Discontinuation of anti-VEGF cancer therapy promotes metastasis through a liver revascularization mechanism.
Yunlong YangYin ZhangHideki IwamotoKayoko HosakaTakahiro SekiPatrik AnderssonSharon LimCarina FischerMasaki NakamuraMitsuhiko AbeRenhai CaoPeter Vilhelm SkovFang ChenXiaoyun ChenYongtian LuGuohui NieYihai CaoPublished in: Nature communications (2016)
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.
Keyphrases
- vascular endothelial growth factor
- endothelial cells
- drug induced
- liver injury
- cancer therapy
- high glucose
- papillary thyroid
- drug delivery
- adverse drug
- stem cells
- coronary artery bypass grafting
- intellectual disability
- autism spectrum disorder
- renal cell carcinoma
- venous thromboembolism
- childhood cancer
- direct oral anticoagulants
- induced pluripotent stem cells