Matrix metalloproteinases (MMP9 and MMP2) induce the release of vascular endothelial growth factor (VEGF) by ovarian carcinoma cells: Implications for ascites formation

• Published in: Cancer research (Chicago, Ill.) Ill.), 2003-09, Vol.63 (17), p.5224-5229
• Main Authors: BELOTTI, Dorina, PAGANONI, Paola, MANENTI, Luigi, GAROFALO, Angela, MARCHINI, Sergio, TARABOLETTI, Giulia, GIAVAZZI, Raffaella
• Format: Article
• Language: English
• Subjects: Animals; Ascites - enzymology; Ascites - pathology; Biological and medical sciences; Cell Movement - physiology; Culture Media, Conditioned; Dissemination; Endothelial Growth Factors - antagonists & inhibitors; Endothelial Growth Factors - metabolism; Endothelial Growth Factors - secretion; Enzyme Activation; Female; Humans; Intercellular Signaling Peptides and Proteins - metabolism; Intercellular Signaling Peptides and Proteins - secretion; Lymphokines - antagonists & inhibitors; Lymphokines - metabolism; Lymphokines - secretion; Matrix Metalloproteinase 2 - metabolism; Matrix Metalloproteinase 9 - metabolism; Matrix Metalloproteinase 9 - pharmacology; Medical sciences; Mice; Mice, Nude; Ovarian Neoplasms - enzymology; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Ovarian Neoplasms - secretion; Peritoneal Cavity - pathology; Phenylalanine - analogs & derivatives; Phenylalanine - pharmacology; Thiophenes - pharmacology; Transplantation, Heterologous; Tumor cell; Tumors; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors
• ISSN: 0008-5472; 1538-7445

This study investigated the functional interplay between vascular endothelial growth factor (VEGF) and metalloproteinases (MMPs) in ovarian carcinomas. Levels of MMP9 (pro and activated form) and proMMP2 in ascites correlated with VEGF and with the ascitic volume in nude mice bearing human ovarian carcinoma xenografts (HOC22 and HOC8). The MMP inhibitor batimastat (BB-94) reduced VEGF release and ascitic fluid formation. Exogenous, activated MMP9, and, to a lesser extent, MMP2, increased VEGF release by SKOV3 and OVCAR3 ovarian carcinoma cells. The effect was dose and time dependent and inhibited by BB-94. MMP9-released VEGF was biologically active, because it induced endothelial cell motility, and its activity was prevented by the VEGF inhibitor SU5416. Our results indicate that MMPs, mainly MMP9, play a role in the release of biologically active VEGF and consequently in the formation of ascites.