Abstract
Tumor formation is an extensive process requiring complex interactions that involve both tumor cell-intrinsic pathways and soluble mediators within the microenvironment. Tumor cells exploit the intrinsic functions of many soluble molecules, including chemokines and their receptors, to regulate pro-tumorigenic phenotypes that are required for growth and progression of the primary tumor. Previous studies have shown that activation of inducible FGFR1 (iFGFR1) in mammary epithelial cells resulted in increased proliferation, migration, and invasion in vitro and tumor formation in vivo. These studies also demonstrated that iFGFR1 activation stimulated recruitment of macrophages to the epithelium where macrophages contributed to iFGFR1-mediated epithelial cell proliferation and angiogenesis. The studies presented here further utilize this model to identify the mechanisms that regulate FGFR1-induced macrophage recruitment. Results from this study elucidate a novel role for the inflammatory chemokine CX3CL1 in FGFR1-induced macrophage migration. Specifically, we illustrate that activation of both the inducible FGFR1 construct in mouse mammary epithelial cells and endogenous FGFR in the triple negative breast cancer cell line, HS578T, leads to expression of the chemokine CX3CL1. Furthermore, we demonstrate that FGFR-induced CX3CL1 is sufficient to recruit CX3CR1-expressing macrophages in vitro. Finally, blocking CX3CR1 in vivo leads to decreased iFGFR1-induced macrophage recruitment, which correlates with decreased angiogenesis. While CX3CL1 is a known target of FGF signaling in the wound healing environment, these studies demonstrate that FGFR activation also leads to induction of CX3CL1 in a tumor setting. Furthermore, these results define a novel role for CX3CL1 in promoting macrophage recruitment during mammary tumor formation, suggesting that the CX3CL1/CX3CR1 axis may represent a potential therapeutic approach for targeting breast cancers associated with high levels of tumor-associated macrophages.
Highlights
Activation of oncogenes in tumor cells results in the release of soluble factors into the microenvironment [1,2]
We demonstrated that activation of an inducible fibroblast growth factor receptor 1 (FGFR1) that had been expressed in HC-11 mammary epithelial cells using retroviral transduction led to the production of soluble mediators that could promote macrophage recruitment in vitro [15]
Treatment of HS578T cells with the FGFR inhibitor PD173074 for 8 hours led to a decrease in the ability of conditioned media from these cells to promote recruitment of phorbol myristate acetate (PMA)-differentiated THP-1 macrophages, suggesting that FGFR activity regulates the production of soluble factors important for mediating macrophage recruitment by breast cancer cells (Figure 1b)
Summary
Activation of oncogenes in tumor cells results in the release of soluble factors into the microenvironment [1,2]. These factors act on the tumor cells in an autocrine manner and on nontumoral cells in a paracrine manner to promote tumor formation and progression [3,4]. Using an inducible model of fibroblast growth factor receptor 1 (FGFR1), we have demonstrated that activation of FGFR1 in mammary epithelial cells induces a number of secreted factors that are capable of acting in both autocrine and paracrine manners to promote tumorigenesis [5,6,7]. Understanding the paracrine effects of FGF signaling in a tumor setting is important for identifying effective therapeutic strategies to target cancers associated with high levels of FGF signaling
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