Overexpression of macrophage colony-stimulating factor (CSF-1) and its receptor, c-fms, in normal ovarian granulosa cells leads to cell proliferationand tumorigenesis

OBJECTIVE: To investigate the interdependent role of macrophage colony-stim ulating factor (CSF-1) and its receptor (c-fms) on their induction and thei r role in granulosa cell tumorigenesis. METHODS: Normal ovarian granulosa cells were used to develop stable transfe ctants the overexpress CSF-1 or CSF-1/c-fms. CSF-1 was expressed under the control of tissue/cell specific alpha-inhibin promoter, and c-fms was expre ssed constitutively using a viral promoter. Stable transfectants were used to examine the effect of overexpression of these molecules on the prolifera tion, induction of autocrine loop, and tumorigenesis. RESULTS: Expression vectors were developed for CSF-1 and its receptor, c-fm s, and used to generate stable transfects overexpressing these genes in gra nulosa cells. Data show that overexpression of CSF-1 leads to the induction of its receptor. Stable transfectants that overexpress CSF-1 show about a 2.5-fold increase in cell proliferation compared with normal granulosa cell s, and these cells are also converted to anchorage-independent and tumorige nic phenotype. Using and antisense RNA approach, we also demonstrated that the increased cell proliferation is CSF-1 specific. Concomitant overexpress ion of CSF-1 and c-fms further results in increased cell proliferation (six fold), rapid anchorage-independent growth, and aggressive tumor formation. CONCLUSION: CSF-1 is capable of inducing its own receptor, and, similarly, the CSF-1 receptor, c-fms, can also induce its growth factor ligand. These studies also demonstrate the interdependent role of these genes in transfor mation of normal ovarian granulosa cells to a tumorigenic phenotype and sug gest the possibility of a similar role for these genes in progression of ov arian cancer. Copyright (C) 1999 by the Society for Gynecologic Investigati on.