Identification and Cloning of an inhibitor of Cancer Metastasis and Invasion

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Conditioned media of normal peritoneal, myometrial, and ovarian tissues increased MMP-2 and -9 secretion from ovarian cancer (NOM1) cells in a concentration dependent manner. Especially, MMP-9 was markedly augmented by addition of normal peritoneal tissue conditioned medium. To estimate MMP-9 stimulating factors, conditioned medium of normal peritoneal tissue was fractionated and the influence of each fraction on MMP-9 secretion was examined by zymography. More than 100 kD fraction increased mostly MMP-9 secretion from NOM1 cells. Extracellular matrix, laminine, fibronectin, and type IV collagen, were added to NOM1 cells to identify the more than 100 kD factors. Fibronectin could increase MMP-9 secretion from NOM1 cells in a concentration dependent manner. Furthermore, fibronectin induced secretion of MMP-9 was inhibited by pretreatment with RGD peptides (fibronectin receptor) and antibody against integrin alpha5 receptor. Concentration of fibronectin was 164 ng/ml after 24 hours-culture of normal peritoneal tissue. Since 100 ng/ml fibronectin was enough to stimulate MMP-9 secretion from ovarian cancer cells, fibronectin was suggested to be an important stimulating factor.