Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) is an important mediator of tumor-induced angiogenesis and represents a potential target for innovative anticancer therapy. In several animal models, neutralizing anti-VEGF/VPF antibodies have shown encouraging inhibitory effects on solid tumor growth, ascites formation and metastatic dissemination. Targeting the VEGF signaling pathway by means of VEGF receptor tyrosine-kinase inhibitors has shown similar efficacy in animal tumor models. Several of these anti-VEGF therapies are currently being tested in clinical trials in cancer patients. The profiles and effects of the neutralizing anti-VEGF/VPF antibodies and the VEGF receptor tyrosine-kinase inhibitors in animal models are reviewed and of the risks and benefits of VEGF blockade by one or the other treatments are discussed.
Cancer Metastasis Rev 1999
PMID:Targeting vascular endothelial growth factor (VEGF) for anti-tumor therapy, by anti-VEGF neutralizing monoclonal antibodies or by VEGF receptor tyrosine-kinase inhibitors. 1085 90

Upregulation of vascular endothelial growth factor (VEGF) expression induced by hypoxia is crucial event leading to neovascularization. Cyclooxygenase-2, an inducible enzyme that catalyzes the formation of prostaglandins (PGs) from arachidonic acid, has been demonstrated to be induced by hypoxia and play role in angiogenesis and metastasis. To investigate the potential effect of COX-2 on hypoxia-induced VEGF expression in prostate cancer. We examined the relationship between COX-2 expression and VEGF induction in response to cobalt chloride (CoCl2)-simulated hypoxia in three human prostate cancer cell lines with differing biological phenotypes. Northern blotting and ELISA revealed that all three tested cell lines constitutively expressed VEGF mRNA, and secreted VEGF protein to different degrees (LNCaP > PC-3 > PC3ML). However, these cell lines differed in the ability to produce VEGF in the presence of CoCl2-simulated hypoxia. CoCl2 treatment resulted in 40% and 75% increases in VEGF mRNA, and 50% and 95% in protein secretion by LNCaP and PC-3 cell lines, respectively. In contrast, PC-3ML cell line, a PC-3 subline with highly invasive, metastatic phenotype, exhibits a dramatic upregulation of VEGF, 5.6-fold in mRNA and 6.3-fold in protein secretion after treatment with CoCl2. The upregulation of VEGF in PC-3ML cells is accompanied by a persistent induction of COX-2 mRNA (6.5-fold) and protein (5-fold). Whereas COX-2 expression is only transiently induced in PC-3 cells and not affected by CoCl2 in LNCaP cells. Moreover, the increases in VEGF mRNA and protein secretion induced by CoCl2 in PC-3ML cells were significantly suppressed following exposure to NS398, a selective COX-2 inhibitor. Finally, the effect of COX-2 inhibition on CoCl2-induced VEGF production was reversed by the treatment with exogenous PGE2. Our data demonstrate that VEGF induction by cobalt chloride-simulated hypoxia is maintained by a concomitant, persistent induction of COX-2 expression and sustained elevation of PGE2 synthesis in a human metastatic prostate cancer cell line, and suggest that COX-2 activity, reflected by PGE2 production, is involved in hypoxia-induced VEGF expression, and thus, modulates prostatic tumor angiogenesis.
Clin Exp Metastasis 1999
PMID:Upregulation of vascular endothelial growth factor by cobalt chloride-simulated hypoxia is mediated by persistent induction of cyclooxygenase-2 in a metastatic human prostate cancer cell line. 1091 14

Angiogenesis is the formation of new blood vessels and occurs physiologically during embryonal growth, wound healing and during the menstrual cycle. It is essential for the proliferation and metastases of most malignant neoplasms. Recent evidence suggests that angiogenesis is increased in multiple myeloma and has prognostic value in the disease. Angiogenic cytokines such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor are expressed by myeloma cells and appear to play a role in the increased angiogenesis seen in myeloma. In addition, VEGF may serve as a paracrine growth factor for myeloma cells. Based on the increased angiogenesis observed in myeloma, thalidomide has been studied as antiangiogenic therapy. Although its mechanism of action in myeloma is still unclear, thalidomide appears to be active in 25-30% of patients with refractory myeloma. Major toxicities include constipation, sedation, skin rash, fatigue, and peripheral neuropathy. Studies are ongoing to determine its role as initial treatment for myeloma. This paper reviews the available data on angiogenesis in myeloma, and summarizes the role of thalidomide therapy in this disease. The pharmacology and toxicity of thalidomide are also discussed.
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PMID:A review of angiogenesis and antiangiogenic therapy with thalidomide in multiple myeloma. 1100 36

We aim to determine the clinical usefulness of pre-operative serum vascular endothelial growth factor (VEGF) as a predictor of outcome in patients undergoing curative resection for colorectal cancer. Serum VEGF was assayed by quantitative ELISA in 81 patients prior to curative resection for node-negative (n = 53) and node-positive (n = 28) disease. Median follow-up for patients without cancer death was 27 months (range 21-37). Pre-operative serum VEGF was significantly higher in patients who went on to develop metastases than those who did not (median, 713 pg ml-1 vs. 314 pg ml-1, P < 0.0001). Using multivariate Cox regression analysis, pre-operative serum VEGF was the most important prognostic factor independent of nodal status and adjuvant chemotherapy, and was superior to nodal status in predicting outcome (P < 0.00001). At 575 pg ml-1, pre-operative serum VEGF was 64% sensitive and 89% specific in predicting the development of metastases in curative resections, with a positive predictive value of 73% and a negative predictive value of 85%. Pre-operative serum VEGF is a powerful predictor of outcome following curative surgery for colorectal cancer. These data support the measurement of pre-operative serum VEGF as a method for selecting patients who require adjuvant therapy.
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PMID:Pre-operative serum vascular endothelial growth factor can select patients for adjuvant treatment after curative resection in colorectal cancer. 1107 48

We determined the role that vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF), plays in the progression of human renal cell cancer in nude mice. Low metastatic and low VEGF/VPF-expressing human renal cancer cells SN12C were transfected with the VEGF165 cDNA or plasmid alone as control. VEGF165-transfected SN12C cells produced large amounts of biologically active VEGF in culture that did not affect cell doubling time or confluence. Subsequent to implantation into the renal subcapsule of nude mice, the VEGF165-transfected SN12C cells produced fast-growing (PCNA labeling), large tumors that expressed high levels of VEGF/VPF and were well vascularized (CD3-positive vessels). The tumors produced hyperpermeability of peritoneal blood vessels (Evans blue dye-leak assay), bloody ascites, and short survival time. Parental or control transfected SN12C cells produced less vascularized, slower growing tumors with no ascites. Regardless of in vivo expression level of VEGF, the incidence of spontaneous lung metastasis was low, suggesting that in itself, the expression of VEGF/VPF by renal cancer cells is not sufficient to produce metastasis.
Clin Exp Metastasis 1999
PMID:Expression of vascular endothelial growth factor by human renal cancer cells enhances angiogenesis of primary tumors and production of ascites but not metastasis to the lungs in nude mice. 1108 81

Our objective was to present current data pertaining to the role of angiogenesis in the accumulation of peritoneal fluid in both benign conditions and in the development of malignant ascites in the female. To this goal, we conducted a computerized search to identify all relevant studies published in the English literature. MEDLINE, Current Contents and Index Medicus were searched utilizing the terms: angiogenesis, peritoneal fluid, ascites, vascular endothelial growth factor (VEGF), therapy and carcinoma through May 2000. Review of the literature supports that angiogenesis promoted by VEGF is associated with fluid accumulation in animal and human tumor effusions. Benign conditions involving accumulation of peritoneal fluid and associated angiogenesis in the female include ovulation, endometriosis and severe ovarian hyperstimulation syndrome. Malignant intra-abdominal conditions associated with increased VEGF activity include primary epithelial ovarian, gastric and colon carcinomas, omental and hepatic metastatic disease. Initial trials with antiangiogenic (angioinhibitor) therapy such as anti-VEGF antibodies, anti-VEGF receptor antibodies, tumor necrosis factor, and metalloproteinase inhibitors have been reported and antitumor activity observed in a limited number of patients with advanced (inoperable or metastatic) disease.
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PMID:The role of angiogenesis in the accumulation of peritoneal fluid in benign conditions and the development of malignant ascites in the female. 1109 42

In order to grow beyond minimal size and to metastasize, tumors need to induce the growth of new blood vessels (angiogenesis). Whereas in normal tissues, vascular quiescence is maintained by the dominant influence of endogenous angiogenesis inhibitors over angiogenic stimuli, tumor angiogenesis is induced by increased secretion of angiogenic factors and/or by downregulation of angiogenesis inhibitors. Recent evidence suggests vascular endothelial growth factor (VEGF) as the major tumor angiogenesis factor, promoting tumor growth, invasion, and metastasis. Conversely, blocking of VEGF function inhibits angiogenesis and suppresses tumor growth in vivo. Newly identified members of the VEGF family of angiogenesis factors include placental growth factor, VEGF-B, VEGF-C, and VEGF-D, and show overlapping binding patterns to specific endothelial cell receptors. VEGF-C appears to play a major role as a lymphangiogenesis factor and as a growth factor for Kaposi's sarcoma. In contrast, endogenous inhibitors prevent blood vessel growth in normal tissues. In particular, thrombospondin-1 (TSP-1) and TSP-2 are expressed in normal skin and, when introduced into squamous cell carcinomas, potently inhibit malignant tumor growth via inhibition of tumor angiogenesis.
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PMID:Tumor angiogenesis. 1114 70

Previous retrospective studies suggest that the phase of the menstrual cycle at surgery (proliferative versus secretory) for breast cancer may significantly affect patient survival. Fluctuations during the menstrual cycle of the expression of genes involved in metastases in breast cancer tissue have also been reported. We hypothesized that the menstrual phase may also affect similar changes in gene expression of other cancers. We focused our attention on cancer of the uterine cervix because the hysterectomy specimen obtained at original surgery for the cancer can be used retrospectively to determine cycle phase. We analyzed tumor specimens from 36 premenopausal cervical cancer patients who had undergone hysterectomy as their primary treatment. We used reverse transcription-PCR to quantify gene expression during the different phases of the menstrual cycle as determined from the endometrial specimen. We explored a panel of genes that may affect metastatic propensity, namely, metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinase-2 (TIMP-2), cyclooxygenase 1 and 2 (COX-1 and COX-2), and vascular endothelial growth factor (VEGF). A significantly higher level of TIMP-2 and COX-2 gene expression (P = 0.007 and 0.030, respectively) was detected during the proliferative phase compared to the secretory phase of the cycle. The expression of the other genes was not significantly affected by the stage of the menstrual cycle. The finding that TIMP-2 and COX-2 expression in cervical cancer may be affected by the stage of the menstrual cycle supports the hypothesis that ovarian hormones may affect the expression of genes involved in metastasis. These findings need to be replicated, and their implications for tumor angiogenesis, invasion, and metastatic propensity need to be explored both in human studies and in experimental models.
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PMID:Expression of metastases-associated genes in cervical cancers resected in the proliferative and secretory phases of the menstrual cycle. 1115 16

We examined the expression levels of a number of metastasis-related genes to determine the relationship of these levels to the development of metastasis in renal cell carcinoma. Gene expression was examined in 46 formalin-fixed, paraffin-embedded, archival specimens of primary organ-confined, clear-cell, renal cell carcinoma from patients who had undergone radical nephrectomy. Twenty samples were from patients who did not have metastasis after a median of 48 months; 26 were from patients with either synchronous or metachronous metastases. Microvessel density was assessed by anti-CD-34 immunohistochemical analysis. The expression levels of basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), interleukin-8 (IL-8), matrix metalloproteinases (MMP)-2 and -9, and E-cadherin were examined at the periphery of the tumor by a colorimetric in situ mRNA. The expression levels of bFGF, VEGF, IL-8, MMP-2, and MMP-9 were significantly higher in primary renal tumors from patients with either synchronous or metachronous metastases than those who were disease-free at a median of 48 months of follow-up. Multivariate analysis of disease-free survival showed that the ratio of MMP-9 to E-cadherin (P = 0.012) and the expression level of bFGF expression (P = 0.045), were independent predictors for the development of metastases. The expression levels of bFGF, VEGF, and IL-8 did not correlate with microvessel density, which in itself was not a significant predictor of progression (P = 0.21). In summary, expression levels of genes that regulate metastasis angiogenesis can predict the metastatic potential in individual patients with organ-confined clear-cell renal carcinoma.
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PMID:Expression levels of genes that regulate metastasis and angiogenesis correlate with advanced pathological stage of renal cell carcinoma. 1115 11

Metastasis to local lymph nodes via the lymphatic vessels is a common step in the spread of solid tumors. To investigate the molecular mechanisms underlying the spread of cancer by the lymphatics, we examined the ability of vascular endothelial growth factor (VEGF)-D, a ligand for the lymphatic growth factor receptor VEGFR-3/Flt-4, to induce formation of lymphatics in a mouse tumor model. Staining with markers specific for lymphatic endothelium demonstrated that VEGF-D induced the formation of lymphatics within tumors. Moreover, expression of VEGF-D in tumor cells led to spread of the tumor to lymph nodes, whereas expression of VEGF, an angiogenic growth factor which activates VEGFR-2 but not VEGFR-3, did not. VEGF-D also promoted tumor angiogenesis and growth. Lymphatic spread induced by VEGF-D could be blocked with an antibody specific for VEGF-D. This study demonstrates that lymphatics can be established in solid tumors and implicates VEGF family members in determining the route of metastatic spread.
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PMID:VEGF-D promotes the metastatic spread of tumor cells via the lymphatics. 1117 37


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