The c-fms proto-oncogene encodes the receptor for a hematopoietic growth factor, CSF-1. While the importance of c-fms and its ligand CSF-1 to hematopoietic malignancies is well recognized, we believe that activation of the c-fms proto-oncogene by binding to CSF-1 is important to the biology of ovarian cancer, and may underlie some of our findings of its malignant phenotype. Although during macrophage activation, the active cytokine CSF-1 stimulates the secretion of urokinase-type plasminogen activator (uPA) important to macrophage motility and invasion, until now, no such association between CSF-1 and uPA has been described for ovarian cancer. Our initial studies suggest that CSF-1 plays an important role in the neoplastic progression of ovarian cancer; we show that CSF-1, through the induction of uPA activity, stimulates invasion of ovarian cancer cells through an extracellular matrix. Moreover studies of the role of uPA, its receptor, and its inhibitors in ascites of ovarian cancer patients suggests that uPA is an important protease in the biology of ovarian cancer. In this application, we will focus on (1) elucidation of the mechanism behind overexpression of CSF-1 in ovarian cancer cell lines. Our preliminary studies suggest that a labile regulatory protein is involved in CSF-1 mRNA decay in ovarian cancer cells, and that an instability determinant which is sensitive to the actions of protein synthesis inhibitors, may reside in the AU-rich exon-10 of the 3' untranslated region of the CSF-1 transcript. We will determine the importance of the 3' AU-rich region of the CSF-1 transcript to its overexpression, to CSF-1 mRNA stability, and to RNA-protein binding. We plan to determine if proteins which may bind to the 3' end of CSF-1 mRNA may also bind to the 3' AU-rich region of the uPA transcript, and have identity with those that have been implicated in c-myc mRNA destabilization. We will then pursue (2) study of the effect of CSF-1 on factors important to uPA mediated plasminogen activation in ovarian cancer. Lastly, we plan to (3) define the clinical correlates of expression of CSF-1 and of uPA, its receptor, and its inhibitors, in the primary and metastatic tumor of ovarian cancer patients, in order to assess the importance of CSF-1/uPA to neoplastic progression. If the results of our studies suggest that the same trans-acting factor is responsible for regulation of CSF-1, uPA, c-myc and/or other transcripts that contain a 3' AU-rich element, then these findings would significantly impact on our understanding of the biology of ovarian and other cancers, and could lead to the development of new therapeutics. If the gene for the common trans-acting factor could be identified in the future, then development of gene-directed therapy using transduction of genes encoding high levels of the common destabilizing protein could be envisioned.
