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

Research output: Contribution to journalJournal article – Annual report year: 2016Researchpeer-review

  • Author: Yang, Yunlong

    The First Affiliated Hospital of Shenzhen University, China

  • Author: Zhang, Yin

    Karolinska Institutet, Sweden

  • Author: Iwamoto, Hideki

    Karolinska Institutet, Sweden

  • Author: Hosaka, Kayoko

    Karolinska Institutet, Sweden

  • Author: Seki, Takahiro

    Karolinska Institutet, Sweden

  • Author: Andersson, Patrik L.

    Karolinska Institutet, Sweden

  • Author: Lim, Sharon

    Karolinska Institutet, Sweden

  • Author: Fischer, Carina

    Karolinska Institutet, Sweden

  • Author: Nakamura, Masaki

    Karolinska Institutet, Sweden

  • Author: Abe, Mitsuhiko

    Karolinska Institutet, Sweden

  • Author: Skov, Peter Vilhelm

    Section for Aquaculture, National Institute of Aquatic Resources, Technical University of Denmark, Willemoesvej 2, 9850, Hirtshals, Denmark

  • Author: Feng, Chang

    Zhejiang University, China

  • Author: Chen, Xiaoyun

    National Sun Yat-sen University, China

  • Author: Lu, Yongtian

    The First Affiliated Hospital of Shenzhen University, China

  • Author: Nie, Guohui

    The First Affiliated Hospital of Shenzhen University, China

  • Author: Cao, Yihai

    Karolinska Institutet, Sweden

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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.
Original languageEnglish
Article number12680
JournalNature Communications
Volume7
ISSN2041-1723
DOIs
Publication statusPublished - 2016
CitationsWeb of Science® Times Cited: No match on DOI

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