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

Sophia Frentzas; Eve Simoneau; Victoria L Bridgeman; Peter B Vermeulen; Shane Foo; Eleftherios Kostaras; Mark R Nathan; Andrew Wotherspoon; Zu-Hua Gao; Yu Shi; Gert Van den Eynden; Frances Daley; Clare Peckitt; Xianming Tan; Ayat Salman; Anthoula Lazaris; Patrycja Gazinska; Tracy J Berg; Zak Eltahir; Laila Ritsma; Jacco van Rheenen; Alla Khashper; Gina Brown; Hanna Nyström; Malin Sund; Steven Van Laere; Evelyne Loyer; Luc Dirix; David Cunningham; Peter Metrakos; Andrew R Reynolds

doi:10.1038/nm.4197

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

Sophia Frentzas, Eve Simoneau, Victoria L Bridgeman, Peter B Vermeulen, Shane Foo, Eleftherios Kostaras, Mark R Nathan, Andrew Wotherspoon, Zu-Hua Gao, Yu Shi, Gert Van den Eynden, Frances Daley, Clare Peckitt, Xianming Tan, Ayat Salman, Anthoula Lazaris, Patrycja Gazinska, Tracy J Berg, Zak Eltahir, Laila RitsmaJacco van Rheenen, Alla Khashper, Gina Brown, Hanna Nyström, Malin Sund, Steven Van Laere, Evelyne Loyer, Luc Dirix, David Cunningham, Peter Metrakos, Andrew R Reynolds

Hubrecht Institute

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

351 Citations (Scopus)

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.

Original language	English
Pages (from-to)	1294-1302
Number of pages	9
Journal	Nature Medicine
Volume	22
Issue number	11
DOIs	https://doi.org/10.1038/nm.4197
Publication status	Published - Nov 2016

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Frentzas, S., Simoneau, E., Bridgeman, V. L., Vermeulen, P. B., Foo, S., Kostaras, E., Nathan, M. R., Wotherspoon, A., Gao, Z.-H., Shi, Y., Van den Eynden, G., Daley, F., Peckitt, C., Tan, X., Salman, A., Lazaris, A., Gazinska, P., Berg, T. J., Eltahir, Z., ... Reynolds, A. R. (2016). Vessel co-option mediates resistance to anti-angiogenic therapy in liver metastases. Nature Medicine, 22(11), 1294-1302. https://doi.org/10.1038/nm.4197

@article{efd0512ecdf34dcd96cda6bf92edca16,

title = "Vessel co-option mediates resistance to anti-angiogenic therapy in liver metastases",

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.",

author = "Sophia Frentzas and Eve Simoneau and Bridgeman, {Victoria L} and Vermeulen, {Peter B} and Shane Foo and Eleftherios Kostaras and Nathan, {Mark R} and Andrew Wotherspoon and Zu-Hua Gao and Yu Shi and {Van den Eynden}, Gert and Frances Daley and Clare Peckitt and Xianming Tan and Ayat Salman and Anthoula Lazaris and Patrycja Gazinska and Berg, {Tracy J} and Zak Eltahir and Laila Ritsma and {van Rheenen}, Jacco and Alla Khashper and Gina Brown and Hanna Nystr{\"o}m and Malin Sund and {Van Laere}, Steven and Evelyne Loyer and Luc Dirix and David Cunningham and Peter Metrakos and Reynolds, {Andrew R}",

year = "2016",

month = nov,

doi = "10.1038/nm.4197",

language = "English",

volume = "22",

pages = "1294--1302",

journal = "Nature Medicine",

issn = "1078-8956",

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Frentzas, S, Simoneau, E, Bridgeman, VL, Vermeulen, PB, Foo, S, Kostaras, E, Nathan, MR, 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, Nyström, H, Sund, M, Van Laere, S, Loyer, E, Dirix, L, Cunningham, D, Metrakos, P & Reynolds, AR 2016, 'Vessel co-option mediates resistance to anti-angiogenic therapy in liver metastases', Nature Medicine, vol. 22, no. 11, pp. 1294-1302. https://doi.org/10.1038/nm.4197

TY - JOUR

T1 - Vessel co-option mediates resistance to anti-angiogenic therapy in liver metastases

AU - Frentzas, Sophia

AU - Simoneau, Eve

AU - Bridgeman, Victoria L

AU - Vermeulen, Peter B

AU - Foo, Shane

AU - Kostaras, Eleftherios

AU - Nathan, Mark R

AU - Wotherspoon, Andrew

AU - Gao, Zu-Hua

AU - Shi, Yu

AU - Van den Eynden, Gert

AU - Daley, Frances

AU - Peckitt, Clare

AU - Tan, Xianming

AU - Salman, Ayat

AU - Lazaris, Anthoula

AU - Gazinska, Patrycja

AU - Berg, Tracy J

AU - Eltahir, Zak

AU - Ritsma, Laila

AU - van Rheenen, Jacco

AU - Khashper, Alla

AU - Brown, Gina

AU - Nyström, Hanna

AU - Sund, Malin

AU - Van Laere, Steven

AU - Loyer, Evelyne

AU - Dirix, Luc

AU - Cunningham, David

AU - Metrakos, Peter

AU - Reynolds, Andrew R

PY - 2016/11

Y1 - 2016/11

N2 - 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.

AB - 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.

U2 - 10.1038/nm.4197

DO - 10.1038/nm.4197

M3 - Article

C2 - 27748747

SN - 1078-8956

VL - 22

SP - 1294

EP - 1302

JO - Nature Medicine

JF - Nature Medicine

IS - 11

ER -

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

Abstract

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