UMLS:C0024623 - FACTA Search

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

Rebamipide, a gastro-protective drug, was developed in Japan for the treatment of peptic ulcer disease. It was proven superior to the former same category drug cetraxate in a randomized, controlled, double-blind, comparative clinical study in 1989. Rebamipide's mechanisms of actions are different from anti-secretory drugs; it accelerates and improves the quality of ulcer healing and reduces ulcer recurrence rate. Numerous studies have been conducted to explain the mechanisms responsible for these actions, 37 papers were published by 1998. Major properties of rebamipide include: stimulation of prostaglandin and mucus glycoprotein synthesis, inhibition of reactive oxygen species, inflammatory cytokines and chemokines, and inhibition of neutrophils activation. Since 1998, 107 papers were published, clarifying further effects of rebamipide on cyclooxygenase-2, prostaglandin E receptors, growth factors (i.e., HGF, EGF, and VEGF), heat-shock proteins, nitric oxide, adhesion molecules, neutrophils, and Helicobacter pylori- and NSAID-related pathology. Moreover, inhibitory action of rebamipide on gastric cancer growth has also been shown. In this issue we reviewed recent advances in understanding of rebamipide's mechanism of action and its newest clinical applications.
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PMID:15th anniversary of rebamipide: looking ahead to the new mechanisms and new applications. 1618 18

Tumour hypoxia is well recognised in oncology to be a key factor resulting in treatment resistance and poor prognosis. Hypoxia leads to the expression of a number of gene products that are involved in tumour progression, invasion and metastasis formation. The most important of these proteins is thought to be hypoxia-inducible factor-1alpha (HIF-1alpha), which appears to be a master regulator of the cellular response to hypoxia. HIF-1alpha expression is associated with a poor prognosis and treatment response in a number of tumour sites. There is some evidence that the HIF-1alpha pathway might be involved in gastric carcinogenesis. Studies have shown reactive oxygen species from Helicobacter pylori, associated with the development of gastric cancer, stabilise HIF-1alpha. Non-steroidal anti-inflammatory drugs, shown to reduce the risk of gastric cancer, can decrease HIF-1alpha expression. Although a large study correlating HIF-1alpha expression with prognosis is lacking in gastric cancer, the immunohistochemical expression of HIF-1alpha target genes (Glut-1, VEGF, CA9, iNOS) is associated with a poor prognosis. In addition, the targeted inhibition of HIF-1alpha has been shown to inhibit the growth of gastric tumours in animals. Increased understanding of the importance of hypoxia and the HIF-1alpha pathways may therefore hold the key to prevention strategies, improved selection of patients for adjuvant therapy and new treatments for the disease.
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PMID:Is the hypoxia-inducible factor pathway important in gastric cancer? 1629 Jan 33

Although the considerable progress against gastric cancer, it remains a complex lethal disease defined by peculiar histological and molecular features. The purpose of the present study was to investigate pRb2/p130, VEGF, EZH2, p53, p16(INK4A), p27(KIP1), p21(WAF1), Ki-67 expressions, and analyze their possible correlations with clinicopathological factors. The expression patterns were examined by immunohistochemistry in 47 patients, 27 evaluated of intestinal-type, and 20 of diffuse-type, with a mean follow up of 56 months and by Western blot in AGS, N87, KATO-III, and YCC-2, -3, -16 gastric cell lines. Overall, stomach cancer showed EZH2 correlated with high levels of p53, Ki-67, and cytoplasmic pRb2/p130 (P < 0.05, and P < 0.01, respectively). Increased expression of EZH2 was found in the intestinal-type and correlated with the risk of distant metastasis (P < 0.05 and P < 0.01, respectively), demonstrating that this protein may have a prognostic value in this type of cancer. Interestingly, a strong inverse correlation was observed between p27(KIP1) expression levels and the risk of advanced disease and metastasis (P < 0.05), and a positive correlation between the expression levels of p21(WAF1) and low-grade (G1) gastric tumors (P < 0.05), confirming the traditionally accepted role for these tumor-suppressor genes in gastric cancer. Finally, a direct correlation was found between the expression levels of nuclear pRb2/p130 and low-grade (G1) gastric tumors that was statistically significant (P < 0.05). Altogether, these data may help shed some additional light on the pathogenetic mechanisms related to the two main gastric cancer histotypes and their invasive potentials.
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PMID:Immunohistochemical analysis of pRb2/p130, VEGF, EZH2, p53, p16(INK4A), p27(KIP1), p21(WAF1), Ki-67 expression patterns in gastric cancer. 1699 11

Previously we have shown that hypoxia strongly induces the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 and -4 (PFKFB-3 and PFKFB-4) genes in several cancer cell lines via a HIF-dependent mechanism. In this paper we studied the expression and hypoxic regulation of PFKFB-4 and PFKFB-3 mRNA as well as its correlation with HIF-1alpha, HIF-2alpha, VEGF and Glut1 mRNA expression in the pancreatic cancer cell line Panc1 and two gastric cancer cell lines MKN45 and NUGC3. This study clearly demonstrated that PFKFB-3 and PFKFB-4 mRNA are expresses in MKN45, NUGC3 and Panc1 cancers cells and that both genes are responsive to hypoxia in vitro. However, their basal level of expression and hypoxia responsiveness vary in the different cells studied. Particularly, PFKFB-3 mRNA is highly expressed in MKN45 and NUGC3 cancer cells, with the highest response to hypoxia in the NUGC3 cell line. The PFKFB-4 mRNA has a variable low basal level of expression in both gastric and pancreatic cancer cell lines. However, the highest hypoxia response of PFKFB-4 mRNA is found in the pancreatic cancer cell line Panc1. The basal level of PFKFB-4 protein expression is the highest in NUGC3 gastric cancer cell line and lowest in Panc1 cells, with the highest response to hypoxia in the pancreatic cancer cell line. Further studies showed that PFKFB-3 and PFKFB-4 gene expression was highly responsive to the hypoxia mimic dimethyloxalylglycine, a specific inhibitor of HIF-alpha hydroxylase enzymes, suggesting that the hypoxia responsiveness of PFKFB-3 and PFKFB-4 genes in these cell lines is regulated by the HIF transcription complex. The expression of VEGF and Glut1, which are known HIF-dependent genes, is also strongly induced under hypoxic conditions in gastric and pancreatic cancer cell lines. The levels of HIF-1alpha protein are increased in both gastric and pancreatic cancer cell lines under hypoxic conditions. However, the basal level of HIF-1alpha as well as HIF-2alpha mRNA expression and their hypoxia responsiveness are different in the MKN45 and NUGC3 cancer cells. Thus, the expression of HIF-1alpha mRNA is decreased in both gastric cancer cell lines treated by hypoxia or dimethyloxalylglycine, but HIF-2alpha mRNA expression is not changed significantly in NUGC3 and slightly increased in MKN45 cells. Expression of PFKFB-4 and PFKFB-3 was also studied in gastric cancers and corresponding nonmalignant tissue counterparts from the same patients on both the mRNA and protein levels. The expression of PFKFB-3 and PFKFB-4 mRNA as well as PFKFB-1 and PFKFB-2 mRNA was observed in normal human gastric tissue and was increased in malignant gastric tumors. The basal level of PFKFB-4 protein expression in gastric cancers was much higher as compared to the PFKFB-3 isoenzyme. In conclusion, this study provides evidence that PFKFB-4 and PFKFB-3 genes are also expressed in gastric and pancreatic cancer cells, they strongly respond to hypoxia via a HIF-1alpha dependent mechanism and, together with the expression of PFKFB-1 and PFKFB-2 genes, possibly have a significant role in the Warburg effect which is found in malignant cells.
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PMID:Hypoxic regulation of PFKFB-3 and PFKFB-4 gene expression in gastric and pancreatic cancer cell lines and expression of PFKFB genes in gastric cancers. 1714 38

Thymidine phosphorylase (TP) has been reported to stimulate angiogenesis in a variety of human malignancies. We investigated TP expression and its association with angiogenesis in 73 cases of resected gastric cancer. In addition, we compared the expression of the other angiogenesis related factors (VEGF, eNOS and p53) with that of TP with respect to angiogenesis. TP expression was not detected in most of the non-tumoral glandular epithelial cells except for 5 cases. TP expression of the cancer cells and the stroma was assessed separately. The stromal TP expression was not associated with the TP expression of the cancer cells. The mean percent of TP reactive cancer cells was 18.36+/-2.61 (median, 10.00; range, 0-90) and cases showing a percentage higher than the mean were considered as bearing high reactivity. The mean microvessel score assessed was 90.44+/-3.69 (median, 86; range, 31-174). The TP expression of cancer cells was strongly associated with microvessel density (p=0.030), but the stromal TP expression was not. The microvessel density of the tumor showed strong correlation with VEGF expression (p<0.001), but a marginally significant association with eNOS (p=0.055). On the contrary, there was no association with p53 expression and microvessel density of the tumor. No significant correlation was detected between lymph node metastasis and tumoral or stromal TP expression or VEGF/TP coexpression. In gastric cancer, TP expression of the cancer cells, not stromal cells may play an important role in tumor growth by microvessel formation.
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PMID:Angiogenesis in gastric cancer: importance of the thymidine phosphorylase expression of cancer cells as an angiogenic factor. 1714 79

Cyclooxygenase-2 (COX-2) plays a crucial role in the development and invasion of gastric cancer. COX-2 inhibitors have been shown to be chemopreventive against gastrointestinal cancers. In vitro studies have suggested that the mechanisms may be related to induction of apoptosis and inhibition of angiogenesis. COX-2 may also have impact on E-cadherin. In our study we investigate the effect of Celecoxib on expression of E-cadherin and serum soluble E-cadherin, as well as on apoptosis and angiogenesis in patients with gastric cancer. Fifty nine gastric cancer patients were randomly divided into two groups: Surgery group (n = 22), in which patients underwent surgical resection after diagnosis, and Celecoxib + Surgery group (n = 37), in which patients received oral Celecoxib 200 mg twice daily for 7 days before curative resection. Twenty healthy subjects (Healthy controls) were recruited as normal controls. After curative resection, COX-2, E-cadherin, VEGF, and MVD were detected by immunohistochemistry. Serum soluble E-cadherin was quantitatively measured using a commercially available enzyme-linked immunosorbent assay kit. Apoptosis was determined by TUNEL assay. Significantly decreased expression of COX-2, increased E-cadherin and apoptosis, decreased VEGF and MVD were observed in gastric cancer tissues from patients receiving Celecoxib compared to Surgery group. Compared to Healthy controls, the serum soluble E cadherin levels were higher in gastric cancer patients which were decreased by Celecoxib. This in vivo study demonstrated that Celecoxib induces apoptosis and inhibit angiogenesis of gastric cancer. Its impact on E-cadherin may suggest that this agent may suppress the invasion of advanced gastric cancer.
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PMID:Effect of celecoxib on E-cadherin, VEGF, Microvessel density and apoptosis in gastric cancer. 1742 34

Previous studies by our laboratory indicated that zinc ribbon domain-containing 1 (ZNRD1) suppressed the growth of gastric cancer cells with a G(1) cell cycle arrest. However, the precise molecular mechanism underlying the growth-inhibitory effect of ZNRD1 remained fragmentary. In the present study, we have demonstrated that ZNRD1 could significantly inhibit the in vitro and in vivo growth of gastric cell line MKN28. Human cDNA microarray, reverse transcription-polymerase chain reaction and western blot analyses were used to identify differentially expressed cell cycle-related genes in MKN28 cells over-expressing ZNRD1. ZNRD1-induced growth suppression was found at least partially to regulate various proteins and signaling pathways controlling G(1) to S progression, including inhibition of cyclin D1 and CDK4, up-regulation of p21(CIP1/WAF1) and p27(Kip1) and acceleration of pRb dephosphorylation. Furthermore, ZNRD1 significantly inhibited the transcriptional activity of cyclin D1. p27(Kip1) might play a pivotal role in ZNRD1-induced cell cycle arrest because the p27(Kip1) anti-sense could block the cytostatic effects of ZNRD1. Moreover, ZNRD1 suppressed Skp2 expression via an increase in the protein instability, and induced significant decrease in cyclin E-CDK2 kinase activity. In addition, ZNRD1 could reduce tumor microvessel densities through inhibition of VEGF. Taken together, these results suggested that ZNRD1 might inhibit cell growth by targeting cell cycle-related genes and reducing tumor angiogenesis.
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PMID:Mechanisms of growth arrest by zinc ribbon domain-containing 1 in gastric cancer cells. 1738 17

The aim of this study was to establish an orthotopic implantation model with high metastasis of gastric cancer to the peritoneum which is more faithful to clinical metastasis. A human gastric carcinoma cell line, GC9811, was injected as a single-cell suspension into the stomach of nude mice. The cells from some peritoneum metastatic foci were expanded in vitro and subsequently implanted to the stomach wall of nude mice. By repeating the in vivo stepwise selection method for four rounds and cloning culture, we obtained a cell line designated GC9811-P, which developed peritoneal metastasis in 13 of 13 (100%) of mice, compared with only 20% of those implanted with parental GC9811. The metastatic foci in the peritoneum showed essentially the same histological appearance as those induced by parental cells. Tumor cell growth of GC9811-P in vitro was faster than that of GC9811. Motility assays demonstrated higher motility of GC9811-P than of GC9811. The adhesive ability of GC9811-P cells to laminin was lower than that of GC9811 cells, whereas the ability of GC9811-P cells to adhere to fibronectin was significantly higher than that of parental cells. Differences between GC9811-P and their parental GC9811 cells were found in expression levels of various molecules by flow cytometric and western blot. The findings indicated that up-regulation in the expressions of CD155, VEGF, syndecan-1, and syndecan-2 or down-regulation in the expressions of IL-6 and E-cadherin play an important role in the peritoneal metastasis of human gastric carcinoma cells. The high-metastatic cell line appears to be useful for investigating the mechanisms of peritoneal metastasis and preventing peritoneal metastasis of human gastric cancer.
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PMID:Establishment and characterization of a high metastatic potential in the peritoneum for human gastric cancer by orthotopic tumor cell implantation. 1740 72

The ets-1 transcription factor plays an important role in cell proliferation, differentiation, apoptosis and tissue remodeling. Aberrant ets-1 expression correlates with aggressive tumor behavior and poorer prognosis in patients with various malignancies. This study evaluated the efficacy of double-stranded decoy oligonucleotides targeting ets-1-binding cis elements for the suppression of ets-1 in treatment of a peritoneal dissemination model of gastric cancer. In vitro, MTT assay was performed to evaluate the effect of the ets-1 decoy on cell growth. Electrophoretic mobility shift assay (EMSA) was performed to determine ets-1 activity. In vivo, the effect of the ets-1 decoy was investigated in the peritoneal dissemination nude mice model. Disseminated nodules were analyzed immunohistochemically. Ets-1 decoy, but not scrambled decoy, significantly inhibited cell growth in 2 gastric cancer cell lines, which showed overexpression of ets-1 protein by inhibiting the binding activity of ets-1. In the peritoneal dissemination model, the ets-1 decoy significantly suppressed the disseminated nodules, and tended to prolong the survival rate. PCNA index, microvessel density and VEGF expression were also reduced in peritoneal tumors treated with ets-1 decoy. Intraperitoneal injection of ets-1 decoy inhibited peritoneal dissemination of gastric cancer in a nude mice model. The results indicate that the decoy strategy for ets-1 offers a promising therapy for patients with incurable peritoneal dissemination of gastric cancer, most of which show overexpression of ets-1 protein.
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PMID:Gene therapy using ets-1 transcription factor decoy for peritoneal dissemination of gastric cancer. 1754 98

Angiotensin II (Ang II) has been reported to promote tumor progression, tumor growth and angiogenesis in many cancers. We previously observed that angiotensin II type 1 receptors (AT1R) were upregulated in human gastric cancer and may be involved in the progression of gastric cancer. We studied the effects of AT1R antagonist on angiogenesis and growth in gastric cancer xenografts to observe the mechanism action of AT1R in the gastric cancer. The results showed that the growth of gastric cancer cells was significantly suppressed by treatment with AT1R antagonist. In vivo, TCV-116, at doses of both 2 and 5 mg/kg/day, significantly suppressed tumor growth in mice (47.3 and 70.2%). Microvessel density was significantly decreased by TCV-116 (3.4 +/- 0.9 and 2.8 +/- 0.5 per field) compared with the control group (12.9 +/- 1.1 per field), and VEGF expression was significantly suppressed by AT1R antagonist. These results demonstrate that AT1R plays an important role in the progression of gastric cancer. Suppression tumor angiogenesis could be one of the mechanisms by which AT1R antagonist suppresses the growth of gastric cancer. These findings also provide a theoretical basis for the future clinical application of AT1R antagonist against gastric cancer.
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PMID:Angiotensin II type 1 receptor antagonist suppress angiogenesis and growth of gastric cancer xenografts. 1793 50

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