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, Peter Vilhelm Skov, Chang Feng, Xiaoyun Chen, Yongtian Lu, Guohui Nie, Yihai Cao

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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
Publication statusPublished - 2016

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