Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Correlation between HGP and pathological response in patients treated pre-operatively with bevacizumab.
Figure 2: Liver metastasis HGP correlates with morphological responses on CT in patients treated pre-operatively with bevacizumab.
Figure 3: Cancer cells infiltrate the hepatic plates and co-opt sinusoidal blood vessels in the replacement HGP.
Figure 4: The replacement HGP occurs in progressive disease and is associated with a poor outcome in patients treated with bevacizumab.
Figure 5: The replacement HGP predominates in breast cancer liver metastases.
Figure 6: Inhibition of vessel co-option and angiogenesis is more effective than targeting angiogenesis alone.

References

  1. Ferrara, N., Hillan, K.J., Gerber, H.P. & Novotny, W. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat. Rev. Drug Discov. 3, 391–400 (2004).

    Article  CAS  PubMed  Google Scholar 

  2. Kerbel, R.S. Tumor angiogenesis. N. Engl. J. Med. 358, 2039–2049 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Hurwitz, H. et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N. Engl. J. Med. 350, 2335–2342 (2004).

    Article  CAS  PubMed  Google Scholar 

  4. Cunningham, D. et al. Bevacizumab plus capecitabine versus capecitabine alone in elderly patients with previously untreated metastatic colorectal cancer (AVEX): an open-label, randomised phase 3 trial. Lancet Oncol. 14, 1077–1085 (2013).

    Article  CAS  PubMed  Google Scholar 

  5. Ebos, J.M. & Kerbel, R.S. Antiangiogenic therapy: impact on invasion, disease progression, and metastasis. Nat. Rev. Clin. Oncol. 8, 210–221 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Vasudev, N.S. & Reynolds, A.R. Anti-angiogenic therapy for cancer: current progress, unresolved questions and future directions. Angiogenesis 17, 471–494 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Pezzella, F. et al. Angiogenesis in primary lung cancer and lung secondaries. Eur. J. Cancer 32A, 2494–2500 (1996).

    Article  CAS  PubMed  Google Scholar 

  8. Vermeulen, P.B. et al. Liver metastases from colorectal adenocarcinomas grow in three patterns with different angiogenesis and desmoplasia. J. Pathol. 195, 336–342 (2001).

    Article  CAS  PubMed  Google Scholar 

  9. Döme, B., Hendrix, M.J., Paku, S., Tóvári, J. & Tímár, J. Alternative vascularization mechanisms in cancer: Pathology and therapeutic implications. Am. J. Pathol. 170, 1–15 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Donnem, T. et al. Vessel co-option in primary human tumors and metastases: an obstacle to effective anti-angiogenic treatment? Cancer Med. 2, 427–436 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Jayson, G.C., Kerbel, R., Ellis, L.M. & Harris, A.L. Antiangiogenic therapy in oncology: current status and future directions. Lancet 388, 518–529 (2016).

    Article  CAS  PubMed  Google Scholar 

  12. Adams, R.B. et al. Selection for hepatic resection of colorectal liver metastases: expert consensus statement. HPB (Oxford) 15, 91–103 (2013).

    Article  PubMed Central  Google Scholar 

  13. Van den Eynden, G.G. et al. The multifaceted role of the microenvironment in liver metastasis: biology and clinical implications. Cancer Res. 73, 2031–2043 (2013).

    Article  CAS  PubMed  Google Scholar 

  14. Stessels, F. et al. Breast adenocarcinoma liver metastases, in contrast to colorectal cancer liver metastases, display a non-angiogenic growth pattern that preserves the stroma and lacks hypoxia. Br. J. Cancer 90, 1429–1436 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Gruenberger, B. et al. Bevacizumab, capecitabine, and oxaliplatin as neoadjuvant therapy for patients with potentially curable metastatic colorectal cancer. J. Clin. Oncol. 26, 1830–1835 (2008).

    Article  CAS  PubMed  Google Scholar 

  16. Chaudhury, P. et al. Perioperative chemotherapy with bevacizumab and liver resection for colorectal cancer liver metastasis. HPB 12, 37–42 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Wong, R. et al. A multicentre study of capecitabine, oxaliplatin plus bevacizumab as perioperative treatment of patients with poor-risk colorectal liver-only metastases not selected for upfront resection. Ann. Oncol. 22, 2042–2048 (2011).

    Article  CAS  PubMed  Google Scholar 

  18. Chun, Y.S. et al. Association of computed tomography morphologic criteria with pathologic response and survival in patients treated with bevacizumab for colorectal liver metastases. J. Am. Med. Assoc. 302, 2338–2344 (2009).

    Article  CAS  Google Scholar 

  19. Shindoh, J. et al. Optimal morphologic response to preoperative chemotherapy: an alternate outcome end point before resection of hepatic colorectal metastases. J. Clin. Oncol. 30, 4566–4572 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Boonsirikamchai, P. et al. CT findings of response and recurrence, independent of change in tumor size, in colorectal liver metastasis treated with bevacizumab. AJR Am. J. Roentgenol. 197, W1060–W1066 (2011).

    Article  PubMed  Google Scholar 

  21. Van den Eynden, G.G. et al. The histological growth pattern of colorectal cancer liver metastases has prognostic value. Clin. Exp. Metastasis 29, 541–549 (2012).

    Article  CAS  PubMed  Google Scholar 

  22. Nürnberg, A., Kitzing, T. & Grosse, R. Nucleating actin for invasion. Nat. Rev. Cancer 11, 177–187 (2011).

    Article  PubMed  CAS  Google Scholar 

  23. Otsubo, T. et al. Involvement of Arp2/3 complex in the process of colorectal carcinogenesis. Mod. Pathol. 17, 461–467 (2004).

    Article  CAS  PubMed  Google Scholar 

  24. Iwaya, K. et al. Correlation between liver metastasis of the colocalization of actin-related protein 2 and 3 complex and WAVE2 in colorectal carcinoma. Cancer Sci. 98, 992–999 (2007).

    Article  CAS  PubMed  Google Scholar 

  25. Kopetz, S. et al. Synergistic activity of the SRC family kinase inhibitor dasatinib and oxaliplatin in colon carcinoma cells is mediated by oxidative stress. Cancer Res. 69, 3842–3849 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Nyati, M.K. et al. The potential of 5-fluorocytosine/cytosine deaminase enzyme prodrug gene therapy in an intrahepatic colon cancer model. Gene Ther. 9, 844–849 (2002).

    Article  CAS  PubMed  Google Scholar 

  27. Gray, M.J. et al. Therapeutic targeting of Id2 reduces growth of human colorectal carcinoma in the murine liver. Oncogene 27, 7192–7200 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Liang, W.C. et al. Cross-species vascular endothelial growth factor (VEGF)-blocking antibodies completely inhibit the growth of human tumor xenografts and measure the contribution of stromal VEGF. J. Biol. Chem. 281, 951–961 (2006).

    Article  CAS  PubMed  Google Scholar 

  29. Miller, K.D. et al. Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J. Clin. Oncol. 23, 792–799 (2005).

    Article  CAS  PubMed  Google Scholar 

  30. Miller, K. et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N. Engl. J. Med. 357, 2666–2676 (2007).

    Article  CAS  PubMed  Google Scholar 

  31. Miles, D.W. et al. Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J. Clin. Oncol. 28, 3239–3247 (2010).

    Article  CAS  PubMed  Google Scholar 

  32. Robert, N.J. et al. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J. Clin. Oncol. 29, 1252–1260 (2011).

    Article  CAS  PubMed  Google Scholar 

  33. Brufsky, A.M. et al. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J. Clin. Oncol. 29, 4286–4293 (2011).

    Article  CAS  PubMed  Google Scholar 

  34. Naresh, K.N., Nerurkar, A.Y. & Borges, A.M. Angiogenesis is redundant for tumour growth in lymph node metastases. Histopathology 38, 466–470 (2001).

    Article  CAS  PubMed  Google Scholar 

  35. Jeong, H.S. et al. Investigation of the lack of angiogenesis in the formation of lymph node metastases. J. Natl. Cancer Inst. 107, djv155 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Colpaert, C.G. et al. Cutaneous breast cancer deposits show distinct growth patterns with different degrees of angiogenesis, hypoxia and fibrin deposition. Histopathology 42, 530–540 (2003).

    Article  CAS  PubMed  Google Scholar 

  37. Breast Cancer Progression Working Party. Evidence for novel nonangiogenic pathway in breast-cancer metastasis. Lancet 355, 1787–1788 (2000).

  38. Szabo, V. et al. Mechanism of tumour vascularization in experimental lung metastases. J. Pathol. 235, 384–396 (2015).

    Article  CAS  PubMed  Google Scholar 

  39. Carbonell, W.S., Ansorge, O., Sibson, N. & Muschel, R. The vascular basement membrane as “soil” in brain metastasis. PLoS One 4, e5857 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Bugyik, E. et al. Lack of angiogenesis in experimental brain metastases. J. Neuropathol. Exp. Neurol. 70, 979–991 (2011).

    Article  PubMed  Google Scholar 

  41. Valiente, M. et al. Serpins promote cancer cell survival and vascular co-option in brain metastasis. Cell 156, 1002–1016 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Jain, R.K. et al. Biomarkers of response and resistance to antiangiogenic therapy. Nat. Rev. Clin. Oncol. 6, 327–338 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Semelka, R.C., Hussain, S.M., Marcos, H.B. & Woosley, J.T. Perilesional enhancement of hepatic metastases: correlation between MR imaging and histopathologic findings-initial observations. Radiology 215, 89–94 (2000).

    Article  CAS  PubMed  Google Scholar 

  44. Kuczynski, E.A. et al. Co-option of liver vessels and not sprouting angiogenesis drives acquired sorafenib resistance in hepatocellular carcinoma. J. Natl. Cancer Inst. 108, djw030 (2016).

    Article  PubMed Central  CAS  Google Scholar 

  45. Rubenstein, J.L. et al. Anti-VEGF antibody treatment of glioblastoma prolongs survival but results in increased vascular cooption. Neoplasia 2, 306–314 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Küsters, B. et al. Vascular endothelial growth factor-A(165) induces progression of melanoma brain metastases without induction of sprouting angiogenesis. Cancer Res. 62, 341–345 (2002).

    PubMed  Google Scholar 

  47. Leenders, W.P. et al. Antiangiogenic therapy of cerebral melanoma metastases results in sustained tumor progression via vessel co-option. Clin. Cancer Res. 10, 6222–6230 (2004).

    Article  CAS  PubMed  Google Scholar 

  48. Pàez-Ribes, M. et al. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 15, 220–231 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. de Groot, J.F. et al. Tumor invasion after treatment of glioblastoma with bevacizumab: radiographic and pathologic correlation in humans and mice. Neuro-oncol. 12, 233–242 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Lu, K.V. et al. VEGF inhibits tumor cell invasion and mesenchymal transition through a MET/VEGFR2 complex. Cancer Cell 22, 21–35 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Sennino, B. et al. Suppression of tumor invasion and metastasis by concurrent inhibition of c-Met and VEGF signaling in pancreatic neuroendocrine tumors. Cancer Discov. 2, 270–287 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Depner, C. et al. EphrinB2 repression through ZEB2 mediates tumour invasion and anti-angiogenic resistance. Nat. Commun. 7, 12329 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Bland, J.M. & Altman, D.G. Statistical methods for assessing agreement between two methods of clinical measurement. Lancet 1, 307–310 (1986).

    Article  CAS  PubMed  Google Scholar 

  54. Ribero, D. et al. Bevacizumab improves pathologic response and protects against hepatic injury in patients treated with oxaliplatin-based chemotherapy for colorectal liver metastases. Cancer 110, 2761–2767 (2007).

    Article  PubMed  Google Scholar 

  55. Chang, H.H., Leeper, W.R., Chan, G., Quan, D. & Driman, D.K. Infarct-like necrosis: a distinct form of necrosis seen in colorectal carcinoma liver metastases treated with perioperative chemotherapy. Am. J. Surg. Pathol. 36, 570–576 (2012).

    Article  PubMed  Google Scholar 

  56. Goldhirsch, A. et al. Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013. Ann. Oncol. 24, 2206–2223 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Hammond, M.E. et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer (unabridged version). Arch. Pathol. Lab. Med. 134, e48–e72 (2010).

    Article  CAS  PubMed  Google Scholar 

  58. Wolff, A.C. et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J. Clin. Oncol. 31, 3997–4013 (2013).

    Article  PubMed  Google Scholar 

  59. Gourlaouen, M., Welti, J.C., Vasudev, N.S. & Reynolds, A.R. Essential role for endocytosis in the growth factor-stimulated activation of ERK1/2 in endothelial cells. J. Biol. Chem. 288, 7467–7480 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Grambsch, P.M. & Therneau, T.M. Proportional hazards tests and diagnostics based on weighted residuals. Biometrika 81, 515–526 (1994).

    Article  Google Scholar 

Download references

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

Authors and Affiliations

Authors

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.

Corresponding authors

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

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text, Figures and Tables

Supplementary Figures 1–17 and Supplementary Tables 1–13 (PDF 4133 kb)

Source data

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Frentzas, S., Simoneau, E., Bridgeman, V. et al. Vessel co-option mediates resistance to anti-angiogenic therapy in liver metastases. Nat Med 22, 1294–1302 (2016). https://doi.org/10.1038/nm.4197

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

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

This article is cited by

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer