Therapeutic paradigm of dual targeting VEGF and PDGF for effectively treating FGF-2 off-target tumors.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 32709869.
- Also identified by DOI 10.1038/s41467-020-17525-6 and PMC identifier 7382445.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
FGF-2 displays multifarious functions in regulation of angiogenesis and vascular remodeling. However, effective drugs for treating FGF-2<sup>+</sup> tumors are unavailable. Here we show that FGF-2 modulates tumor vessels by recruiting NG2<sup>+</sup> pricytes onto tumor microvessels through a PDGFRβ-dependent mechanism. FGF-2<sup>+</sup> tumors are intrinsically resistant to clinically available drugs targeting VEGF and PDGF. Surprisingly, dual targeting the VEGF and PDGF signaling produces a superior antitumor effect in FGF-2<sup>+</sup> breast cancer and fibrosarcoma models. Mechanistically, inhibition of PDGFRβ ablates FGF-2-recruited perivascular coverage, exposing anti-VEGF agents to inhibit vascular sprouting. These findings show that the off-target FGF-2 is a resistant biomarker for anti-VEGF and anti-PDGF monotherapy, but a highly beneficial marker for combination therapy. Our data shed light on mechanistic interactions between various angiogenic and remodeling factors in tumor neovascularization. Optimization of antiangiogenic drugs with different principles could produce therapeutic benefits for treating their resistant off-target cancers.
Medical subject headings
- Angiogenesis Inhibitors
- Fibroblast Growth Factor 2
- Neoplasms
- Platelet-Derived Growth Factor
- Vascular Endothelial Growth Factor A