TY - JOUR
T1 - Overexpression of macrophage colony-stimulating factor (CSF-1) and its receptor, c-fms, in normal ovarian granulosa cells leads to cell proliferation and tumorigenesis
AU - Keshava, Nagalakshmi
AU - Gubba, Siddeswar
AU - Tekmal, Rajeshwar Rao
PY - 1999/1
Y1 - 1999/1
N2 - 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.
AB - 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.
KW - C-fms
KW - CSF-1
KW - Granulosa tumor model
KW - MCSF
KW - Ovarian cancer
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U2 - 10.1016/S1071-5576(98)00041-0
DO - 10.1016/S1071-5576(98)00041-0
M3 - Article
C2 - 10065425
AN - SCOPUS:0032961633
SN - 1071-5576
VL - 6
SP - 41
EP - 49
JO - Journal of the Society for Gynecologic Investigation
JF - Journal of the Society for Gynecologic Investigation
IS - 1
ER -