Abstract 4096: Fibroblast growth factor-2-derived from cancer-associated fibroblasts stimulates proliferation and migration of human breast cancer cells

Abstract

Abstract Cancer-associated fibroblasts (CAFs) constitute a major compartment of the tumor microenvironment. CAFs produce a variety of cytokines, growth factors and extracellular matrix proteins, thereby stimulating tumor progression. CAFs are distinct from normal fibroblasts for their overexpression of α-smooth muscle actin and fibroblast specific protein-1. Recent studies suggest that CAFs play an important role in proliferation and migration of cancer cells through crosstalk with them.In the present study, we investigated the role for CAFs in proliferation and migration of breast cancer cells and underlying molecular mechanisms.When triple-negative human mammary MDA-MB-231 cells were treated with the conditioned medium (CM) collected from cultured CAFs, the cell viability and migration were significantly elevated. Furthermore, these cells manifest a more proliferative phenotype, exhibiting enhanced mRNA expression of cycinD1, c-Myc and PCNA as well as increased phosphorylation of Akt and STAT3.In addition, MDA-MB-231 cells exhibited elevated expression of proliferative and invasive genes including MMP2 and MMP9 when incubated with CAFs in the indirect co-culture system. Notably, mRNA levels of fibroblast growth factor-2 (FGF2), stromal-derived factor-1, interleukin-6 and interleukin-8 detected in CAFs were higher than those in normal fibroblasts of the same patients. In contrast, FGF2 was expressed at a relatively low level in breast cancer cells. FGF2 exerts its biological effects by binding to and activating FGF receptor (FGFR), a subfamily of cell surface receptor tyrosine kinases. Notably, the expression of FGFR1 was up-regulated in triple-negative breast cancer cells including MDA-MB-231 cells while another major FGF2-corresponding receptor FGFR2 was rarely expressed. Therefore, we focused on FGF2-FGFR1 signaling in the context of paracrine communication between breast cancer cells and CAFs. CAF-stimulated MDA-MB-231 cell migration as well as FGFR1 expression was abolished when FGF2-neutralizing antibody was added to the CAF-CM. In addition, treatment of MDA-MB-231 cells with FGF2 induced the phosphorylation of FRS2 and Akt. FGF2-induced cell migration and up-regulation of cyclinD1 expression were abrogated by siRNA-mediated FGFR1 silencing. Furthermore, FGF2 promotes nuclear localization of FGFR1. Taken together, above findings suggest that secretion of FGF2 by CAFs stimulates proliferation and migration of breast cancer cells through interaction with FGFR1 which may contribute to human breast cancer progression. Citation Format: Jinyoung Suh, Do-Hee Kim, Young-Joon Surh. Fibroblast growth factor-2-derived from cancer-associated fibroblasts stimulates proliferation and migration of human breast cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4096.