Abstract 470: Role of Fli1 in hematopoietic stem cell-derived fibroblast promotion of tumor cell migration and invasion

Abstract

Abstract Cells and paracrine factors of the tumor microenvironment play a central role in tumor angiogenesis, invasion, migration and proliferation, making the tumor microenvironment an exciting therapeutic target. Among the most prominent cell types in the tumor stroma are fibroblasts, termed carcinoma-associated fibroblasts (CAFs). We have identified a novel population of CAFs and CAF precursors (circulating fibroblast precursors, CFPs) that are of hematopoietic stem cell (HSC) origin. These cells preferentially migrate and differentiate in response to tumor and their inhibition results in decreased tumor size. While these studies have identified a novel HSC-derived CAF population, the mechanisms by which these cells promote tumorigenesis are unknown. Previous studies have indicated a critical role for Fli1, an Ets family transcription factor, in regulation of HSCs and differentiation/maturation of hematopoietic lineages. Additionally, loss of Fli1 has been associated with cancer progression. Based on these findings, we hypothesize that HSC-derived CFPs/CAFs directly affect tumor cell migration and invasion and that loss of Fli1 in CFPs/CAFs enhances these effects. To address this hypothesis, we examined the ability of HSC-derived fibroblast populations to affect tumor cell migration and invasion in vitro. Fibroblasts were established from peripheral blood and bone marrow of normal mice and mutant Fli1 mice expressing a truncated Fli1 protein (Fli1ΔCTA) lacking the carboxy-terminal regulatory (CTA) domain. The effects of conditioned media from these fibroblast populations on tumor cell migration and invasion were examined in chemotactic transwell migration assays and matrigel-based invasion assays, respectively. Data show that conditioned media from all HSC-derived fibroblast populations promoted migration and invasion of tumor cells versus control, and that this effect was significantly enhanced using conditioned media from fibroblasts derived from Fli1ΔCTA/Fli1ΔCTA mice. Ongoing studies are directed at identifying the mechanisms by which Fli1 target genes affect HSC-derived fibroblast modulation of tumor cell migration and invasion. 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 470. doi:10.1158/1538-7445.AM2011-470