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

Author

Listed:
  • Kayoko Hosaka

    (Karolinska Institute)

  • Yunlong Yang

    (Karolinska Institute
    Fudan University)

  • Takahiro Seki

    (Karolinska Institute
    Kagoshima University Graduate School of Medical and Dental Sciences)

  • Qiqiao Du

    (Karolinska Institute)

  • Xu Jing

    (Karolinska Institute
    The Second Hospital of Shandong University)

  • Xingkang He

    (Karolinska Institute)

  • Jieyu Wu

    (Karolinska Institute)

  • Yin Zhang

    (Karolinska Institute
    Binzhou Medical University)

  • Hiromasa Morikawa

    (Karolinska Institute)

  • Masaki Nakamura

    (Karolinska Institute
    The University of Tokyo Hospital 7-3-1)

  • Martin Scherzer

    (Karolinska Institute)

  • Xiaoting Sun

    (Karolinska Institute
    Shuguang Hospital Shanghai University of Traditional Chinese Medicine)

  • 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)

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.

Suggested Citation

  • 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 &, 2020. "Therapeutic paradigm of dual targeting VEGF and PDGF for effectively treating FGF-2 off-target tumors," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17525-6
    DOI: 10.1038/s41467-020-17525-6
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    Cited by:

    1. Sagar Mahale & Meenakshi Setia & Bharat Prajapati & Santhilal Subhash & Mukesh Pratap Yadav & Subazini Thankaswamy Kosalai & Ananya Deshpande & Jagannath Kuchlyan & Mirco Di Marco & Fredrik Westerlund, 2022. "HnRNPK maintains single strand RNA through controlling double-strand RNA in mammalian cells," Nature Communications, Nature, vol. 13(1), pages 1-20, December.

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