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Overexpression of Macrophage Colony-Stimulating Factor (CSF-1) and Its Receptor, c-fms, in Normal Ovarian Granulosa Cells Leads to Cell Proliferation and Tumorigenesis

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Abstract

Objective

TO investigate the interdependent role of macrophage colony-stimulating factor (CSF-1) and its receptor (c-fms) on their induction and their role in granulosa cell tumorigenesis.

Methods

Normal ovarian granulosa cells were used to develop stable transfectants that overexpress CSF-1 or CSF-1/c-fms. CSF-1 was expressed under the control of tissue/cell specific α-inhibin promoter, and c-fms was expressed constitutively using a viral promoter. Stable transfectants were used to examine the effect of overexpression of these molecules on the proliferation, induction of autocrine loop, and tumorigenesis.

Results

Expression vectors were developed for CSF-1 and its receptor, c-fms, and used to generate stable transfects overexpressing these genes in granulosa 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 cells, and these cells are also converted to anchorage-independent and tumorigenic phenotype. Using an antisense RNA approach, we also demonstrated that the increased cell proliferation is CSF-1 specific. Concomitant overexpression of CSF-1 and c-fms further results in increased cell proliferation (sixfold), 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 transformation of normal ovarian granulosa cells to a tumorigenic phenotype and suggest the possibility of a similar role for these genes in progression of ovarian cancer.

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Authors and Affiliations

  1. Department of Gynecology and Obstetrics and Winship Cancer Center, Emory University School of Medicine, 4219 WMB, 1639 Pierce Drive, Atlanta, Georgia, 30322-4710, USA

    Nagalakshmi Keshava PhD, Siddeswar Gubba PhD & Rajeshwar Rao Tekmal PhD

  2. Department of Pathology, Baylor College of Medicine, Houston, Texas, USA

    Nagalakshmi Keshava PhD, Siddeswar Gubba PhD & Rajeshwar Rao Tekmal PhD

Authors
  1. Nagalakshmi Keshava PhD
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  2. Siddeswar Gubba PhD
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  3. Rajeshwar Rao Tekmal PhD
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Corresponding author

Correspondence to Rajeshwar Rao Tekmal PhD.

Additional information

The authors thank Dr. George Stoica for providing SIGC cell line, Dr. Dirk Dillehay for histopathologic evaluation, and Dr. Neil Sidell for critical evaluation of the manuscript.

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Keshava, N., Gubba, S. & Tekmal, R.R. Overexpression of Macrophage Colony-Stimulating Factor (CSF-1) and Its Receptor, c-fms, in Normal Ovarian Granulosa Cells Leads to Cell Proliferation and Tumorigenesis. Reprod. Sci. 6, 41–49 (1999). https://doi.org/10.1177/107155769900600109

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