Vessel co-option mediates resistance to anti-angiogenic therapy in liver metastases.
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Date
2016-11-01Author
Frentzas, S
Simoneau, E
Bridgeman, VL
Vermeulen, PB
Foo, S
Kostaras, E
Nathan, M
Wotherspoon, A
Gao, Z-H
Shi, Y
Van den Eynden, G
Daley, F
Peckitt, C
Tan, X
Salman, A
Lazaris, A
Gazinska, P
Berg, TJ
Eltahir, Z
Ritsma, L
Van Rheenen, J
Khashper, A
Brown, G
Nystrom, H
Sund, M
Van Laere, S
Loyer, E
Dirix, L
Cunningham, D
Metrakos, P
Reynolds, AR
Type
Journal Article
Metadata
Show full item recordAbstract
The efficacy of angiogenesis inhibitors in cancer is limited by resistance mechanisms that are poorly understood. Notably, instead of through the induction of angiogenesis, tumor vascularization can occur through the nonangiogenic mechanism of vessel co-option. Here we show that vessel co-option is associated with a poor response to the anti-angiogenic agent bevacizumab in patients with colorectal cancer liver metastases. Moreover, we find that vessel co-option is also prevalent in human breast cancer liver metastases, a setting in which results with anti-angiogenic therapy have been disappointing. In preclinical mechanistic studies, we found that cancer cell motility mediated by the actin-related protein 2/3 complex (Arp2/3) is required for vessel co-option in liver metastases in vivo and that, in this setting, combined inhibition of angiogenesis and vessel co-option is more effective than the inhibition of angiogenesis alone. Vessel co-option is therefore a clinically relevant mechanism of resistance to anti-angiogenic therapy and combined inhibition of angiogenesis and vessel co-option might be a warranted therapeutic strategy.
Subject
HT29 Cells
Humans
Carcinoma
Carcinoma, Ductal, Breast
Carcinoma, Lobular
Breast Neoplasms
Colorectal Neoplasms
Liver Neoplasms
Neovascularization, Pathologic
Angiogenesis Inhibitors
Antineoplastic Combined Chemotherapy Protocols
Cell Movement
Drug Resistance, Neoplasm
Adult
Aged
Aged, 80 and over
Middle Aged
Female
Male
Actin-Related Protein 2-3 Complex
Gene Knockdown Techniques
Neoplasm Grading
Bevacizumab
Research team
Medicine (RMH Smith Cunningham)
Tumour Biology
Translational Immunotherapy
Language
eng
Date accepted
2016-09-09
License start date
2016-11
Citation
Nature medicine, 2016, 22 (11), pp. 1294 - 1302
Publisher
NATURE PUBLISHING GROUP
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