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 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.
Highlights
The tumor microenvironment (TME) is constituted of the extracellular matrix and various cellular components including malignant cells, stromal fibroblasts, inflammatory cells, immune cells, vascular endothelial cells, and perivascular cells[1, 2]
We show that the FGF2–FGFR2 signaling augments high-pericyte contents in TME and promotes pericyte coverage in tumor vessels
The identity of NG2+ pericytes in Fibroblast growth factor-2 (FGF-2) positive (FGF-2+) tumors was further validated with the αSMA known as one of pericyte markers in tumors10. αSMA expressions were co-localized with NG2 positive signals (Supplementary Fig. S1)
Summary
The tumor microenvironment (TME) is constituted of the extracellular matrix and various cellular components including malignant cells, stromal fibroblasts, inflammatory cells, immune cells, vascular endothelial cells, and perivascular cells[1, 2]. These various cells communicate to each other through cell–cell interactions and production of various growth factors and cytokines[2]. Pericyte coverage on microvessels is regulated by multiple signaling molecules that are produced by endothelial cells and other cell types[10]. Endothelial cells produce PDGF-BB to recruit PDGFRβ+ pericytes onto the nascent vasculature.
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