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.

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Acknowledgements

The study was supported by Breakthrough Breast Cancer (which recently merged with the Breast Cancer Campaign to form Breast Cancer Now), NHS funding to the NIHR Biomedical Research Centre at RM/ICR (London), the Liver Disease Biobank (Montreal) and De Stichting tegen Kanker (Antwerp). We thank I. Hart, K. Hodivala-Dilke, C. Isacke, R. Kerbel, A. Tutt and the members of the Liver Metastasis Research Network for their critical comments on the work. We thank Genentech for providing B20-4.1.1, S. Petrillo for assistance with the Liver Disease Biobank, J. Campbell for advice on statistical analysis and M. Balazsi for assistance with digital pathology. For their technical assistance, we thank the staff of the ICR Biological Services Unit and the staff of the Breast Cancer Now Histopathology Core Facility.

Author information

Author notes

    • Sophia Frentzas
    • , Eve Simoneau
    • , Victoria L Bridgeman
    • , Peter B Vermeulen
    •  & Shane Foo

    These authors contributed equally to this work.

    • David Cunningham
    • , Peter Metrakos
    •  & Andrew R Reynolds

    Co-senior authors.

Affiliations

  1. Tumour Biology Team, The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.

    • Sophia Frentzas
    • , Victoria L Bridgeman
    • , Peter B Vermeulen
    • , Shane Foo
    • , Eleftherios Kostaras
    • , Mark R Nathan
    • , Tracy J Berg
    •  & Andrew R Reynolds
  2. The Royal Marsden Hospital, London, UK.

    • Sophia Frentzas
    • , Andrew Wotherspoon
    • , Clare Peckitt
    • , Zak Eltahir
    • , Gina Brown
    •  & David Cunningham
  3. McGill University Health Centre, Royal Victoria Hospital–Glen Site, Montreal, Quebec, Canada.

    • Eve Simoneau
    • , Zu-hua Gao
    • , Yu Shi
    • , Ayat Salman
    • , Anthoula Lazaris
    • , Alla Khashper
    •  & Peter Metrakos
  4. Translational Cancer Research Unit, Gasthuiszusters Antwerpen Hospitals St. Augustinus, Antwerp, Belgium.

    • Peter B Vermeulen
    • , Gert Van den Eynden
    • , Hanna Nyström
    • , Steven Van Laere
    •  & Luc Dirix
  5. Breast Cancer Now Histopathology Core Facility, The Royal Marsden Hospital, London, UK.

    • Frances Daley
  6. Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA.

    • Xianming Tan
  7. Breast Cancer Now Unit, Guy's Hospital, King's College London School of Medicine, London, UK.

    • Patrycja Gazinska
  8. Cancer Genomics Center the Netherlands–Hubrecht Institute–Royal Netherlands Academy of Arts and Sciences & University Medical Centre Utrecht, Utrecht, the Netherlands.

    • Laila Ritsma
    •  & Jacco van Rheenen
  9. Department of Surgical and Perioperative Sciences, Umeå University, Umeå, Sweden.

    • Hanna Nyström
    •  & Malin Sund
  10. University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

    • Evelyne Loyer

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Contributions

S. Frentzas, E.S., V.L.B., P.B.V. and S. Foo performed experiments, collected data, analysed data, provided input on the study design and assisted with interpretation of the data; P.B.V., A.W., Z.G., Y.S. and G.V.D.E. performed histopathological analysis of tissue specimens; E.K., M.R.N., F.D., P.G., T.J.B. and Z.E. provided essential technical assistance with experiments; C.P. and X.T. performed statistical analysis on clinical data; A.S. and A.L. assisted with the retrieval of tissue specimens and the associated clinical data; L.R., J.V.R. and S.V.L. shared unpublished data that were crucial to the successful execution of the study and provided critical comments on the manuscript; A.K., G.B., E.L., H.N. and M.S. provided expert assistance with the analysis of clinical data and critical comments on the manuscript; L.D., D.C. and P.M. provided tissue specimens for the study and critical comments on the design of the study and the writing of the manuscript; A.R.R. conceived of and designed the study, supervised the research and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to David Cunningham or Peter Metrakos or Andrew R Reynolds.

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https://doi.org/10.1038/nm.4197

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