Journal
NATURE COMMUNICATIONS
Volume 7, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms12680
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Funding
- Swedish Research Council
- Swedish Cancer Foundation
- Karolinska Institute Foundation
- Karolinska Institute distinguished professor award
- Torsten Soderbergs Foundation
- Tore Nilsons Foundation
- Ruth and Richard Julin Foundation
- Ogonfonden Foundation
- Martin Rinds Foundation
- Maud and Birger Foundation
- Lars Hiertas Minne Foundation
- Alex and Eva Wallstroms Foundation
- Robert Lundbergs Memorial Foundation
- Swedish Diabetes Foundation
- Swedish Children Cancer Foundation
- European Research Council (ERC) [250021]
- Knut Alice Wallenberg Foundation
- NOVO Nordisk Foundation
- Shenzhen Science and Technology Innovation Committee [JCYJ 20150403091443336, JCYJ 20150330102720136]
- Guangdong Science and Technology Department [2014A020212654]
- Shenzhen finance committee
- Municipal Development and Reform Commission (programme Shenzhen Auditognosis and Balancing Function Medical Technology Engineering Laboratory)
- Novo Nordisk Fonden [NNF14OC0012835] Funding Source: researchfish
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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.
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