Vessel co-option mediates resistance to anti-angiogenic therapy in liver metastases
Author(s)
Type
Journal Article
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.
Date Issued
2016-10-17
Date Acceptance
2016-09-09
Citation
Nature Medicine, 2016, 22 (11), pp.1294-1302
ISSN
1078-8956
Publisher
Nature Publishing Group
Start Page
1294
End Page
1302
Journal / Book Title
Nature Medicine
Volume
22
Issue
11
Copyright Statement
© 2016 Nature America, Inc., part of Springer Nature. All rights reserved.
Sponsor
NIHR
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000387302300022&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Grant Number
NIHR BRC Royal Marsden
Subjects
Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Cell Biology
Medicine, Research & Experimental
Research & Experimental Medicine
BEVACIZUMAB PLUS CAPECITABINE
PHASE-III TRIAL
ANTIANGIOGENIC THERAPY
COLORECTAL-CANCER
BREAST-CANCER
TUMOR INVASION
FUTURE-DIRECTIONS
BRAIN METASTASIS
VEGF ANTIBODY
GROWTH
Publication Status
Published