Dual roles of endothelial FGF-2-FGFR1-PDGF-BB and perivascular FGF-2-FGFR2-PDGFRβ signaling pathways in tumor vascular remodeling.pdf (4.1 MB)
Dual roles of endothelial FGF-2-FGFR1-PDGF-BB and perivascular FGF-2-FGFR2-PDGFRβ signaling pathways in tumor vascular remodeling.
journal contributionposted on 2019-08-29, 15:48 authored by K Hosaka, Y Yang, M Nakamura, P Andersson, X Yang, Y Zhang, T Seki, M Scherzer, O Dubey, X Wang, Y Cao
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 PDGFRβ signaling for vascular recruitment. FGF-2 sensitizes the PDGFRβ signaling through increasing PDGFRβ levels in pericytes. To ensure activation of PDGFRβ, the FGF-2-FGFR1-siganling induces PDGF-BB and PDGF-DD, two ligands for PDGFRβ, in angiogenic endothelial cells. Thus, FGF-2 directly and indirectly stimulates pericyte proliferation and recruitment by modulating the PDGF-PDGFRβ 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.
European Research Council (ERC) advanced grant ANGIOFAT (Project No. 250021), the Swedish Research Council, the Swedish Cancer Foundation, the Karolinska Institute Foundation, the Karolinska Institute distinguished professor award, the Torsten Soderbergs Foundation, the Maud and Birger Gustavsson Foundation, the NOVO Nordisk Foundation, and the Knut and Alice Wallenbergs Foundation.
CitationCell Discovery, 2018, 4, pp. 3
Author affiliation/Organisation/COLLEGE OF LIFE SCIENCES/School of Medicine/Department of Cardiovascular Sciences
- VoR (Version of Record)