journal contribution posted on 11.11.2016, 14:43 by Y. Yang, Y. Zhang, H. Iwamoto, K. Hosaka, T. Seki, P. Andersson, S. Lim, C. Fischer, M. Nakamura, M. Abe, R. Cao, P. V. Skov, F. Chen, X. Chen, Y. Lu, G. Nie, Yihai Cao
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.
We thank Simcere Pharmaceuticals, Nanjing, China for providing a rabbit anti-VEGF neutralizing monoclonal antibody. Y.C.’s laboratory is supported through research grants from: the Swedish Research Council; the Swedish Cancer Foundation; the Karolinska Institute Foundation; the Karolinska Institute distinguished professor award; the Torsten Soderbergs Foundation; the Tore Nilsons Foundation; the Ruth and Richard Julin Foundation; the Ogonfonden Foundation; the Martin Rinds Foundation; the Maud and Birger Foundation; the Lars Hiertas Minne Foundation; the Alex and Eva Wallströms Foundation; the Robert Lundbergs Memorial Foundation; the Swedish Diabetes Foundation; the Swedish Children Cancer Foundation; the European Research Council (ERC) advanced grant ANGIOFAT (Project no 250021); the Knut Alice Wallenberg Foundation and the NOVO Nordisk Foundation for the advanced grant. The Lab in Shenzhen is supported by Shenzhen Science and Technology Innovation Committee (Projects no JCYJ 20150403091443336 and JCYJ 20150330102720136); Guangdong Science and Technology Department (project no 2014A020212654); Shenzhen finance committee (High level disciplinary development program for university-affiliated hospital); Municipal Development and Reform Commission (programme Shenzhen Auditognosis and Balancing Function Medical Technology Engineering Laboratory).
CitationNature Communications, 2016, 7:12680
Author affiliation/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Medicine/Department of Cardiovascular Sciences
VersionVoR (Version of Record)
Published inNature Communications
PublisherNature Publishing Group
NotesThe authors declare that the data supporting the findings of this
study are available within the article and its Supplementary Information files.