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

In vitro morphologic change of mesothelial cells was observed following the addition of serum-free conditioned medium (SF-CM) from peritoneal dissemination cell line OCUM-2MD3. The same morphologic change of mesothelial cells was observed following the addition of 10 ng/ml TGF-beta1, but not following the addition of b-FGF, IGF-I, VEGF or PDGF-AA. In the in vivo study, mesothelial cells of mice treated with SF-CM from OCUM-2MD3 and TGF- beta1 were separated from one another, resulting in exposure of the submesothelial connective tissue. The molecular size of the mesothelial morphology changing activity was estimated by running the SF-CM from OCUM-2MD3 through a gel filtration column TSK-gel G2000SW. The mesothelial morphology changing activity was recognized at positions equivalent of Mr 6, 500-30,000. 25 kDa TGF-beta1 was detected in the active fraction from the TSK-gel G2000SW column and the SF-CM of OCUM-2MD3 by Western blotting using a monoclonal antibody against TGF-beta1. These findings suggest that TGF-beta1 produced by gastric cancer cells changes the morphology of mesothelial cells and may thus be closely associated with peritoneal dissemination.
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PMID:TGF-beta1 produced by gastric cancer cells affects mesothelial cell morphology in peritoneal dissemination. 949 45

VEGF (vascular endothelial growth factor) is known to play crucial roles in tumor angiogenesis. In 281 gastric cancer patients, aberrant increase of VEGF level was observed in 36 patients (12.8%). In 14 recurrent patients, 8 showed an increase of VEGF. The serum VEGF levels of stage IV cancer were significantly higher than those of stage I. The serum levels of recurrent patients were significantly higher than those of stage I, II and III. VEGF levels of patients with serosal invasion were significantly higher than those of patients without serosal invasion. In depth of invasion (t-factor), VEGF levels of t4 cancer were significantly higher than those of t1-t3. In venous infiltration of tumors, VEGF levels of v3 were significantly higher than v0 and v1. There was no significant difference with respect to H-factor and P-factor status. In eleven recurrent or advanced gastric cancer patients, serum VEGF was sequentially examined between pre- and post-chemotherapy. All of them showed a decrease of serum VEGF concentration after partial response by chemotherapy. The patients who had progressive disease after chemotherapy showed an increase of VEGF levels. Serum VEGF levels were closely related to the extent of gastric cancer and the response of chemotherapy.
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PMID:Concentrations of vascular endothelial growth factor in the sera of gastric cancer patients. 976 80

Many studies have reported a close association between VEGF and tumor angiogenesis. The aim of the present study was to evaluate the effectiveness of gene therapy against cancer, including peritoneal metastasis, using a cDNA encoding a soluble type of Flt-1, one of the VEGF receptors. In a peritoneal metastasis model of MKN45 human gastric cancer cells, mice repetitively treated with intraperitoneal injections of HVJ-Fex, a type of HVJ-cationic liposome encapsulating a plasmid expressing soluble mFlt-1, exhibited smaller disseminated foci with fewer microvessels, thus resulting in a significantly longer survival period than the control mice. In another peritoneal metastasis model using HT1080S cells, a clone of HT1080 human fibrosarcoma cells stably transfected with hVEGF, treatments with HVJ-Fex also reduced the growth of disseminated foci without ascites formation. In conclusion, this study demonstrated that the peritoneal metastases of some cancers were largely dependent on VEGF, and that the repeated intraperitoneal transduction of a soluble flt-1 gene using HVJ-cationic liposomes suppressed peritoneal metastases, thereby contributing to a longer survival period.
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PMID:Soluble Flt-1 gene therapy for peritoneal metastases using HVJ-cationic liposomes. 1087 51

Antiangiogenic therapy has been proposed as a new strategy for the treatment of solid tumors. To enhance the therapeutic effect of antiangiogenic agents, combination with conventional anticancer therapy should be investigated. In the present study, we investigated the therapeutic effect of the combination of vascular endothelial growth factor neutralizing antibody (VEGF Ab) and mitomycin C (MMC) on MT-2, a human gastric cancer xenograft. When small pieces of MT-2 were transplanted orthotopically into 62 nude mice, liver metastasis developed 6 weeks after transplantation. The VEGF Ab (100 micro g / mouse) was administered i.p. in the VEGF Ab group (n = 14) and the combination group (n = 16) twice a week from day 10 after transplantation. MMC (2 mg / kg) was administered in the MMC group (n = 16) and the combination group (n = 16) on days 10, 17 and 24 after transplantation. Compared with the control group, in which saline solution was administered i.p., all three treatments inhibited tumor growth significantly and the effects of MMC and combination therapy were potent. Liver metastases were also inhibited significantly by the administration of VEGF Ab alone, MMC alone or combination therapy. Liver metastasis developed in 9 mice of the control group, 3 of the VEGF Ab group, and 4 of the MMC group, but no mice had liver metastasis in the combination therapy group. However a significant body weight loss and a decrease in spleen weight were observed in the MMC and combination groups, with no significant difference between the two groups. These results suggest that combination therapy with VEGF Ab and MMC may be a potent therapy for human gastric cancer.
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PMID:Combination therapy with vascular endothelial growth factor neutralizing antibody and mitomycin C on human gastric cancer xenograft. 1092 Feb 83

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

Elevated VEGF blood concentrations have been proven to be associated with poor prognosis in human neoplasms. This finding is generally explained as a consequence of the potential angiogenic properties of VEGF itself. However, preliminary experimental studies suggest that VEGF, in addition to its angiogenic activity, may also play an immunosuppressant role by inhibiting dendritic cell (DC) maturation. The present study was performed to analyze blood levels of VEGF in cancer patients in relation to those of another potentially angiogenic tumor growth factor, endothelin-1 (ET-1), and to the absolute number of circulating immature and mature DC, and serum levels of the best known antitumor cytokine, IL-12. The study was performed in 100 healthy controls and in 80 solid tumor patients (colorectal cancer: 24; gastric cancer: 17; cancer of pancreas: 4; lung cancer: 13; breast cancer: 11; renal cell cancer: 6; gynecologic tumors: 5), 48 of whom showed distant organ metastases. In each patient, we have evaluated serum concentrations of VEGF-165, total VEGF, ET-1, IL-12 and the circulating number of immature (CD123+) and mature (CD11c+) DC. Mean serum levels of VEGF-165 were significantly higher in metastatic patients than in controls or in non-metastatic patients, whereas the total amounts of VEGF were not significantly higher. Moreover, it has been observed that patients with abnormally elevated blood concentrations of VEGF-165 showed significantly lower mean values of immature DC, mature DC and IL-12 and significantly higher mean levels of ET-1 than those with normal concentrations. This study, by confirming that advanced neoplastic disease may be associated with increased endogenous secretion of VEGF, seems to suggest that the association between high blood levels of VEGF and poor prognosis in cancer does not depend only on VEGF-induced stimulation of the neovascularization, but also on VEGF-related immunosuppression.
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PMID:Abnormally enhanced blood concentrations of vascular endothelial growth factor (VEGF) in metastatic cancer patients and their relation to circulating dendritic cells, IL-12 and endothelin-1. 1150 71

It was previously reported that monocytes/macrophages play an important role in mediating T-cell dysfunction in tumor-bearing hosts, in which monocytes/macrophages were found to induce the loss of T-cell functions concomitantly with induction of defects in T-cell signaling molecules. These observations encouraged us to investigate monocyte status in cancer-bearing hosts. We characterized peripheral blood monocytes in gastric cancer patients with advanced disease (n = 14), in those with early disease (n = 17) and in healthy individuals (n = 14), based on surface marker, oxygen-burst capacity, and intracellular cytokine status (IL-10 and IL-12). To clarify which mediators induced the characteristic differences of monocytes in cancer-bearing hosts, healthy donor-derived monocytes were co-incubated with the patients' plasma. Intracellular IL-10 and IL-12 status on monocytes in advanced disease was significantly increased in comparison with early disease or healthy individuals, while there were no differences in the surface marker or oxygen-burst capacity of monocytes. The plasma from the patients with advanced disease could induce increased intracellular IL-10 and IL-12 status in healthy monocytes. The phenomenon was significantly inhibited with neutralizing mAbs specific for VEGF.
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PMID:[Study of monocyte intracellular cytokine and heterogeneity of monocytes in a gastric cancer patient]. 1461 35

Although the VEGF-Flk-1-pathway has been known as the major driving force of angiogenesis, new evidence has shown that VEGFR-1/Flt-1 plays important roles during the neovascularization under pathological conditions including tumor, atherosclerosis and arthritis. In search of Flt-1 receptor antagonizing peptides, we screened a phage display 12-mer-peptide library with recombinant Flt-1 protein. Seven candidate peptides were identified that specifically bound to VEGF receptor Flt-1, of which peptide F56 (WHSDMEWWYLLG) almost abolished VEGF binding to receptor Flt-1 in vitro. In vivo, F56 fused with DHFR (DHFR-F56) inhibited angiogenesis in a CAM assay. Moreover, DHFR-F56 significantly inhibited the growth of nodules of human gastric cancer cell line MGC-803 in BALB/c nude mice. Histological analyses showed that necrosis of the implanted tumor was markedly enhanced following treatment with DHFR-F56. In the severe combined immunodeficiency disease (SCID) mouse model for studying metastasis of the human breast cancer cell line BICR-H1, synthetic peptide F56 significantly inhibited tumor growth and lung metastases. Taken together, our results have demonstrated that peptide F56, as a Flt-1 receptor antagonist, fulfilled the antiangiogenic and antimetastatic effects by specifically interfering with the interaction between VEGF and receptor Flt-1. Thus, short peptide F56 may have clinical potential in tumor therapy.
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PMID:Suppression of tumor growth and metastasis by a VEGFR-1 antagonizing peptide identified from a phage display library. 1519 67

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


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