Thus, targeting the FGF-2 signaling pathway may have profound implications for cancer treatment, drug sensitivity, and possible metastasis.įGF-2 markedly modulates the pericyte content in tumors FGF-2 synchronizes with the PDGF-BB–PDGFRβ signaling pathway by modulating their expression and activation. Mechanistically, FGF-2 triggers both direct and indirect signaling pathways to stimulate pericyte proliferation and recruitment. In the present work, we show that the FGF-2–FGFR2 signaling augments high-pericyte contents in TME and promotes pericyte coverage in tumor vessels. Tumors often produce high levels of FGF-2 to support their growth by stimulating tumor cell proliferation and angiogenesis 9, 16. Despite the long-known functions of FGF-2, its biological functions on perivascular cells, especially in relation to the PDGF-BB–PDGFRβ signaling is unknown. There are four subtypes of FGFRs FGFR1–4 that are all cell-surface tyrosine kinase receptors distributed in various cell types 16. Thus, imbalanced expression or activation of each of these signaling components would result in vascular dysfunctions.įibroblast growth factor-2 (FGF-2) is a ubiquitously expressed growth factor that displays broad biological functions including angiogenesis through activation of FGF receptors (FGFRs) 15.
While the VEGF–VEGFR2 induces vascular sprouting, the Dll4–Notch signaling prevents excessive vascular sprouting in collaboration with the PDGF-BB–PDGFRβ system 14. The PDGF-BB–PDGFR signaling synchronizes with other signaling pathways including the VEGF–VEGF receptor 2 (VEGFR2) and the delta-like 4 (Dll4)–Notch signaling pathways 12, 13. Pericyte recruitment in angiogenic vessels ensures unidirectional sprouting of endothelial cells toward the gradient of angiogenic factors such as vascular endothelial growth factor (VEGF). In angiogenic vessels, endothelial cells produce PDGF-BB to recruit PDGFRβ + pericytes onto the nascent vasculature. During the early embryonic development, genetic deletion of Pdgfb or Pdgfrb in mice produced severe vascular defects of hemorrhages leading to lethality owing to lack of pericytes 6, 11. Among all known regulatory signaling molecules, the platelet-derived growth factor-BB (PDGF-BB)–platelet-derived growth factor receptor β (PDGFRβ) axis is probably the best-characterized signaling system for perivascular cell recruitment 6, 11. Pericyte coverage on microvessels is regulated by multiple signaling molecules that are produced by endothelial cells and other cell types 10. Perivascular cells are often tightly associated with vascular endothelial cells and modulate vascular functions by stabilizing vascular networks, promoting vessel maturation and stability, preventing excessive sprouting, preventing uncontrollable leakage, and modulation of blood perfusion 4, 5, 6, 7, 8, 9. Consequently, TME is probably the richest source of various signaling molecules that often become activated and execute their biological functions on various cell types 3. These various cells communicate to each other through cell–cell interactions and production of various growth factors and cytokines 2.
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. 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. Thus, FGF-2 directly and indirectly stimulates pericyte proliferation and recruitment by modulating the PDGF–PDGFRβ signaling. To ensure activation of PDGFRβ, the FGF-2–FGFR1-siganling induces PDGF-BB and PDGF-DD, two ligands for PDGFRβ, in angiogenic endothelial cells. FGF-2 sensitizes the PDGFRβ signaling through increasing PDGFRβ levels in pericytes. Mechanistically, FGF-2 binds to FGFR2 to stimulate pericyte proliferation and orchestrates the PDGFRβ signaling for vascular recruitment. Here we show using mice models that FGF-2 is a potent pericyte-stimulating factor in tumors. Perivascular cells are important cellular components in the tumor microenvironment (TME) and they modulate vascular integrity, remodeling, stability, and functions.
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