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Discontinuation of anti-VEGF cancer therapy promotes metastasis through a liver revascularization mechanism

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  • Yunlong Yang

    (Key Laboratory of International Collaborations, Second People’s Hospital of Shenzhen, First Affiliated Hospital of Shenzhen University
    Tumor and Cell Biology, Karolinska Institute)

  • Yin Zhang

    (Tumor and Cell Biology, Karolinska Institute)

  • Hideki Iwamoto

    (Tumor and Cell Biology, Karolinska Institute)

  • Kayoko Hosaka

    (Tumor and Cell Biology, Karolinska Institute)

  • Takahiro Seki

    (Tumor and Cell Biology, Karolinska Institute)

  • Patrik Andersson

    (Tumor and Cell Biology, Karolinska Institute)

  • Sharon Lim

    (Tumor and Cell Biology, Karolinska Institute)

  • Carina Fischer

    (Tumor and Cell Biology, Karolinska Institute)

  • Masaki Nakamura

    (Tumor and Cell Biology, Karolinska Institute)

  • Mitsuhiko Abe

    (Tumor and Cell Biology, Karolinska Institute)

  • Renhai Cao

    (Tumor and Cell Biology, Karolinska Institute)

  • Peter Vilhelm Skov

    (Section for Aquaculture, The North Sea Research Centre, DTU Aqua, Technical University of Denmark)

  • Fang Chen

    (The First Affiliated Hospital of Zhejiang Chinese Medicine University)

  • Xiaoyun Chen

    (State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University)

  • Yongtian Lu

    (Key Laboratory of International Collaborations, Second People’s Hospital of Shenzhen, First Affiliated Hospital of Shenzhen University)

  • Guohui Nie

    (Key Laboratory of International Collaborations, Second People’s Hospital of Shenzhen, First Affiliated Hospital of Shenzhen University)

  • Yihai Cao

    (Tumor and Cell Biology, Karolinska Institute
    University of Leicester and NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital)

Abstract

The impact of discontinuation of anti-VEGF cancer therapy in promoting cancer metastasis is unknown. Here we show discontinuation of anti-VEGF treatment creates a time-window of profound structural changes of liver sinusoidal vasculatures, exhibiting hyper-permeability and enlarged open-pore sizes of the fenestrated endothelium and loss of VE-cadherin. The drug cessation caused highly leaky hepatic vasculatures permit tumour cell intravasation and extravasation. Discontinuation of an anti-VEGF antibody-based drug and sunitinib markedly promotes liver metastasis. Mechanistically, host hepatocyte, but not tumour cell-derived vascular endothelial growth factor (VEGF), is responsible for cancer metastasis. Deletion of hepatocyte VEGF markedly ablates the ‘off-drug’-induced metastasis. These findings provide mechanistic insights on anti-VEGF cessation-induced metastasis and raise a new challenge for uninterrupted and sustained antiangiogenic therapy for treatment of human cancers.

Suggested Citation

  • Yunlong Yang & Yin Zhang & Hideki Iwamoto & Kayoko Hosaka & Takahiro Seki & Patrik Andersson & Sharon Lim & Carina Fischer & Masaki Nakamura & Mitsuhiko Abe & Renhai Cao & Peter Vilhelm Skov & Fang Ch, 2016. "Discontinuation of anti-VEGF cancer therapy promotes metastasis through a liver revascularization mechanism," Nature Communications, Nature, vol. 7(1), pages 1-13, November.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms12680
    DOI: 10.1038/ncomms12680
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