Dual roles of endothelial FGF-2-FGFR1-PDGF-BB and perivascular FGF-2-FGFR2-PDGFR? signaling pathways in tumor vascular remodeling.

ABSTRACT: Perivascular cells are important cellular components in the tumor microenvironment (TME) and they modulate vascular integrity, remodeling, stability, and functions. Here we show using mice models that FGF-2 is a potent pericyte-stimulating factor in tumors. Mechanistically, FGF-2 binds to FGFR2 to stimulate pericyte proliferation and orchestrates the PDGFR? signaling for vascular recruitment. FGF-2 sensitizes the PDGFR? signaling through increasing PDGFR? levels in pericytes. To ensure activation of PDGFR?, the FGF-2-FGFR1-siganling induces PDGF-BB and PDGF-DD, two ligands for PDGFR?, in angiogenic endothelial cells. Thus, FGF-2 directly and indirectly stimulates pericyte proliferation and recruitment by modulating the PDGF-PDGFR? signaling. Our study identifies a novel mechanism by which the FGF-2 and PDGF-BB collaboratively modulate perivascular cell coverage in tumor vessels, thus providing mechanistic insights of pericyte-endothelial cell interactions in TME and conceptual implications for treatment of cancers and other diseases by targeting the FGF-2-FGFR-pericyte axis.

SUBMITTER: Hosaka K 

PROVIDER: S-EPMC5798893 | biostudies-other | 2018

REPOSITORIES: biostudies-other