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Keywords:

  • ovarian cancer;
  • malignant transformation;
  • tumor suppressor genes;
  • cytogenetics;
  • surface epithelium

Abstract

Background. In theory, all the cell types that comprise the human ovary have the potential for malignant transformation. The vast majority of malignant ovarian tumors in the human, however, arise from the ovarian surface epithelium. These cells have important functions during reproductive life; they contribute to follicular rupture and by cell division repair the wound that accompanies ovulation. There has been much speculation that the rapid cycles of cell division associated with wound repair contribute significantly to the development of ovarian cancer. Such speculation is based on the observation that ovarian cancer occurs most frequently at the end of a woman's reproductive life and is associated with nulliparity. It is of potential significance that, unlike most epithelia, these cells are not replaced through replenishment stem cells with the development of one end-stage cell and one cell with continued growth potential. Rather, the division of an ovarian surface epithelial cell yields two daughter cells with equal potential for subsequent growth. Thus, all potential mutations as they accumulate are passed on to near-exponentially expanding subsequent generations of cells that can acquire additional mutations that could confer the malignant phenotype.

Methods. We have developed a model to test the hypothesis that repeated cell division by ovarian surface epithelial cells contributes to development of malignancy. In this model, rat ovarian surface epithelial cells are isolated and subjected in vitro to repetitious cell division to mimic in a simple way growth of the surface epithelium in vivo.

Results. These cells develop a malignant phenotype based on loss of contact inhibition, the ability for substrate independent growth, tumorigenicity in athymic mice, and cytogenetic changes.

Conclusions. Our data support the involvement of tumor suppressor genes in the development of ovarian cancer.