-VEGF receptor 2 antibodies. 2182 46

CD97 is over-expressed in the majority of gastric adenocarcinomas and is associated with its dedifferentiation and aggressiveness. Our previous results demonstrated that out of three CD97 isoforms tested, only the small one was able to promote increased invasiveness in vitro. Based on these data we further aimed to investigate the role of CD97 small isoform in gastric cancer progression in vivo by employing the cells with a stable CD97 small isoform knock-down and an orthotopic gastric cancer mouse model. We could demonstrate that the knock down of CD97/EGF1,2,5, led to a significant decrease in the number of cells penetrating the gelatin coated membrane as compared with control cells. In the gastric cancer mouse model, both the hypodermic and the orthotopic yielded tumor masses of the CD97/EGF1,2,5kd group and were significantly smaller than the control. Metastatic tumor cell number in early metastatic regional lymph nodes on post-operative day 42 was distinctly decreased in the CD97/EGF1,2,5kd group as compared with the SGC-NS group, and was accompanied with the downregulation of CD44, VEGFR, CD31 and CD97. We concluded in this study that CD97 small isoform not only supported gastric cancer local growth, but also promoted metastatic spread in orthotopically implanted mouse model suggesting involvement of the CD97 small isoform in the preparation of (pre)metastatic niche.
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PMID:The invasion and metastasis promotion role of CD97 small isoform in gastric carcinoma. 2276 92


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