Vascular endothelial growth factor activating matrix metalloproteinase in ascitic fluid during peritoneal dissemination of ovarian cancer.
The role of vascular endothelial growth factor (VEGF) during peritoneal dissemination of ovarian carcinoma and the association with tumor microvessel density (MVD) and matrix metalloproteinase (MMP) activity was investigated. To this end, MVD, tumor tissue and ascitic fluid levels of VEGF, and MMP activity of ascitic fluid were examined in patients with ovarian cancer and benign ovarian tumor. The effect of ascites on cell growth, cell invasion activity and angiogenesis was investigated in vitro. Ascitic fluid and tumor tissue samples were obtained from 15 patients with benign ovarian tumor and 24 patients with ovarian carcinoma. Tissue extract and ascitic fluid levels of VEGF were measured using enzyme immunoassay. Tumor microvessels were detected immunohistochemically. MMP activity was measured by gelatin zymography. For the in vitro experiment, the SKOV-3 human ovarian carcinoma cell line was utilized. Cell growth was examined using MTT-assay, cell invasion activity was measured by Matrigel in vitro invasion assay, and neovascularization was assessed using an angiogenesis kit. VEGF levels in tissue extract and ascitic fluid, MVD, expression of active form MMP-2 in ascitic fluid and ascites volume were higher in ovarian cancer patients than in benign ovarian tumor patients. In addition, these were elevated in stage III and IV diseases compared to stage I and II diseases in ovarian cancer patients. MVD and expression of active form MMP-2 in ascitic fluid were closely correlated with VEGF level in tissue extracts, and MVD and ascites volume were closely correlated with VEGF level in ascitic fluid. Cell invasive activity and angiogenesis activity increased when cells were exposed to ascites. These increases were apparent when exposed to ascites obtained from ovarian cancer patients and were related to VEGF concentrations of ascitic fluid and expression of active form MMP-2 in ascitic fluid. The increased VEGF secreted from tumor cells is suggested to enhance tumor growth through angiogenesis, to produce ascites and to elevate ascitic VEGF concentrations and expression of active form MMP-2. The progression of peritoneal involvement may be induced by elevated VEGF and expression of active form MMP-2, followed by increased VEGF in the primary tumor. Control of VEGF in the primary tumor may become an effective strategy against peritoneal dissemination of ovarian carcinoma.
Yabushita
Hiromitsu
H
Department of Obstetrics and Gynecology, Aichi Medical University, School of Medicine, Nagakute-cho, Aichi-gun, Japan. yab@aichi-med-u.ac.jp
Shimazu
Mitsuma
M
Noguchi
Mari
M
Kishida
Tameko
T
Narumiya
Hisao
H
Sawaguchi
Keizo
K
Noguchi
Masayoshi
M
D000236:Adenoma / Q000098:blood supply / Q000378:metabolism; D001202:Ascitic Fluid / Q000378:metabolism*; D018269:Carcinoma, Endometrioid / Q000098:blood supply / Q000378:metabolism / Q000556:secondary; D018282:Cystadenocarcinoma, Mucinous / Q000098:blood supply / Q000378:metabolism / Q000556:secondary; D018284:Cystadenocarcinoma, Serous / Q000098:blood supply / Q000378:metabolism / Q000556:secondary; D016228:Endothelial Growth Factors / Q000378:metabolism*; D004730:Endothelium, Vascular; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008222:Lymphokines / Q000378:metabolism*; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D008833:Microcirculation; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000473:pathology*; D010534:Peritoneal Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000556:secondary*; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D020782:Matrix Metalloproteinases