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

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 Chen, Xiaoyun Chen, Yongtian Lu, Guohui Nie and Yihai Cao ()
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Yunlong Yang: Key Laboratory of International Collaborations, Second People’s Hospital of Shenzhen, First Affiliated Hospital of Shenzhen University
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

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12680

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