Vessel co-option mediates resistance to anti-angiogenic therapy in liver metastases.

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Frentzas accepted version.pdf (4.78 MB)

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ICR Authors

Bridgeman, Victoria
 Foo, Shane
 Nathan, Mark
 Daley, Frances
 Reynolds, Andrew

Authors

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

Document Type

Journal Article

Date

2016-11-01

Date Accepted

2016-09-09

Abstract

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.

Citation

Nature medicine, 2016, 22 (11), pp. 1294 - 1302

DOI

10.1038/nm.4197

URI

https://repository.icr.ac.uk/handle/internal/234

Rights

Source Title

Publisher

NATURE PUBLISHING GROUP

ISSN

1078-8956

eISSN

1546-170X

Collections

Clinical Studies
Closed Research Teams
Radiotherapy and Imaging

Research Team

Medicine (RMH Smith Cunningham)
Tumour Biology
Translational Immunotherapy

Notes