Differentiated Cancer Cell-Derived Fibromodulin Promotes Angiogenesis and Tumor Growth Through Paracrine Signaling in Endothelial Cells

Cancer stem-like cells alone can initiate tumors, but the function of differentiated cancer cells that form the tumor bulk remains poorly understood. Proteomic analysis showed a higher abundance of the collagen-binding proteoglycan Fibromodulin (FMOD) in the conditioned medium of differentiated glioma cells (DGCs) compared to that of glioma stem-like cells (GSCs). DGCs silenced for FMOD fail to cooperate with co-implanted GSCs to promote tumor growth. FMOD downregulation neither affects GSC growth and differentiation nor DGC growth and reprogramming in vitro. DGC-secreted FMOD promotes angiogenesis, which requires activation of Integrin-dependent Notch signaling in endothelial cells. Furthermore, conditional silencing of FMOD in newly generated DGCs in vivo inhibits the growth of GSC-initiated tumors due to poorly developed vasculature and increases mouse survival. Collectively, these findings demonstrate that DGC-secreted FMOD promotes glioma tumor angiogenesis and growth through paracrine signaling in endothelial cells and identifies a DGC-produced protein as a potential therapeutic target in glioma.