Abstract 1131: Differential induction of c-fms promoters by TGFβ in cervical cancer and macrophage cell lines

Abstract

Abstract Cervical cancer is the second most common gynecological malignancy in the world. An expected 12,200 total new diagnosed cases were estimated by the American Cancer Society for 2010 (Cancer Facts and Figures, 2010). Human papillomavirus infection, a major cause for cervical cancer, results in a persistent and pathological inflammatory response, contributing to establishment of disease and malignant progression. Our previous studies have shown that inflammatory factors, like Cox2, tumor associated macrophages, and cytokines such as macrophage colony-stimulating factor (CSF-1) and transforming growth factor beta (TGFβ) are elevated in cervical carcinomas. The receptors for CSF-1 (encoded by the c-fms oncogene) and TGFβ were also elevated in cervical carcinomas compared to normal cervical tissue. Both CSF-1 and c-fms have been implicated in aggressive gynecological malignancies, including cervical cancer. CSF-1/c-fms signaling is involved in proliferation, differentiation and recruitment of macrophages as well as cancer cell growth. We have previously demonstrated that TGFβ induced the expression of c-fms mRNA in cervical cancer cell lines and macrophage cell line THP-1. Using flow cytometry in this study, we have confirmed induction of c-fms protein at the cell surface due to TGFβ treatment, suggesting that TGFβ may enhance CSF-1 signaling by inducing cell surface expression of its receptor. Our goal was to examine the mechanisms underlying the regulation of c-fms in macrophages, relevant leukocytes associated with inflammation and pro-malignant growth within the tumor microenvironment. Two promoters for the c-fms gene exist, promoter one driving expression in trophoblasts (trophoblast specific promoter) and promoter two driving expression in macrophages (macrophage specific promoter). Consistent with our previous findings, TGFβ induced c-fms expression via MAPK p38 mainly at the trophoblast specific promoter in cervical cancer cells, as shown by the use of the p38 inhibitor SB203580. Our data also suggest that Casein kinase 1 mediates c-fms expression via this promoter in cervical cancer cells. In the macrophage cell line THP-1, p38 mediated the expression of c-fms via both promoters, as demonstrated by using exon specific RT-PCR primer sets. The c-fms mRNA induced at the macrophage specific promoter is the major c-fms transcript in THP-1 cells and is likely to mainly contribute to c-fms expression in these cells. Understanding the regulation of c-fms in macrophages and cervical cancer cells may pave the way to targeting c-fms expression to interrupt aberrant CSF-1 signaling in cervical cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1131. doi:10.1158/1538-7445.AM2011-1131