THE ROLE OF COLONY-STIMULATING FACTOR-1 AND ITS RECEPTOR IN THE ETIOPATHOGENESIS OF ENDOMETRIAL ADENOCARCINOMA

Colony-stimulating factor 1 (CSF-1) is a homodimeric growth factor tha t humorally regulates the growth and differentiation of mononuclear ph agocytes, and locally regulates maternal-fetal interactions during pre gnancy. It exerts these actions through a transmembrane tyrosine kinas e receptor, colony-stimulating factor 1 receptor (CSF-1R), the product of the c-fms proto-oncogene, Recent studies have demonstrated overexp ression of CSF-1 and its receptor in breast, ovarian, and endometrial adenocarcinomas. To further investigate the possible role of CSF-1 and its receptor in the pathogenesis of endometrial adenocarcinoma, a pro spective study was undertaken to study CSF-1 expression in benign and neoplastic endometrial epithelium and to compare serum CSF-1 levels in endometrial adenocarcinoma patients with healthy perimenopausal women . The mean serum levels of CSF-1 in 71 patients with endometrial cance r (4.9 +/- 1.8 mu g/liter) were significantly elevated compared with l evels found in the 32 controls (3.5 +/- 1.1 mu g/liter). Within the en dometrial adenocarcinoma group, circulating CSF-1 levels were signific antly elevated in patients with large tumor volume, high grade, myomet rial invasion, residual disease, and circulating CA-125 levels. High s erum levels of serum CSF-1 were associated with elevated serum CA19-9 and CA-125 levels, Immunohistochemistry results revealed in tumor epit helium intense staining for CSF-1R (27 of 54 cases, 50%) and elevated staining for CSF-1 (41 of 54 cases, 75.9%), with intense staining of C SF-1 in 16 of 54 cases (29.6%), Staining was significantly greater in intensity and number of cells involved in malignant compared with beni gn epithelium for CSF-1R and CSF-1 (P = 0.05 and <0.0001, respectively ). A positive correlation between amount and intensity of CSF-1 and CS F-1R staining in endometrial adenocarcinoma tissue was also demonstrat ed (P = 0.007), CSF-1 and CSF-1R mRNA was also detected in the tumor s amples, confirming the expression of the protein in these tissues. Rev erse transcription-PCR demonstrated the presence of mRNA for both the transmembrane and secreted forms of CSF-1 in all tumors analyzed. Thes e results therefore support the hypotheses that CSF-1 and CSF-1R are o verexpressed in endometrial adenocarcinoma, that levels of expression significantly correlate with clinicopathological risk factors for poor outcome, and that CSF-1 in association with its receptor via autocrin e, juxtacrine, and/or paracrine interactions has a causal role in endo metrial adenocarcinoma development and proliferation.