Therapeutic paradigm of dual targeting VEGF and PDGF for effectively treating FGF-2 off-target tumors

Kayoko Hosaka, Yunlong Yang, Takahiro Seki, Qiqiao Du, Xu Jing, Xingkang He, Jieyu Wu, Yin Zhang, Hiromasa Morikawa, Masaki Nakamura, Martin Scherzer, Xiaoting Sun, Yuanfu Xu, Tao Cheng, Xuri Li, Xialin Liu, Qi Li, Yizhi Liu, An Hong, Yuguo Chen and Yihai Cao ()
Additional contact information
Kayoko Hosaka: Karolinska Institute
Yunlong Yang: Karolinska Institute
Takahiro Seki: Karolinska Institute
Qiqiao Du: Karolinska Institute
Xu Jing: Karolinska Institute
Xingkang He: Karolinska Institute
Jieyu Wu: Karolinska Institute
Yin Zhang: Karolinska Institute
Hiromasa Morikawa: Karolinska Institute
Masaki Nakamura: Karolinska Institute
Martin Scherzer: Karolinska Institute
Xiaoting Sun: Karolinska Institute
Yuanfu Xu: Chinese Academy of Medical Sciences and Peking Union Medical College
Tao Cheng: Chinese Academy of Medical Sciences and Peking Union Medical College
Xuri Li: Sun Yat-Sen University
Xialin Liu: Sun Yat-Sen University
Qi Li: Shuguang Hospital Shanghai University of Traditional Chinese Medicine
Yizhi Liu: Sun Yat-Sen University
An Hong: Jinan University
Yuguo Chen: Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital of Shandong University
Yihai Cao: Karolinska Institute

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-17525-6

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