OVARIAN CARCINOMA--ROLE OF LAMININ AND ITS RECEPTORS

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Malignant ovarian carcinoma seen in patients who have a poor prognosis may be due to the inherently more aggressive behavior of their tumor cells compared to patients with benign or borderline cystadenomas, who have a much better prognosis. The proto-oncogene c-erb-B2 has been shown to be amplified in primary epithelial ovarian tumors, and some studies have shown a correlation between gene amplification, oncogene expression, and decreased survival in patients with ovarian cancer. Components of the basement membrane (BM) and extracellular matrix (ECM) are important modulators of growth, development, and differentiation for various cell types. The role of BM and ECM proteins in modulating the phenotypic behavior of ovarian carcinoma cells has not been thoroughly investigated and is poorly understood. Laminin, the major noncollagenous glycoprotein of the BM, has been shown to promote the adhesion, spreading, and migration of a variety of tumor cell types in vitro. In preliminary studies, we have observed that normal human ovarian epithelial cells adhere to laminin and to smaller fragments of laminin. Interestingly, ovarian carcinoma cell lines and transfectants of these ovarian carcinomas cell lines that contain an increased expression of the c-erb- B2 gene product adhere to different fragments of laminin; suggesting that ovarian carcinoma cells may have altered receptor(s) for the various domains of laminin. These preliminary observations may provide an explanation as to the abnormal behavior of the ovarian epithelial carcinoma cells, since they no longer adhere in a normal fashion to the BM; rather, they release from the BM, seed other sites, develop into an ascites form, or invade into the stroma of the ovary. The hypothesis to be tested is that the more aggressive behavior of the malignant ovarian carcinoma cells, compared to normal ovarian epithelial cells, is related to an altered cellular response towards laminin, perhaps due to alterations in laminin receptors. To test this hypothesis, it will be determined whether laminin contains sequences that promote differential adhesion, spreading, migration, and/or invasion of normal ovarian epithelial cells compared to malignant ovarian epithelial carcinoma cells. Correlations will then be made between the behavior of the various cells on laminin and laminin sequences, and the levels of c-erb- B2 in the cells. In addition, the cell surface receptors, in particular, integrin subunits, that these ovarian cells use to interact with laminin and specific sequences of laminin will be identified; this may be important for the differential adhesiveness and migration of ovarian carcinoma cells. Finally, the in vitro assays will be compared to what is observed in vivo, by immunohistochemically localizing laminin and laminin receptors in tissue sections of normal ovarian epithelium, benign serous cystadenomas, borderline serous cystadenomas, and malignant ovarian adenocarcinomas. Correlations will be made between the immunohistochemical staining patterns, the staging of the tumors, and the levels of c-erb-B2. These studies represent an approach towards understanding the molecular mechanisms modulating the phenotypic behavior of ovarian carcinoma cells and potentially aid in designing biopharmaceuticals for therapeutic use in ovarian cancer.