Abstract
FGF-2 displays multifarious functions in regulation of angiogenesis and vascular remodeling. However, effective drugs for treating FGF-2+ tumors are unavailable. Here we show that FGF-2 modulates tumor vessels by recruiting NG2+ pricytes onto tumor microvessels through a PDGFRβ-dependent mechanism. FGF-2+ 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+ 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.
Highlights
fibroblast growth factor 2 (FGF-2) displays multifarious functions in regulation of angiogenesis and vascular remodeling
In our opinion, understanding the fundamental mechanisms that underlie tumor angiogenesis, vascular remodeling, and the druginduced alterations of tumor microenvironment (TME) is crucial for therapeutic improvement
By The Cancer Genome Atlas (TCGA) analysis, we show that FGF-2 expression levels reversely and significantly correlated with survival advantages in breast, ovarian, and bladder cancers (Fig. 7a–d)
Summary
FGF-2 displays multifarious functions in regulation of angiogenesis and vascular remodeling. In the tumor microenvironment (TME), malignant cells and stromal cells produce various angiogenic factors to induce neovascularization, vascular remodeling, tumor growth, and metastasis[1]. Targeting these factors and their signaling pathways provides attractive approaches for treating various cancers[1,2,3,4]. Tumor microvessels distinguish from the healthy ones by possessing several unique features, including disorganization, tortuosity, leakiness, low perfusion, instability, lacking sufficient perivascular cell coverage, and lacking completeness of the basement membrane[9,10] These unique features represent imbalanced production of angiogenic factors, accumulation of metabolites, hypoxia, and alteration of the TME. At this time of writing, such reliable biomarkers are not clinically available
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
