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

The aim of the present study was to investigate the expression of a number of angiogenic factors such as VEGF, VEGF-C, TGF-alpha and apoptosis in an attempt to relate these biological markers to TNM staging, lymph-node status and prognosis. Angiogenic factors and apoptosis were studied immunohistochemically in 72 gastric cancer cases. The search for micrometastases was performed with an immunohistochemical technique in 20 NO cases. Apoptosis determination was assessed with the TUNEL assay. The chi2 test according to Pearson was used for statistical analysis. The apoptotic index was related to both stage and prognosis: high expression cases showed an earlier stage (p < 0.02) and a better prognosis (p < 0.05). The determination of high neovessel density was related to poorer 5-year survival (p < 0.05). Only the expression of VEGF-C correlated inversely with prognosis (p < 0.05). The presence of micrometastases was unrelated to any of the biological markers studied. Our results partly confirm those reported in the literature. The present study revealed a number of biological markers that may be helpful for identifying particular subgroups of patients. More investigation with similar techniques in large prospective series is needed as a support to clinical practice.
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PMID:[Angiogenic factors and their relation to stage, lymph-node micrometastases and prognosis in patients operated on for gastric cancer]. 1796 62

Recent studies have reported that expression of MCP-1 and its receptor, CCR2; and CD40-CD40 ligand (CD40L) interaction on mesenchymal cells play important roles in tumor development. Studies have also connected MCP-1, CCR2, and CD40L to COX-2 expression. The aim of this study was to examine the effect of MCP-1/CCR2 and CD40-CD40L interaction on COX-2 and VEGF expression in endothelial cells. We also investigated the localization of these proteins in gastric cancer tissue. COX-2 and CCR2 levels were evaluated in CD40L-stimulated HUVECs by Western blot and real-time PCR. VEGF secreted in the culture media was quantified by ELISA. Localizations of MCP-1, CD40L, CD34, CD40 and CCR2 in 34 gastric cancer tissue specimens were evaluated by immunohistochemistry. CD40-CD40L interaction-induced COX-2 production and subsequently, upregulated COX-2 production contributed to elevated VEGF and CCR2 levels in CD40L-stimulated HUVECs. CD40L-stimulated VEGF production was COX-2 but not COX-1 dependent. RS-102895, a CCR2-specific antagonist, significantly reduced VEGF production in CD40L- and MCP-1-stimulated HUVECs. MCP-1 had a synergistic effect on COX-2, CCR2 and VEGF levels in CD40L-stimulated HUVECs. In gastric cancer tissue, there was significant correlation between microvessel density and scores for CD40L, MCP-1 and CCR2 protein expression. Thus, MCP-1 had a synergistic effect on COX-2 and CCR2 protein expression in CD40L-stimulated HUVECs and thereby stimulated VEGF production in these cells.
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PMID:COX-2 and CCR2 induced by CD40 ligand and MCP-1 are linked to VEGF production in endothelial cells. 1809 16

Overexpression of the transcription factor Sp1 may play a critical role in human gastric cancer angiogenesis. In the present studies, we determined whether targeting Sp1 has a therapeutic benefit. Treatment with mithramycin A (MIT) suppressed the expression of Sp1 and its downstream target genes in both human gastric cancer cell culture and tumors growing in nude mice. The molecular responses were accompanied by a significant inhibition of gastric cancer angiogenesis, growth and metastasis. Conversely, treatment with bevacizumab (BVZ), a neutralizing antibody against VEGF A, suppressed human gastric cancer growth in nude mice in a dose-dependent manner. Gene expression analyses revealed that treatment with low dose of BVZ substantially upregulated the expression of Sp1 and its downstream target genes, including VEGF and EGFR, in tumor tissues, whereas it did not have this effect on gastric cancer cells in culture. Combined treatment with BVZ and MIT produced synergistic tumor suppression, which was consistent with suppression of the expression of Sp1 and its downstream target genes. Thus, treatment with BVZ may block VEGF function but activate the pathway of its expression via positive feedback. Collectively, Sp1 is an important regulator of the expression of multiple angiogenic factors and functional status of Sp1 signaling pathway may profoundly affect the angiogenic phenotype of and effectiveness of antiangiogenic strategies for human gastric cancer.
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PMID:Targeted inhibition of Sp1-mediated transcription for antiangiogenic therapy of metastatic human gastric cancer in orthotopic nude mouse models. 1857 62

Metronomic dosing of cytotoxic drugs such as cyclophosphamide has shown anti-angiogenic activity, most likely by inducing hypoxia in tumors. Hypoxia leads to activation of escape mechanisms allowing tumor cell survival. This potentially limits the activity of anti-angiogenic strategies. We hypothesized that mTORC1 inhibition by everolimus (RAD001) leads to suppression of HIF-1alpha and VEGF resulting in synergistic anti-tumor activity in combination with anti-angiogenically dosed cyclophosphamide. In vitro, effects of everolimus on mTORC1 signaling, proliferation, cell cycle, HIF-1alpha expression and VEGF secretion were evaluated in two gastric cancer cell lines. In vivo, anti-tumor activity of everolimus in combination with metronomic cyclophosphamide was studied in a NCI-N87 human gastric cancer SCID mouse xenograft model. Expression of Ki-67 and HIF-1alpha, activated caspase 3, microvascular density (MVD) and tumor necrotic area assessed. Everolimus decreased proliferation and attenuated production of HIF-1alpha as well as VEGF in gastric cancer cells in vitro. In vivo, everolimus significantly inhibited tumor growth. This anti-tumor activity was linked to a significant increase in tumor necrotic area (p < 0.02) and trends for decreased proliferation, increased apoptosis, decreased HIF-1alpha and lower tumor MVD (p = n.s.). The combination of everolimus and cyclophosphamide resulted in a striking and highly significant long-term tumor growth control compared to monotherapy (p < 0.001), which was associated with a sharp increase in central tumor necrosis (p < 0.001). In conclusion, the combination of everolimus and metronomic cyclophosphamide showed synergistic anti-tumor activity. Depriving cancer cells by everolimus of factors necessary for their survival under hypoxia induced by anti-angiogenic chemotherapy appears to be a promising approach for treatment of gastric cancer.
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PMID:Everolimus (RAD001) and anti-angiogenic cyclophosphamide show long-term control of gastric cancer growth in vivo. 1876 27

Lymph node metastasis is an important prognostic factor in gastric cancer. Vascular endothelial growth factor-D (VEGF-D) is a lymphangiogenic growth factor that activates VEGF receptor (VEGFR)-3, a receptor expressed in the lymphatic endothelium. We investigated the clinical value of VEGF-D expression and VEGFR-3 positive vessel density in gastric carcinoma with regard to lymphangiogenesis. Immunohistochemical staining was used to determine the expression of VEGF-D and VEGFR- 3 in specimens from 104 cases of resected gastric cancer. VEGF-D expression was observed in 62.5% of the gastric cancers and in 9.6% of the non-neoplastic gastric tissue. The VEGFR-3-positive vessel density was significantly greater in the VEGFD positive group than the negative group. VEGF-D expression was significantly associated with lymph node metastasis, increased serum CEA levels, and the nonsignet ring cell type. The VEGFR-3-positive vessel density was correlated with tumor size, lymphatic invasion, and lymph node metastasis. The VEGF-D expression and high VEGFR-3-positive vessel density were significant poor prognostic factors for relapse-free survival. These results suggest that VEGF-D and VEGFR-3-positive vessel density are potential molecular markers that predict lymphatic involvement in gastric carcinoma.
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PMID:Correlation of vascular endothelial growth factor-D expression and VEGFR-3-positive vessel density with lymph node metastasis in gastric carcinoma. 1875 43

Although thiazolidinediones (TZDs) were found to be ligands for peroxisome proliferators-activated receptorgamma (PPARgamma), the mechanism by which TZDs exert their anticancer effect remains unclear. Furthermore, the effect of TZDs on metastatic and angiogenesis potential of cancer cells is unknown. Our results in this paper show that rosiglitazone inhibited SGC-7901 gastric cancer cells growth, caused G1 cell cycle arrest and induced apoptosis in a dose-dependent manner. The effects of rosiglitazone on SGC-7901 cancer cells were completely reversed by treatment with PPARgamma antagonist GW9662. Rosiglitazone inhibited SGC-7901 cell migration, invasiveness, and the expression of MMP-2 in dose-dependent manner via PPARgamma-independent manner. Rosiglitazone reduced the VEGF induced angiogenesis of HUVEC in dose-dependent manner through PPARgamma-dependent pathway. Moreover, rosiglitazone did not affect the expression of VEGF by SGC-7901 cells. Our results demonstrated that by PPARgamma ligand, rosiglitazone inhibited growth and invasiveness of SGC-7901 gastric cancer cells and angiogenesis in vitro via PPARgamma-dependent or -independent pathway.
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PMID:Rosiglitazone Suppresses the Growth and Invasiveness of SGC-7901 Gastric Cancer Cells and Angiogenesis In Vitro via PPARgamma Dependent and Independent Mechanisms. 3295 39

Tumor angiogenesis plays an important role in the malignancy of solid tumors. A number of recent studies including our own have suggested that Raf-1 is involved in this process, and may be critical in regulating gene activation of several angiogenesis factors. RNA interference (RNAi) provides a powerful method for gene silencing in eukaryotic cells, including proliferating mammalian cells. To further define Raf-1 function in angiogenesis and to explore novel approaches to modulate angiogenesis, we employed the small interference RNA technique to knockdown gene expression of Raf-1 in gastric cancer cells and observed the effect of silencing Raf-1 on gastric cancer tumorigenesis and angiogenesis in vitro and in nude mice. We found that the expression of double stranded RNA leads to the efficient and specific inhibition of endogenous Raf-1 protein expression in gastric cancer cell lines as determined by Western blotting. Raf-1 protein is a potential target for gastric cancer biological therapy. Inhibition of Raf-1 with siRNA technique could inhibit growth of the tumor graft and reduce angiogenesis in nude mice, which probably caused by downregulation of pro-angiogenesis molecules, such as VEGF and HIF-1alpha.Taken together, our findings indicate that specific Raf-1 targeting may have important therapeutic values for cancer therapy, and that individual Raf-1 may be a useful target in developing angiogenic inhibitors.
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PMID:RNAi-mediated inhibition of Raf-1 leads to decreased angiogenesis and tumor growth in gastric cancer. 1983 83

Our previous studies indicated a direct correlation with loss of CIAPIN1 and carcinogenesis of tumor in human gastric cancer. Here we presented that the expression of CIAPIN1 was absent or significantly decreased in 102 cases of clear cell renal cell carcinoma (CCRCC) tissues (P<0.05). Up-regulating CIAPIN1 by adenoviral vectors exhibited significant inhibition of CCRCC-derived cell growth in vitro and in vivo with G1 cell cycle arrest. Simultaneously, CIAPIN1-induced growth suppression was found partially to regulate various proteins, including inhibition of cyclinD1, cyclinE, cdk2, cdk4, p-Rb and VEGF, but up-regulation of p27Kip1 and Rb.
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PMID:CIAPIN1 inhibits the growth and proliferation of clear cell renal cell carcinoma. 1908 Nov 79

The expression of matrix metalloproteinase-2 (MMP2) has been linked with tumor invasion, angiogenesis, and metastasis. It has been reported that angiotensin II (Ang II) can induce MMP2 expression in gastric cancer cells. However, the molecular basis for Ang II regulates MMP2 expression in gastric cancer cells remains unclear. The aim of our study is to explore whether angiotensin II could induce MMP2 expression mediated through the Stat signaling pathway and its potential mechanism. Electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP)-binding assays was employed to determine the DNA-STAT binding activity. MMP2 and VEGF expression was analyzed with real-time PCR and Western blots. To examine the role of Stat3 in angiotensin II-induced MMP2 expression, A JAK-specific inhibitor and AG490 were used. Angiotensin II activated STAT-DNA binding activity in dose-dependent manners in gastric cancer cells. AG490 markedly inhibited angiotensin II-induced Stat3 activation and the expression of MMP2 and VEGF in gastric cancer cells. These results indicate that Stat3 may at least in part mediate angiotensin II-induced MMP2 mRNA expression in human gastric cancer cells. The activation of the JAK/Stat3 signaling pathway plays an important role in the progression of gastric cancer and that blockade of JAK/Stat3 signals may provide a novel therapeutic strategy for gastric cancer.
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PMID:Stat3 is involved in angiotensin II-induced expression of MMP2 in gastric cancer cells. 1908 17

Hypoxia-inducible factors (HIFs) are transcription factors that activate the transcription of target genes involved in crucial aspects of cancer development. This study investigated the expression of HIFs and their contribution to the regulation of target genes related to angiogenesis and glucose metabolism in gastric cancer. The data showed that HIFs were over-expressed in gastric cancer and that activation of the target genes was observed mainly in the early stages. Moreover, the results of the present study revealed that only HIF-1alpha, but not HIF-2alpha dimerizes with HIF-1beta and then regulates expression of target genes in response to hypoxia. The results of the present study demonstrate that HIF-1alpha and HIF-1beta enhances expression of VEGF and glucose metabolism-related genes in response to hypoxia in gastric cancer. These data offer important information regarding HIF pathways in the development of gastric cancer.
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PMID:Regulation of glucose metabolism-related genes and VEGF by HIF-1alpha and HIF-1beta, but not HIF-2alpha, in gastric cancer. 1928


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