Malignant transformation of ovarian epithelium.

Abstract

Ovarian cancer is the leading cause of gynecologic cancer deaths in the United States. In contrast to cervical cancer, where etiologic agents and early neoplastic lesions have been clearly defined, the pathogenesis and natural history of ovarian cancer remain obscure. More than 90% of ovarian cancers in adults are thought to arise from a single layer of epithelial cells that cover the ovarian surface or line inclusion cysts. Following ovulation, the ovarian surface epithelium proliferates to repair the defects produced by rupture of mature follicles. Epidemiologic data suggest that the interruption of ovulation by pregnancy, lactation, or oral contraceptive medications substantially reduces the risk of developing ovarian cancer. Suppression of ovulation may decrease opportunities for tumor progression that are more likely to occur in dividing cells. Conversely, growth of ovarian surface epithelial cells ex vivo, freed from the constraints on proliferation in situ, might lead to malignant transformation. In this issue of the Journal (/), Godwin and colleagues present convincing evidence that repeated passage of rat ovarian surface epithelial cells in culture results in a loss of contact inhibition, as well as in the acquisition of anchorage-ind ependent growth and the ability to form tumors in vivo after injection into athymic mice. Cytogenetic abnormalities have been observed in some cell lines both before and after transformation. Although the correlation between the chromosomal abnormalities described by Godwin et al. and the acquisition of a malignant phenotype is not precise, the potential for this type of analysis is clear. Spontaneous transformation in culture is thought to occur less frequently in cells taken from rats than in those taken from mice (/). Transformation in the absence of apparent carcinogens is not limited, however, to the ovarian epithelium, in that spontaneous transformation has also been observed with repeated passage of rat hepatocytes, fibroblasts, and tracheal epithelial cells (2-4). Whether spontaneous transformation in culture occurs with human ovarian surface epithelial cells remains to be determined. Investigators (5) have defined conditions that facilitate growth of apparently normal human ovarian epithelial cells and that should permit definitive studies with human tissues. Recent reports have begun to compare growth regulation in normal and malignant human ovarian epithelial cells. Preliminary data suggest that a majority of ovarian cancers are derived from single clones of cells. Consistent with studies in other malignancies, multiple genetic changes are likely to be required for malignant transformation of a normal epithelial clone. Different combinations of these changes might produce the same transformed phenotype. Certain changes might be observed more or less frequently in ovarian cancer than in tumors that