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 study was to investigate expression of the active and inactive gelatinases (MMP-2 and -9) in colorectal neoplasia and gastric cancer compared with normal mucosa. A total of 53 colorectal cancers and corresponding normal mucosa were studied using gelatin zymography as well as 15 colorectal adenomas and 13 gastric cancers with corresponding normal mucosa. Overexpression of all the gelatinases occurs in both colorectal and gastric cancer, with activation of MMP-2 appearing to be a feature of the malignant phenotype. Overexpression of MMP-9 occurs in colorectal adenomas. The gelatinases are overexpressed in gastrointestinal neoplasia, suggesting that these enzymes may have an important role in tumour invasion and metastasis.
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PMID:Gelatinase (MMP-2 and -9) expression in gastrointestinal malignancy. 1063 99

Gastric cancer is classified into intestinal and diffuse types, which exhibit different biological behavior. Urokinase-type plasminogen activator (uPA), its receptor (uPAR) and matrix metalloproteinases (MMPs)-1 and -9 are considered to play important roles in cancer invasion and metastasis. We have already suggested a functional duality of these matrix-degrading enzymes/factors; they may also be involved in the matrix turnover (remodeling) or host immune/inflammatory reactions as far as they are expressed by host cells. We performed a retrospective study on the immuno-histochemical expression of these enzymes/factors in surgical specimens from patients with gastric cancer, including 26 with the diffuse and 78 with the intestinal type. We also evaluated macrophages since they are major sources of uPAR. The positivity rate for uPA in cancer cells was significantly lower in diffuse-type than in intestinal-type. Stromal expression was seen mainly along the invasive margin (tumor-host interface). The degree of stromal expression of uPAR and MMP-9 and the macrophage number were markedly decreased in diffuse-type compared with intestinal-type. Stromal expression of uPAR and macrophage number in intestinal-type were higher in patients without liver metastasis than in patients with liver metastasis, while uPA expression in cancer cells was more pronounced in patients with liver metastasis. Studies using frozen sections revealed that the expression of MMP-1, restricted to the stromal area, was more decreased in diffuse-type (18 patients) than in intestinal-type (21 patients). Our results show that the in situ expression of matrix-degrading enzymes/factors in gastric cancer is significantly more diminished in diffuse-type than in intestinal-type, suggesting a multifunctional aspect of the matrix-degradation process in cancer tissue.
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PMID:Differing expression of MMPs-1 and -9 and urokinase receptor between diffuse- and intestinal-type gastric carcinoma. 998 36

The scenario of multiple genetic and epigenetic alterations found in gastric carcinoma differs depending upon the two histological types, indicating that well differentiated or intestinal type and poorly differentiated or diffuse type gastric carcinomas have different genetic pathways. Cancer-stromal interaction through growth factor/cytokine receptor system which plays a central role in invasion and metastasis, is also different between the two types of stomach cancer. The majority of gastric carcinoma exhibit co-expression of IL-8 and its two receptors that evidently confer tumor angiogenesis. IL-8 increases the expression of EGF receptor, VEGF and IL-8 itself by tumor cells themselves, whereas IL-8 decreases expression of E-Cadherin, associated with increase in expression and activity of MMP-9 by tumor cells. These findings overall suggest that IL-8 produced by gastric cancer cells is used for sustained angiogenesis and tissue invasion and metastasis via autocrine/paracrine manners. On the other hand, co-expression of osteopontin (OPN) and CD44v9 in tumor cells correlates well with the degree of lyiphatic vessel invasion or long distant lymph node metastasis in diffuse type gastric carcinoma, indicating that mutual interaction between OPN and CD44v9 on the tumor cells is implicated in lymphogenous metastasis. In addition to these factors, tumor invasion and metastasis requires telomere maintenance regulated by telomerase activity. The human telomerase catalytic subunit, hTERT, is strongly expressed in almost all primary tumors and nodal metastasis.
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PMID:Molecular aspects of invasion and metastasis of stomach cancer. 1121 48

Tumor angiogenesis progresses by a dynamic balance between tumor vascular regression and growth. Angiopoietin (Ang)-2 (the natural antagonist for the angiogenic Tie-2 receptor) and vascular endothelial growth factor (VEGF) are thought to be critical regulators in this process; therefore, these may play a critical role in cancer aggressiveness. The aim of this study was to clarify the clinical and biological significance of the expression of Ang-2 in human gastric cancers and to investigate the relationship between Ang-2 together with VEGF and the induction of proteases such as matrix metalloproteinases (MMPs) in the process of tumor development. Eighty-five individuals with gastric cancer, who had undergone surgery without preoperative treatment, were studied. A stable transfectant of the human MKN-7 gastric cancer cell lines with an Ang-2 expression vector was used for the experimental study. First, we examined the relationship between the mRNA expression of Angs by Northern blot analysis and clinicopathological features. High Ang-2-expression cases showed more frequent vascular involvement and more advanced stages of disease compared with low Ang-2-expression cases (P < 0.05). With regard to prognosis, the survival time for patients in the high-Ang-2 mRNA group was significantly shorter (P < 0.05). When we examined the localization of Ang-2 in human gastric cancers, immunohistochemical analysis revealed that this protein was expressed predominantly in cancer tissues when compared with normal tissues. Interestingly it was expressed not only in endothelia cells (ECs) but also in cancer cells. Second, Ang-2-transfected cells were implanted in vivo into the gastric walls of nude mice. Ang-2-transfectant mice developed highly metastatic tumors with hypervascularity as compared with MKN-7 or control vector-transfectant tumors. There was a significant correlation between Ang-2 mRNA expression and lower grade of vessel maturation. Third, on the basis of the in vivo data, we focused on production of proteases such as MMPs to investigate possible mechanisms in these processes. MMP-1, MMP-9, and urokinase-type plasminogen activator in ECs were strongly up-regulated by Ang-2 in the presence of VEGF in vitro. These data suggest that production of Ang-2 is implicated in tumor development in human gastric cancers. Its production may contribute to tumor angiogenesis by induction of proteases in ECs, which may be enhanced in the presence of VEGF.
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PMID:Angiopoietin-2 is related to tumor angiogenesis in gastric carcinoma: possible in vivo regulation via induction of proteases. 1128 Jul 79

Transforming growth factor beta1 (TGF-beta1) and matrix metalloproteinases (MMPs) produced by tumor cells play important roles in tumor invasion. PSK, a protein-bound polysaccharide, is widely used in Japan as an immunopotentiating biological response modifier for cancer patients. In this study, we focused on the effects of PSK on invasiveness, TGF-beta1 production, and MMPs expression in two human tumor cell lines, pancreatic cancer cell line (NOR-P1) and gastric cancer cell line (MK-1P3). PSK significantly decreased the invasiveness of both cell lines through Matrigel-coated filters but did not affect cell viability, proliferation, or adhesion. Decreased invasion was associated with the inhibition of TGF-beta1, MMP-2, and MMP-9 at both mRNA and protein levels as assessed by reverse transcriptase-polymerase chain reaction, gelatin zymography, and enzyme-linked immunosorbent assay. Antibody against TGF-beta1 neutralized the MMP activities of both cell lines. PSK also suppressed the expression of urokinase plasminogen activator (uPA) and uPA receptor but did not change plasminogen activator inhibitor-1 (PAI-1) expression. Western blot analysis showed that PSK reduced uPA protein expression but not PAI-1 expression in the both cell lines. These results indicate that PSK suppresses tumor cell invasiveness through down-regulation of several invasion-related factors including TGF-beta1, uPA, MMP-2, and MMP-9.
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PMID:Protein-bound polysaccharide PSK inhibits tumor invasiveness by down-regulation of TGF-beta1 and MMPs. 1144 66

The flavonoid nobiletin (5,6,7,8,3',4'-hexamethoxyflavone), found in Citrus depressa Rutaceae, a popular citrus fruit in Okinawa, Japan, reportedly inhibits the production of pro-matrix metalloproteinase (proMMP)-1, 3, and 9 in rabbit synovial fibroblasts in vitro. In the present study, we demonstrated the inhibitory effects of nobiletin on the proliferation of the cancer cell line, TMK- 1, and its production of MMPs. In the SCID mouse model, we found that nobiletin inhibited the formation of peritoneal dissemination nodules from TMK-1. The enzymatic activity of MMP-9 expressed in culture medium obtained from a co-culture of TMK-1 and mouse fibroblastic cells was inhibited by nobiletin in a concentration-dependent manner. In the SCID mouse model, total weight of dissemination nodules was significantly lower in the treated group compared with the vehicle control group (0.07 g vs. 0.78 g, P = 0.0059). The total number of dissemination nodules was also significantly lower than in the vehicle control group (7.5 vs. 69.3 / body, P = 0.0001). These results suggest that nobiletin may be a candidate anti-metastatic drug for prevention of peritoneal dissemination of gastric cancer.
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PMID:The citrus flavonoid, nobiletin, inhibits peritoneal dissemination of human gastric carcinoma in SCID mice. 1174 98

We investigated the biologic behavior of gastric phenotype carcinoma of the stomach, especially in association with degradation of the extracellular matrix. One hundred fourteen lesions of intramucosal gastric carcinoma (IMGC) of differentiated type were studied. IMGCs were classified into 4 phenotypic categories--complete intestinal type (C type), incomplete intestinal type (I type), gastric type (G type), and unclassified type--through a combination of the expression of CD10, MUC2, HGM, and Con A. The expression of MMP-2, MMP-9, TIMP-2, and type IV collagen was investigated by immunohistochemical staining. The incidence of C-type IMGC, I-type IMGC, and G-type IMGC was 7.9%, 55.3%, and 36.8%, respectively. The incidence of positive MMP-9 expression in G-type IMGCs (57%) was significantly higher than that in C-type IMGCs (11%) or I-type IMGCs (35%) (P < .01). There was no significant correlation between phenotypes and expression of MMP-2, TIMP-2, or type IV collagen. There was a reverse correlation between the expression of type IV collagen and the expression of type IV collagenase (P < .001). In conclusion, gastric phenotype carcinomas have been shown to be highly invasive and metastatic, However, although they can potentially degrade the extracellular matrix via overexpression of MMPs compared with intestinal phenotype carcinoma, our data show no statistically significant separation of subtypes of intramucosal gastric cancer based on gross classification, histologic type, lymphatic or venous invasion, or lymph node metastases.
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PMID:Relationship between biologic behavior and phenotypic expression in intramucosal gastric carcinomas. 1182 76

The gastric hormone gastrin regulates the organization of the gastric epithelium, but the cellular control mechanisms are yet unknown. Epithelial remodelling typically involves extracellular proteolysis mediated by the matrix metalloproteinases (MMPs). Since a gene-array analysis of the gastric cancer cell line AGS-G(R) suggested that gastrin increased MMP-9 expression, we examined the control of MMP-9 expression by gastrin. Gelatin zymography confirmed gastrin induction of MMP-9 in AGS-G(R) cells, but showed a small inhibition of MMP-2. Immunocytochemical studies showed that MMP-9 was localized to vesicles that appeared to traffic along the processes that were extended in response to gastrin. Gastrin stimulated the invasion of AGS-G(R) cells through artificial basement membrane, which was reduced by an inhibitor of MMP-2/-9. There was also an increase in MMP-9 in the stomach of patients with elevated plasma gastrin and multiple-endocrine neoplasia type 1 (MEN-1) syndrome, suggesting in vivo regulation of MMP-9 expression by gastrin. Finally, we showed that the expression of 1.9 kb of human MMP-9 gene promoter coupled with luciferase (MMP-9-luc) was increased 7.65+/-1.2-fold by gastrin, via a pathway which includes stimulation of protein kinase C, and activation of Raf and the mitogen-activated protein (MAP) kinase pathway. The tumour suppressor menin (which is mutated in MEN-1 syndrome) inhibited the expression of MMP-9-luc by gastrin. These results suggest that gastrin increases MMP-9 expression, which is associated with increased invasion, and this is a putative mechanism regulating remodelling of the gastric epithelium.
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PMID:Gastrin-stimulated gastric epithelial cell invasion: the role and mechanism of increased matrix metalloproteinase 9 expression. 1197 60

Among the many biological characteristics of cancer, matrix-metalloproteinases (MMPs) are essential for tumor invasion and metastasis. To test the possibility of ex vivo model as a therapeutic guideline for MMP inhibitor (MMPI) treatment, we evaluated IC50 of the gabexate mesylate against MMP-9. Thirty-four paired normal and gastric cancer tissues were tested to measure the IC50 of the gabexate mesylate. MMP-9 activity was measured by zymography. Both MMP-9 expression (p=0.04) and IC50 (p=0.02) were higher in cancer than normal tissues. IC50 of the cancer tissues was higher than paired normal tissues especially in cases with large tumor (> or =5 cm) (p=0.03), higher T-stage (p=0.04), lymph node metastasis (p=0.04) and advanced stage (p=0.04). In cancers extending beyond submucosa or in diffuse/mixed type, a tendency of higher IC50 was observed than tumors confined to submucosa or intestinal type cancer despite similar MMP-9 activity between the groups. Patients with high IC50 showed poorer prognosis than patients with low IC50 in curatively-resected group. In multivariate analysis, high IC50 was suggested as an independent prognostic factor. We were able to differentiate the high risk patients using IC50 of gabexate mesylate in ex vivo model. This model can be applied in detecting patients with poor prognosis and patients who may benefit from MMPI treatment.
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PMID:Biological phenotype determination with ex vivo model in gastric cancer for matrix-metalloproteinase inhibitor treatment. 1216 96

Overexpression of matrix metalloproteinases (MMPs) has been known to correlate closely with tumor cell invasion and strategies to down-regulate their expression may ultimately be of clinical utility. In this study, we investigated the effects of (-)-epigallocatechin gallate (EGCG), a major green tea catechin, on the cell invasiveness and MMP-9 induction in human gastric cancer AGS cells. EGCG inhibited the phorbol 12-myristate 13-acetate (PMA)-induced cell invasiveness and MMP-9 expression in a dose-dependent manner. EGCG treatment was found to reduce the MMP-9 transcriptional activity. To further study the mechanisms for the EGCG-mediated regulation of MMP-9, the effects of EGCG on transcription factor AP-1 and mitogen-activated protein kinase (MAPK) activities were examined. The results showed that EGCG suppressed the PMA-induced AP-1 activation. EGCG also abrogated the PMA-induced activation of extracellular-regulated protein kinase (Erk) and c-jun N-terminal kinase (JNK), which are upstream modulators of AP-1. These results suggest that EGCG may exert at least part of its anti-invasive effect in gastric cancer by controlling MMP expression through the suppression of MAPK and AP-1 activation.
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PMID:EGCG blocks tumor promoter-induced MMP-9 expression via suppression of MAPK and AP-1 activation in human gastric AGS cells. 1516 Oct 22


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