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)

Urokinase plasminogen activating system (PA system) and vascular endothelial growth factor (VEGF) were recently suggested to contribute synergistically to tumor progression. To evaluate the roles of the PA system and VEGF in gastric cancer, the effects of the PA system and VEGF on tumor angiogenesis and the survival of patients with gastric cancer were investigated. Cancer tissues from 101 gastric cancer patients were assayed immunohistochemically for expression of urokinase-type plasminogen activator (uPA), uPA receptor (uPAR), PA inhibitor-1 (PAI-1) and VEGF protein. The positive rates of uPA, uPAR, PAI-1, VEGF expression were 22.8%, 32.7%, 36.6% and 26.7%, respectively. Positive staining was observed in tumor cells (uPA, uPAR, VEGF), or in both tumor cells and stromal cells (PAI-1). The expressions of uPA, uPAR, PAI-1 and VEGF were significantly correlated with the clinicopathological factors: uPA, depth of tumor invasion, differentiation, lymphatic and vascular invasion; uPAR, tumor size, depth, lymph node involvement, differentiation, vascular invasion; PAI-1, tumor size, depth, lymph node involvement, differentiation, vascular invasion; VEGF, differentiation, vascular invasion. The microvessel density (MVD) assessed immunohistochemically was significantly higher in the patients with expression of uPA, uPAR or VEGF, and stepwise analysis identified uPA as an independent correlated factor with MVD. Furthermore, multivariate analysis demonstrated that depth of tumor invasion, lymph node involvement and uPA expression were independent prognostic factors. uPA is a key factor in the PA system, being associated with a poor outcome of gastric cancer, and contributing not only to invasive activity, but also to angiogenesis.
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PMID:Urokinase-type plasminogen activator expression correlates with tumor angiogenesis and poor outcome in gastric cancer. 1270 73

To understand the role of cyclooxygenase-2 (COX-2) in gastric cancer, we examined the abundance of COX-2, vascular endothelial growth factor-A (VEGF-A), and CD34 in 45 surgically resected human gastric cancers and paired normal gastric mucosa by immunohistochemical analysis. In addition, the message RNA (mRNA) expression of COX-2 and VEGF-A was evaluated in ten fresh surgically resected human gastric cancers and paired normal gastric mucosas using semi-quantitative reverse transcriptional polymerase chain reaction analysis. Our results confirmed an increased abundance of COX-2 and VEGF-A, and the microvessel density, which was assessed by CD34 abundance, in gastric cancer tissues compared with normal paired mucosa. Abundance of COX-2 and VEGF-A was significantly associated with tumor-node-metastasis (TNM) stage (P<0.05) and lymph node metastasis (P<0.001). In addition, abundance of VEGF-A associates with distance metastasis. A significant correlation was found between COX-2 and VEGF-A abundances (P<0.001). Both abundance of COX-2 and VEGF-A were significantly correlated with microvessel density (P<0.001, respectively). In six of ten cancerous tissues and in one of ten paired normal mucosas, the mRNA expression of COX-2 and VEGF-A was detected in the same specimen. In one other cancerous tissue, only COX-2 mRNA was detected. This study indicates that COX-2 is related to tumor angiogenesis in gastric cancer. VEGF-A might play a main role in the COX-2 angiogenic pathway.
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PMID:Increased abundance of cyclooxygenase-2 correlates with vascular endothelial growth factor-A abundance and tumor angiogenesis in gastric cancer. 1276 10

Given the high rate of distant spread, effective systemic therapy is key to improving survival in patients with colorectal cancer (CRC). The past 40 years have seen progress. The addition of folinic acid (FA) to 5-fluorouracil (5-FU), the use of infusional rather than bolus 5-FU, and the combination of new active agents such as irinotecan and oxaliplatin with 5-FU/FA have each led to an increase in activity. In trials of current combination regimens first-line, response rates (RRs) in excess of 50% and median survival durations longer than 16 months are seen. A recent controlled trial suggests that overall time to progression is maximized and toxicity minimized when an irinotecan/5-FU/FA combination is used first-line, followed by an oxaliplatin/ 5-FU/FA combination on progression. In the adjuvant setting, 5-FU/FA is the standard of care in stage III disease but of uncertain value in stage II patients. The role of new agents such as irinotecan in adjuvant regimens is being assessed. Use of highly active chemotherapy in patients with unresectable disease (particularly liver metastases) achieves responses that allow a subset of patients to proceed to potentially curative surgery. The emergence of novel agents targeted at processes such as tumor angiogenesis will complement cytotoxic chemotherapy, while improved understanding of tumor biology should enable agents to be selected according to the likely sensitivity of the disease in a particular patient. In gastric cancer also, surgery remains the only potentially curative treatment. The extent of dissection required is debated, as is the potential benefit of adjuvant chemoradiotherapy (indeed the degree of resection may interact with the effect of adjuvant treatment). In untreated metastatic gastric cancer, median survival is 3-4 months. This can be increased to around 10 months using chemotherapy. Quality of life is also enhanced. There is no clearly defined standard of care. However, some form of cisplatin/5-FU combination can serve as a reference regimen. As single agents, both irinotecan and docetaxel achieve RRs of around 20% in metastatic CRC. In combination with cisplatin and/or 5-FU a very high and promising RR is achieved. The promise of these agents in combination with 5-FU and 5-FU plus cisplatin is currently being tested in phase III trials.
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PMID:Current treatments and future perspectives in colorectal and gastric cancer. 1281 Apr 59

Angiogenesis is a key prerequisite for the successful establishment, growth, and dissemination of tumors. Vascular endothelial growth factor (VEGF) has a potent angiogenic activity and cyclooxygenase-2 (COX-2) promotes angiogenesis by modulated production of angiogenic factors including VEGF. The current study was designed to investigate the possible roles of COX-2 and VEGF in gastric cancer angiogenesis. In this study, we conducted an immunohistochemical investigation of COX-2 and VEGF expression in 97 patients with gastric cancer. To assess tumor angiogenesis, microvessel density (MVD) was determined by CD34 immunohistochemical staining. Expression of COX-2 and VEGF in gastric cancer tissues, was demonstrated in 63.9% and 75.3% of cases, respectively. The expression of COX-2 correlated significantly with VEGF expression. High MVD was significantly associated with depth of tumor invasion and poor survival. The mean MVD value of VEGF positive tumors was 79.8 +/- 32.0 and significantly higher than that of VEGF negative tumors. The mean MVD value of COX-2 positive tumors was 77.9 +/- 29.9 and not significantly higher than that of COX-2 negative tumor. The mean value of MVD in tumors positive for both COX-2 and VEGF was significantly higher than that in tumors negative for both. However, there was no correlation between COX-2 or VEGF expression and various clinicopathological features including patient survival. These results suggest that COX-2 may play an important role in carcinogenesis by stimulating tumor angiogenesis in concert with VEGF in human gastric cancer.
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PMID:Cyclooxygenase-2 overexpression correlates with vascular endothelial growth factor expression and tumor angiogenesis in gastric cancer. 1281 Dec

Marimastat is a broad-spectrum matrix metalloproteinase (MMP) inhibitor that inhibits almost all major MMPs, key enzymes in gastric cancer invasion and metastasis. We investigated the ability of marimastat to inhibit tumor angiogenesis in the severe combined immuno-deficient (SCID) mouse/human gastric cancer model of peritoneal dissemination. A human stomach adenocarcinoma cell line, TMK-1, was injected intraperitoneally into SCID mice. On the 7th day after tumor inoculation, the administration of marimastat (27 mg/kg/day) was initiated and the treatment was continued for 2 weeks using subcutaneously-inoculating mini-osmotic pumps. On the 21st day, the mice were killed and the disseminated nodules were evaluated. Total weights, numbers, and the microvascular density of the disseminating nodules were significantly lower in mice treated with marimastat compared to the control group. Film in situ zymography demonstrated that net gelatinolytic activity in the tissues was weaker in treated-group nodules than in control-group nodules. Thus, our results suggested that marimastat inhibited peritoneal dissemination of human gastric cancer cells through inhibition of tumor angiogenesis, possibly involving the down-regulation of gelatinases, in SCID mice injected with human gastric cancer cells.
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PMID:Reduced angiogenesis in peritoneal dissemination of gastric cancer through gelatinase inhibition. 1452 32

Hypoxia-induced angiogenesis plays an important role in the malignancy of solid tumors. A number of recent studies including our own have suggested that Rho family small GTPases are involved in this process, and Racl, a prominent member of the Rho family, may be critical in regulating hypoxia-induced gene activation of several angiogenesis factors and tumor suppressors. To fur-ther define Racl function in angiogenesis and to explore novel approaches to modulate angiogenesis, we employed the small interference RNA technique to knock down gene expression of Racl in gastric cancer cell line AGS that expresses a high level of Racl. Both the mRNA and protein levels of Racl in the AGS cells were decreased dramatically after transfection with a Racl-specific siRNA vector. When the conditioned medium derived from the Racl downregulated AGS cells was applied to the human endothelial cells. it could significantly inhibit the cell proliferation. Further study proved that, VEGF and HIF-la, two angiogenesis promoting factors, were found to be downregulated whereas p53 and VHL, which are tumor suppressors and angiogenesis inhibitors. were upregulated in the Racl siRNA transfected cells. Our results suggest that Racl may be involved in angiogenesis by controlling the expression of angiogenesis-related factors and provide a possible strategy for the treatment of tumor angiogenesis by targeting the Racl GTPase.
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PMID:Inhibition of endothelial cell proliferation by targeting Rac1 GTPase with small interference RNA in tumor cells. 1530 76

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. To further define Raf-1 function in angiogenesis and to explore novel approaches to modulate angiogenesis, we employed the small interference RNA technique to knock-down gene expression of Raf-1 in gastric cancer cell line SGC7901 that expresses a high level of Raf-1. The protein level of Raf-1 in the SGC7901cells was decreased dramatically after transfection with a Raf-1 specific siRNA vector. Further study proved that, VEGF and HIF-1alpha, two angiogenesis promoting factors, were found to be downregulated. And we also find that Vector-based RNA interference for Raf-1 increases transfected gastric cell apoptosis and inhibits cellular proliferation. Our results suggest that Raf-1 may be involved in angiogenesis by controlling the expression of angiogenesis-related factors and provide a possible strategy for the treatment of tumor angiogenesis by targeting Raf-1.
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PMID:Inhibition of gastric cancer angiogenesis by vector-based RNA interference for Raf-1. 1566 29

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

Many researches have confirmed the tumor-prophylactic effects of cyclooxygenase-2 (COX-2) inhibitors. We previously observed their anti-cancer effects in vivo in nude mice and found that sulindac, a traditional non-steroidal anti-inflammatory drug (NSAID), and celecoxib, a selective COX-2 inhibitor, depressed the growth of SGC7901 xenografts via altering cell kinetics. Then we deeply studied the relationship between the two drugs and angiogenesis in gastric cancer. The results showed both sulindac and celecoxib decreased the micro-vessel density (MVD), which was labeled by either CD34 or VWF staining, within xenografts. Expression of both vascular endothelial growth factor (VEGF) and FGF-1 was suppressed. In addition, a positive correlation between MVD and the volume of SGC7901 xenografts was found. The effect of selective COX-2 inhibitor was stronger than non-special one despite of the insignificant difference. These results demonstrate that COX-2 plays an important role in angiogenesis of cancer. Apart from interfering cell kinetics, decreasing the expression of angiogenic factors and then inhibiting tumor angiogenesis could also be one of the mechanisms that COX-2 inhibitors suppress the growth of gastric cancer. These findings offer another theory basis for the future clinical application of NSAIDs against cancer.
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PMID:Cyclooxygenase-2 inhibitors suppress angiogenesis and growth of gastric cancer xenografts. 1650 95

Angiogenesis, formation of new microvessels providing oxygen and nutrient supply, is essential for tumor growth. It is dependent on the production of angiogenic growth factors by tumor cells. Angiopoietin 1 (Ang-1) and 2 (Ang-2) and their common receptor, Tie2, are thought to be critical regulators of tumor angiogenesis. We examined expression of Ang-1, Ang-2, and their common receptor Tie2 mRNAs and proteins in gastric cancers using in situ hybridization and immunohistochemistry. We also investigated the relationship between their expression and differentiation of cancer cells, lymph node metastasis, tumor size, depth of cancer cell invasion, TNM staging and microvessel density (MVD). The expression of Ang-1, Ang-2, and Tie2 mRNA in cancer cells significantly correlated with the MVD (p<0.001, <0.001 and =0.019, respectively). Ang-1 and Tie2 positivity correlated with advanced gastric cancers (p<0.05) and larger cancers had higher positive rates of Ang-1, Ang-2, and Tie2 mRNA expression (p<0.001, =0.010 and =0.039, respectively). Significant positive correlations were also found between mRNA expression of Tie2 and those of Ang-1 and Ang-2 (p<0.01 and <0.001, respectively). These findings indicate that the expression of Ang-1 and Ang-2 is important for tumor angiogenesis, and suggest a possible role of autocrine/paracrine function of angiopoietin/Tie2 system in gastric cancer progression.
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PMID:Expression of angiopoietin 1, 2 and their common receptor Tie2 in human gastric carcinoma: implication for angiogenesis. 1661 13


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