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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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.
Original languageEnglish
Article number12680
JournalNature Communications
Volume7
ISSN2041-1723
DOIs
Publication statusPublished - 2016

Cite this

Yang, Yunlong ; Zhang, Yin ; Iwamoto, Hideki ; Hosaka, Kayoko ; Seki, Takahiro ; Andersson, Patrik ; Lim, Sharon ; Fischer, Carina ; Nakamura, Masaki ; Abe, Mitsuhiko ; Skov, Peter Vilhelm ; Feng, Chang ; Chen, Xiaoyun ; Lu, Yongtian ; Nie, Guohui ; Cao, Yihai. / Discontinuation of anti-VEGF cancer therapy promotes metastasis through a liver revascularization mechanism. In: Nature Communications. 2016 ; Vol. 7.
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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.",
author = "Yunlong Yang and Yin Zhang and Hideki Iwamoto and Kayoko Hosaka and Takahiro Seki and Patrik Andersson and Sharon Lim and Carina Fischer and Masaki Nakamura and Mitsuhiko Abe and Skov, {Peter Vilhelm} and Chang Feng and Xiaoyun Chen and Yongtian Lu and Guohui Nie and Yihai Cao",
year = "2016",
doi = "10.1038/ncomms12680",
language = "English",
volume = "7",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",

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Yang, Y, Zhang, Y, Iwamoto, H, Hosaka, K, Seki, T, Andersson, P, Lim, S, Fischer, C, Nakamura, M, Abe, M, Skov, PV, Feng, C, Chen, X, Lu, Y, Nie, G & Cao, Y 2016, 'Discontinuation of anti-VEGF cancer therapy promotes metastasis through a liver revascularization mechanism', Nature Communications, vol. 7, 12680. https://doi.org/10.1038/ncomms12680

Discontinuation of anti-VEGF cancer therapy promotes metastasis through a liver revascularization mechanism. / Yang, Yunlong; Zhang, Yin; Iwamoto, Hideki; Hosaka, Kayoko; Seki, Takahiro; Andersson, Patrik; Lim, Sharon; Fischer, Carina; Nakamura, Masaki; Abe, Mitsuhiko; Skov, Peter Vilhelm; Feng, Chang; Chen, Xiaoyun; Lu, Yongtian; Nie, Guohui; Cao, Yihai.

In: Nature Communications, Vol. 7, 12680, 2016.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - Discontinuation of anti-VEGF cancer therapy promotes metastasis through a liver revascularization mechanism

AU - Yang, Yunlong

AU - Zhang, Yin

AU - Iwamoto, Hideki

AU - Hosaka, Kayoko

AU - Seki, Takahiro

AU - Andersson, Patrik

AU - Lim, Sharon

AU - Fischer, Carina

AU - Nakamura, Masaki

AU - Abe, Mitsuhiko

AU - Skov, Peter Vilhelm

AU - Feng, Chang

AU - Chen, Xiaoyun

AU - Lu, Yongtian

AU - Nie, Guohui

AU - Cao, Yihai

PY - 2016

Y1 - 2016

N2 - 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.

AB - 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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