title: Discontinuation of anti-VEGF cancer therapy promotes metastasis through a liver revascularization mechanism.
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.
authors: Key Laboratory of International Collaborations, Second People's Hospital of Shenzhen, First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China.|Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden.
authors: Yunlong
authors: Y
authors: Yang
authors: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden.
authors: Yin
authors: Y
authors: Zhang
authors: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden.
authors: Hideki
authors: H
authors: Iwamoto
authors: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden.
authors: Kayoko
authors: K
authors: Hosaka
authors: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden.
authors: Takahiro
authors: T
authors: Seki
authors: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden.
authors: Patrik
authors: P
authors: Andersson
authors: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden.
authors: Sharon
authors: S
authors: Lim
authors: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden.
authors: Carina
authors: C
authors: Fischer
authors: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden.
authors: Masaki
authors: M
authors: Nakamura
authors: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden.
authors: Mitsuhiko
authors: M
authors: Abe
authors: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden.
authors: Renhai
authors: R
authors: Cao
authors: Section for Aquaculture, The North Sea Research Centre, DTU Aqua, Technical University of Denmark Hirtshals 1019850, Denmark.
authors: Peter Vilhelm
authors: 0000-0001-7900-4431
authors: PV
authors: Skov
authors: The First Affiliated Hospital of Zhejiang Chinese Medicine University, 54 Youdian Road, Hangzhou, Zhejiang 310006, China.
authors: Fang
authors: F
authors: Chen
authors: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou 510060, China.
authors: Xiaoyun
authors: X
authors: Chen
authors: Key Laboratory of International Collaborations, Second People's Hospital of Shenzhen, First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China.
authors: Yongtian
authors: Y
authors: Lu
authors: Key Laboratory of International Collaborations, Second People's Hospital of Shenzhen, First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China.
authors: Guohui
authors: G
authors: Nie
authors: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden.|Department of Cardiovascular Sciences, University of Leicester and NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester LE3 9QP, UK.
authors: Yihai
authors: Y
authors: Cao
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D005260:Female; D006801:Humans; D007211:Indoles / Q000627:therapeutic use*; D008099:Liver / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009362:Neoplasm Metastasis / Q000473:pathology; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology*; D011758:Pyrroles / Q000627:therapeutic use*; D000077210:Sunitinib; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D020533:Angiogenesis Inhibitors; D007211:Indoles; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D000077210:Sunitinib