Overexpression Of CSF1 Research Articles

Translocation and Expression of CSF1 in Pigmented Villonodular Synovitis, Tenosynovial Giant Cell Tumor, Rheumatoid Arthritis and Other Reactive Synovitides

We recently demonstrated that CSF1, the ligand of the tyrosine kinase receptor, CSF1R, can be translocated in pigmented villonodular synovitis (PVNS) and tenosynovial giant cell tumor (TGCT). In this study, we evaluated the staining characteristics of PVNS/TGCT and reactive synovitides for CSF1 and CSF1R by in situ hybridization and immunohistochemistry on tissue microarrays and correlated these findings with the recently described translocation. We collected specimens of TGCT/PVNS from 60 patients and of rheumatoid arthritis and other reactive synovitides from 74 patients. We identify 2 groups of PVNS and TGCT cases by the presence of CSF1 translocation and CSF1 expression. The first group (35 of 57 cases; 61%) had both the CSF1 translocation and high expression of CSF1 RNA, confirming our previous findings. Interestingly, a second group (22 of 57 cases; 39%) was identified that showed high expression of CSF1 RNA or CSF1 protein but did not have the translocation. The rheumatoid arthritis and reactive synovitis specimens showed localization of CSF1 RNA and protein to the synovial lining cells, implying a possible role for CSF1 in the pathogenesis of these lesions. As the CSF1 translocation is postulated to play an important role in the biology of PVNS/TGCT, the consistent presence of CSF1 expression in translocation-negative cases implies that other mechanisms can lead to CSF1 up-regulation. The consistent presence of CSF1 overexpression in all cases of PVNS/TGCT and reactive synovitides suggests both an important role for CSF1 in the spectrum of synovial pathologies and the possibility of targeting the CSF1/CSF1R interaction therapeutically.

A landscape effect in tenosynovial giant-cell tumor from activation of CSF1 expression by a translocation in a minority of tumor cells

Tenosynovial giant-cell tumor (TGCT) and pigmented villonodular synovitis (PVNS) are related conditions with features of both reactive inflammatory disorders and clonal neoplastic proliferations. Chromosomal translocations involving chromosome 1p13 have been reported in both TGCT and PVNS. We confirm that translocations involving 1p13 are present in a majority of cases of TGCT and PVNS and show that CSF1 is the gene at the chromosome 1p13 breakpoint. In some cases of both TGCT and PVNS, CSF1 is fused to COL6A3 (2q35). The CSF1 translocations result in overexpression of CSF1. In cases of TGCT and PVNS carrying this translocation, it is present in a minority of the intratumoral cells, leading to CSF1 expression only in these cells, whereas the majority of cells express CSF1R but not CSF1, suggesting a tumor-landscaping effect with aberrant CSF1 expression in the neoplastic cells, leading to the abnormal accumulation of nonneoplastic cells that form a tumorous mass.

Phospho-fms (p-fms) Expression in Ovarian Sex Cord-stromal Tumors

The macrophage colony stimulating factor receptor (CSF-1 R) is encoded by the c-fms protooncogene. Overexpression of CSF-1 R has been observed to be a poor prognostic factor in epithelial ovarian cancer. Little is known about the significance of CSF-1 R (fms) expression in other ovarian tumors such as sex cord-stromal tumors.

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

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. 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 alpha-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. 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. 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.

Overexpression of CSF-1, its receptor and cell cycle genes in ectopic endometrial tissue compared to eutopic endometrial tissue

Overexpression of CSF-1, its receptor and cell cycle genes in ectopic endometrial tissue compared to eutopic endometrial tissue

Messenger RNA decay of macrophage colony-stimulating factor in human ovarian carcinomas in vitro.

Recently, the importance of the macrophage colony-stimulating factor (CSF-1) and its receptor (encoded by the c-fms proto-oncogene) in patients with epithelial ovarian cancer has been recognized. Overexpression of CSF-1 denotes poor prognosis. Macrophage colony-stimulating factor may be one of a group of inflammatory cytokines, whose 3' untranslated region (UTR) contains AU-rich stretches and whose expression may be largely dependent on mRNA decay. The purposes of this study were to investigate the effect of protein synthesis inhibition on CSF-1 transcript expression, to help determine whether there is a role for labile intermediary proteins in the regulation of CSF-1 expression, and to explore the transcriptional or post-transcriptional mechanisms that could underlie such overexpression of CSF-1 transcripts by protein synthesis inhibitors. Although regulation of CSF-1 gene expression has been investigated in hematopoietic cells, such studies have not been carried out in any epithelial cancer. Northern blot analyses for CSF-1 expression were performed on total cellular RNA extracted from primary and established ovarian cancer cell lines in the absence or presence of proteins synthesis inhibitors with different modes of action. The probe for the AU-rich exon 10 of CSF-1 was prepared by amplification of the terminal 143 bp of the 3' UTR of human CSF-1 by polymerase chain reaction. Transcription rates were assessed in the presence or absence of cycloheximide (CH) in nuclei of ovarian cancer cells by run-off analyses. The effect of CH on CSF-1 mRNA half-life was measured by actinomycin D chase experiments in SKOV3 cells. We demonstrate that CSF-1 mRNA was expressed by all of a panel of primary and established ovarian cancer cell lines. There are at least three CSF-1 transcripts expressed by ovarian cancer cells; we demonstrate that the 4.2-kb CSF-1 transcript contains exon-6 sequences, which are spliced from the 3.4- and 1.9-kb transcripts, whereas both the 4.2- and 3.4-kb CSF-1 transcripts contain the 3' AU-rich exon 10. Treatment with several different protein synthesis inhibitors resulted in marked overexpression of CSF-1 transcript levels, suggesting a potential role for labile proteins in the regulation of CSF-1 expression. The predominant effect of CH is on the two CSF-1 transcripts that contain exon 10. Although CH does not change the rate of CSF-1 gene transcription, measurement of CSF-1 mRNA stability reveals a prolongation of CSF-1 transcript half-life by CH from 4.5 hours to significantly greater than 6 hours in ovarian cancer cells. Augmented CSF-1 transcript stability underlies the marked overexpression of CSF-1 seen with protein synthesis inhibitors. Our results suggest the involvement of a labile regulatory protein that contributes to CSF-1 mRNA decay in ovarian cancer cells. Our data suggest further that exon 10 (not the spliced exon-6 sequences) of the CSF-1 transcript may contain an instability determinant.