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.

  • Opinion
  • Published:

Controlling escape from angiogenesis inhibitors

Abstract

Selective inhibition of vascular endothelial growth factor (VEGF) increases the efficacy of chemotherapy and has beneficial effects on multiple advanced cancers, but response is often limited and the disease eventually progresses. Changes in the tumour microenvironment — hypoxia among them — that result from vascular pruning, suppressed angiogenesis and other consequences of VEGF inhibition can promote escape and tumour progression. New therapeutic approaches that target pathways that are involved in the escape mechanisms add the benefits of blocking tumour progression to those of slowing tumour growth by inhibiting angiogenesis.

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

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Overcoming resistance to inhibitors of VEGF signalling by blocking angiogenesis and tumour progression.
Figure 2: Reversal of tumour progression.

Similar content being viewed by others

References

  1. Ferrara, N. & Kerbel, R. S. Angiogenesis as a therapeutic target. Nature 438, 967–974 (2005).

    Article  CAS  PubMed  Google Scholar 

  2. Ferrara, N., Mass, R. D., Campa, C. & Kim, R. Targeting VEGF-A to treat cancer and age-related macular degeneration. Annu. Rev. Med. 58, 491–504 (2007).

    Article  CAS  PubMed  Google Scholar 

  3. Ellis, L. M. & Hicklin, D. J. VEGF-targeted therapy: mechanisms of anti-tumour activity. Nature Rev. Cancer 8, 579–591 (2008).

    Article  CAS  Google Scholar 

  4. Inai, T. et al. Inhibition of vascular endothelial growth factor (VEGF) signaling in cancer causes loss of endothelial fenestrations, regression of tumor vessels, and appearance of basement membrane ghosts. Am. J. Pathol. 165, 35–52 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Jain, R. K. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307, 58–62 (2005).

    Article  CAS  PubMed  Google Scholar 

  6. Gerber, H. P. & Ferrara, N. Pharmacology and pharmacodynamics of bevacizumab as monotherapy or in combination with cytotoxic therapy in preclinical studies. Cancer Res. 65, 671–680 (2005).

    CAS  PubMed  Google Scholar 

  7. Bagri, A. et al. Effects of anti-VEGF treatment duration on tumor growth, tumor regrowth, and treatment efficacy. Clin. Cancer Res. 16, 3887–3900 (2010).

    Article  CAS  PubMed  Google Scholar 

  8. Verma, S. et al. In the end what matters most? A review of clinical endpoints in advanced breast cancer. Oncologist 16, 25–35 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  Google Scholar 

  10. Strickler, J. H. & Hurwitz, H. I. Bevacizumab-based therapies in the first-line treatment of metastatic colorectal cancer. Oncologist 17, 513–524 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Zhong, H. & Bowen, J. P. Recent advances in small molecule inhibitors of VEGFR and EGFR signaling pathways. Curr. Top. Med. Chem. 11, 1571–1590 (2011).

    Article  CAS  PubMed  Google Scholar 

  12. Bhargava, P. & Robinson, M. O. Development of second-generation VEGFR tyrosine kinase inhibitors: current status. Curr. Oncol. Rep. 13, 103–111 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Benjamin, D., Colombi, M., Moroni, C. & Hall, M. N. Rapamycin passes the torch: a new generation of mTOR inhibitors. Nature Rev. Drug Discov. 10, 868–880 (2012).

    Article  CAS  Google Scholar 

  14. Zaytseva, Y. Y., Valentino, J. D., Gulhati, P. & Evers, B. M. mTOR inhibitors in cancer therapy. Cancer Lett. 319, 1–7 (2012).

    Article  CAS  PubMed  Google Scholar 

  15. Falcon, B. L. et al. Reduced VEGF production, angiogenesis, and vascular regrowth contribute to the antitumor properties of dual mTORC1/mTORC2 inhibitors. Cancer Res. 71, 1573–1583 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Bhagwat, S. V. et al. Preclinical characterization of OSI-027, a potent and selective inhibitor of mTORC1 and mTORC2: distinct from rapamycin. Mol. Cancer Ther. 10, 1394–1406 (2011).

    Article  CAS  PubMed  Google Scholar 

  17. Chiu, C. W., Nozawa, H. & Hanahan, D. Survival benefit with proapoptotic molecular and pathologic responses from dual targeting of mammalian target of rapamycin and epidermal growth factor receptor in a preclinical model of pancreatic neuroendocrine carcinogenesis. J. Clin. Oncol. 28, 4425–4433 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. 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 

  19. Gray, R., Bhattacharya, S., Bowden, C., Miller, K. & Comis, R. L. Independent review of E2100: a phase III trial of bevacizumab plus paclitaxel versus paclitaxel in women with metastatic breast cancer. J. Clin. Oncol. 27, 4966–4972 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. 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 

  21. 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 

  22. Lohmann, A. E. & Chia, S. Patients with metastatic breast cancer using bevacizumab as a treatment: is there still a role for it? Curr. Treat. Options Oncol. 13, 249–262 (2012).

    Article  PubMed  Google Scholar 

  23. Dowlati, A., Gray, R., Sandler, A. B., Schiller, J. H. & Johnson, D. H. Cell adhesion molecules, vascular endothelial growth factor, and basic fibroblast growth factor in patients with non-small cell lung cancer treated with chemotherapy with or without bevacizumab-an Eastern Cooperative Oncology Group Study. Clin. Cancer Res. 14, 1407–1412 (2008).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  25. Loges, S., Schmidt, T. & Carmeliet, P. Mechanisms of resistance to anti-angiogenic therapy and development of third-generation anti-angiogenic drug candidates. Genes Cancer 1, 12–25 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Duda, D. G., Ancukiewicz, M. & Jain, R. K. Biomarkers of antiangiogenic therapy: how do we move from candidate biomarkers to valid biomarkers? J. Clin. Oncol. 28, 183–185 (2010).

    Article  CAS  PubMed  Google Scholar 

  27. Jubb, A. M. & Harris, A. L. Biomarkers to predict the clinical efficacy of bevacizumab in cancer. Lancet Oncol. 11, 1172–1183 (2010).

    Article  CAS  PubMed  Google Scholar 

  28. Van Cutsem, E. et al. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a biomarker evaluation from the AVAGAST randomized phase III trial. J. Clin. Oncol. 30, 2119–2127 (2012).

    Article  CAS  PubMed  Google Scholar 

  29. Lambrechts, D. et al. VEGF pathway genetic variants as biomarkers of treatment outcome with bevacizumab: an analysis of data from the AViTA and AVOREN randomised trials. Lancet Oncol. 13, 724–733 (2012).

    Article  CAS  PubMed  Google Scholar 

  30. De Bock, K., Mazzone, M. & Carmeliet, P. Antiangiogenic therapy, hypoxia, and metastasis: risky liaisons, or not? Nature Rev. Clin. Oncol. 8, 393–404 (2011).

    Article  CAS  Google Scholar 

  31. Bergers, G. & Hanahan, D. Modes of resistance to anti-angiogenic therapy. Nature Rev. Cancer 8, 592–603 (2008).

    Article  CAS  Google Scholar 

  32. Arao, T. et al. Acquired drug resistance to vascular endothelial growth factor receptor 2 tyrosine kinase inhibitor in human vascular endothelial cells. Anticancer Res. 31, 2787–2796 (2011).

    CAS  PubMed  Google Scholar 

  33. Sitohy, B., Nagy, J. A., Jaminet, S. C. & Dvorak, H. F. Tumor-surrogate blood vessel subtypes exhibit differential susceptibility to anti-VEGF therapy. Cancer Res. 71, 7021–7028 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Arrondeau, J. et al. Sorafenib exposure decreases over time in patients with hepatocellular carcinoma. Invest. New Drugs 30, 2046–2049 (2012).

    Article  CAS  PubMed  Google Scholar 

  35. Gotink, K. J. et al. Lysosomal sequestration of sunitinib: a novel mechanism of drug resistance. Clin. Cancer Res. 17, 7337–7346 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Bocci, G. & Loupakis, F. The possible role of chemotherapy in antiangiogenic drug resistance. Med. Hypotheses 78, 646–648 (2012).

    Article  CAS  PubMed  Google Scholar 

  37. Grothey, A. et al. Bevacizumab beyond first progression is associated with prolonged overall survival in metastatic colorectal cancer: results from a large observational cohort study (BRiTE). J. Clin. Oncol. 26, 5326–5334 (2008).

    Article  CAS  PubMed  Google Scholar 

  38. Cartwright, T. H. et al. Survival outcomes of bevacizumab beyond progression in metastatic colorectal cancer patients treated in US community oncology. Clin Colorectal Cancer 1 Jun 2012 (doi:10.1016/j.clcc.2012.05.005).

  39. Chaffer, C. L. & Weinberg, R. A. A perspective on cancer cell metastasis. Science 331, 1559–1564 (2011).

    Article  CAS  PubMed  Google Scholar 

  40. Kerbel, R. S. Reappraising antiangiogenic therapy for breast cancer. Breast 20, S56–S60 (2011).

    Article  PubMed  Google Scholar 

  41. Macedo, L. T., da Costa Lima, A. B. & Sasse, A. D. Addition of bevacizumab to first-line chemotherapy in advanced colorectal cancer: a systematic review and meta-analysis, with emphasis on chemotherapy subgroups. BMC Cancer 12, 89 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Gaya, A. & Tse, V. A preclinical and clinical review of aflibercept for the management of cancer. Cancer Treat. Rev. 38, 484–493 (2012).

    Article  CAS  PubMed  Google Scholar 

  43. Hanahan, D., Bergers, G. & Bergsland, E. Less is more, regularly: metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice. J. Clin. Invest. 105, 1045–1047 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Kerbel, R. S. Improving conventional or low dose metronomic chemotherapy with targeted antiangiogenic drugs. Cancer Res. Treat. 39, 150–159 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Montagna, E. et al. Metronomic chemotherapy combined with bevacizumab and erlotinib in patients with metastatic HER2-negative breast cancer: clinical and biological activity. Clin. Breast Cancer 12, 207–214 (2012).

    Article  CAS  PubMed  Google Scholar 

  46. Lee, K. et al. Anthracycline chemotherapy inhibits HIF-1 transcriptional activity and tumor-induced mobilization of circulating angiogenic cells. Proc. Natl Acad. Sci. USA 106, 2353–2358 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Rapisarda, A. et al. Increased antitumor activity of bevacizumab in combination with hypoxia inducible factor-1 inhibition. Mol. Cancer Ther. 8, 1867–1877 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Hashimoto, K. et al. Potent preclinical impact of metronomic low-dose oral topotecan combined with the antiangiogenic drug pazopanib for the treatment of ovarian cancer. Mol. Cancer Ther. 9, 996–1006 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Schmitt, J. M. et al. Sunitinib plus paclitaxel in patients with advanced esophageal cancer: a phase II study from the Hoosier Oncology Group. J. Thorac Oncol. 7, 760–763 (2012).

    Article  CAS  PubMed  Google Scholar 

  50. Heath, E. I. et al. Sunitinib in combination with paclitaxel plus carboplatin in patients with advanced solid tumors: phase I study results. Cancer Chemother. Pharmacol. 68, 703–712 (2011).

    Article  CAS  PubMed  Google Scholar 

  51. Kindler, H. L. et al. Gemcitabine plus sorafenib in patients with advanced pancreatic cancer: a phase II trial of the University of Chicago Phase II Consortium. Invest. New Drugs 30, 382–386 (2012).

    Article  CAS  PubMed  Google Scholar 

  52. Goncalves, A. et al. BAYPAN study: a double-blind phase III randomized trial comparing gemcitabine plus sorafenib and gemcitabine plus placebo in patients with advanced pancreatic cancer. Ann. Oncol. 5 Jul 2012 (doi:10.1093/annonc/mds135).

  53. Bergh, J. et al. First-line treatment of advanced breast cancer with sunitinib in combination with docetaxel versus docetaxel alone: results of a prospective, randomized phase III study. J. Clin. Oncol. 30, 921–929 (2012).

    Article  CAS  PubMed  Google Scholar 

  54. Rugo, H. S. et al. Randomized, placebo-controlled, double-blind, phase II study of axitinib plus docetaxel versus docetaxel plus placebo in patients with metastatic breast cancer. J. Clin. Oncol. 29, 2459–2465 (2011).

    Article  CAS  PubMed  Google Scholar 

  55. Casanovas, O., Hicklin, D. J., Bergers, G. & Hanahan, D. Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell 8, 299–309 (2005).

    Article  CAS  PubMed  Google Scholar 

  56. Huang, J. et al. Angiopoietin-1/Tie-2 activation contributes to vascular survival and tumor growth during VEGF blockade. Int. J. Oncol. 34, 79–87 (2009).

    CAS  PubMed  Google Scholar 

  57. Alessi, P. et al. Anti-FGF2 approaches as a strategy to compensate resistance to anti-VEGF therapy: long-pentraxin 3 as a novel antiangiogenic FGF2-antagonist. Eur. Cytokine Netw. 20, 225–234 (2009).

    CAS  PubMed  Google Scholar 

  58. Saharinen, P., Eklund, L., Pulkki, K., Bono, P. & Alitalo, K. VEGF and angiopoietin signaling in tumor angiogenesis and metastasis. Trends Mol. Med. 17, 347–362 (2011).

    Article  CAS  PubMed  Google Scholar 

  59. Rolny, C. et al. HRG inhibits tumor growth and metastasis by inducing macrophage polarization and vessel normalization through downregulation of PlGF. Cancer Cell 19, 31–44 (2011).

    Article  CAS  PubMed  Google Scholar 

  60. Saylor, P. J., Escudier, B. & Michaelson, M. D. Importance of fibroblast growth factor receptor in neovascularization and tumor escape from antiangiogenic therapy. Clin. Genitourin. Cancer 10, 77–83 (2012).

    Article  PubMed  Google Scholar 

  61. Tammela, T. et al. Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation. Nature 454, 656–660 (2008).

    Article  CAS  PubMed  Google Scholar 

  62. Sallinen, H. et al. Antiangiogenic gene therapy with soluble VEGFR-1, -2, and -3 reduces the growth of solid human ovarian carcinoma in mice. Mol. Ther. 17, 278–284 (2009).

    Article  CAS  PubMed  Google Scholar 

  63. Gordon, M. S. Antiangiogenic therapies: is VEGF-A inhibition alone enough? Expert Rev. Anticancer Ther. 11, 485–496 (2011).

    Article  CAS  PubMed  Google Scholar 

  64. Ribatti, D. Endogenous inhibitors of angiogenesis: a historical review. Leuk. Res. 33, 638–644 (2009).

    Article  CAS  PubMed  Google Scholar 

  65. Abdollahi, A. & Folkman, J. Evading tumor evasion: current concepts and perspectives of anti-angiogenic cancer therapy. Drug Resist. Updat. 13, 16–28 (2010).

    Article  CAS  PubMed  Google Scholar 

  66. Carmeliet, P. & Jain, R. K. Molecular mechanisms and clinical applications of angiogenesis. Nature 473, 298–307 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Fischer, C., Mazzone, M., Jonckx, B. & Carmeliet, P. FLT1 and its ligands VEGFB and PlGF: drug targets for anti-angiogenic therapy? Nature Rev. Cancer 8, 942–956 (2008).

    Article  CAS  Google Scholar 

  68. Hashizume, H. et al. Complementary actions of inhibitors of angiopoietin-2 and VEGF on tumor angiogenesis and growth. Cancer Res. 70, 2213–2223 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Fischer, C. et al. Anti-PlGF inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels. Cell 131, 463–475 (2007).

    Article  CAS  PubMed  Google Scholar 

  70. Van de Veire, S. et al. Further pharmacological and genetic evidence for the efficacy of PlGF inhibition in cancer and eye disease. Cell 141, 178–190 (2010).

    Article  CAS  PubMed  Google Scholar 

  71. Bais, C. et al. PlGF blockade does not inhibit angiogenesis during primary tumor growth. Cell 141, 166–177 (2010).

    Article  CAS  PubMed  Google Scholar 

  72. Willett, C. G. et al. Surrogate markers for antiangiogenic therapy and dose-limiting toxicities for bevacizumab with radiation and chemotherapy: continued experience of a phase I trial in rectal cancer patients. J. Clin. Oncol. 23, 8136–8139 (2005).

    Article  PubMed  Google Scholar 

  73. Rini, B. I. et al. Antitumor activity and biomarker analysis of sunitinib in patients with bevacizumab-refractory metastatic renal cell carcinoma. J. Clin. Oncol. 26, 3743–3748 (2008).

    Article  CAS  PubMed  Google Scholar 

  74. Batchelor, T. T. et al. AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 11, 83–95 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Bagley, R. G. et al. Placental growth factor upregulation is a host response to antiangiogenic therapy. Clin. Cancer Res. 17, 976–988 (2011).

    Article  CAS  PubMed  Google Scholar 

  76. Tong, R. T. et al. Vascular normalization by vascular endothelial growth factor receptor 2 blockade induces a pressure gradient across the vasculature and improves drug penetration in tumors. Cancer Res. 64, 3731–3736 (2004).

    Article  CAS  PubMed  Google Scholar 

  77. Dickson, P. V. et al. Bevacizumab-induced transient remodeling of the vasculature in neuroblastoma xenografts results in improved delivery and efficacy of systemically administered chemotherapy. Clin. Cancer Res. 13, 3942–3950 (2007).

    Article  CAS  PubMed  Google Scholar 

  78. Zhou, Q. & Gallo, J. M. Differential effect of sunitinib on the distribution of temozolomide in an orthotopic glioma model. Neuro Oncol. 11, 301–310 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Vangestel, C. et al. 99mTc-(CO)3 His-annexin A5 micro-SPECT demonstrates increased cell death by irinotecan during the vascular normalization window caused by bevacizumab. J. Nucl. Med. 52, 1786–1794 (2011).

    Article  CAS  PubMed  Google Scholar 

  80. Zhang, Q. et al. Time-course imaging of therapeutic functional tumor vascular normalization by antiangiogenic agents. Mol. Cancer Ther. 10, 1173–1184 (2011).

    Article  CAS  PubMed  Google Scholar 

  81. Turley, R. S. et al. Bevacizumab-induced alterations in vascular permeability and drug delivery: a novel approach to augment regional chemotherapy for in-transit melanoma. Clin. Cancer Res. 18, 3328–3339 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Chauhan, V. P. et al. Normalization of tumour blood vessels improves the delivery of nanomedicines in a size-dependent manner. Nature Nanotechnol. 7, 383–388 (2012).

    Article  CAS  Google Scholar 

  83. Willett, C. G. et al. Combined vascular endothelial growth factor-targeted therapy and radiotherapy for rectal cancer: theory and clinical practice. Semin. Oncol. 33, S35–S40 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Hoang, T., Huang, S., Armstrong, E., Eickhoff, J. C. & Harari, P. M. Enhancement of radiation response with bevacizumab. J. Exp. Clin. Cancer Res. 31, 37 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Willett, C. G. et al. Efficacy, safety, and biomarkers of neoadjuvant bevacizumab, radiation therapy, and fluorouracil in rectal cancer: a multidisciplinary phase II study. J. Clin. Oncol. 27, 3020–3026 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Sennino, B. et al. Sequential loss of tumor vessel pericytes and endothelial cells after inhibition of platelet-derived growth factor B by selective aptamer AX102. Cancer Res. 67, 7358–7367 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Helfrich, I. et al. Resistance to antiangiogenic therapy is directed by vascular phenotype, vessel stabilization, and maturation in malignant melanoma. J. Exp. Med. 207, 491–503 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Nakahara, T., Norberg, S. M., Shalinsky, D. R., Hu-Lowe, D. D. & McDonald, D. M. Effect of inhibition of vascular endothelial growth factor signaling on distribution of extravasated antibodies in tumors. Cancer Res. 66, 1434–1445 (2006).

    Article  CAS  PubMed  Google Scholar 

  89. Ribatti, D. Vascular normalization: a real benefit? Cancer Chemother. Pharmacol. 68, 275–278 (2011).

    Article  CAS  PubMed  Google Scholar 

  90. Van der Veldt, A. A. et al. Rapid decrease in delivery of chemotherapy to tumors after anti-VEGF therapy: implications for scheduling of anti-angiogenic drugs. Cancer Cell 21, 82–91 (2012).

    Article  CAS  PubMed  Google Scholar 

  91. Pastuskovas, C. V. et al. Effects of anti-VEGF on pharmacokinetics, biodistribution, and tumor penetration of trastuzumab in a preclinical breast cancer model. Mol. Cancer Ther. 11, 752–762 (2012).

    Article  CAS  PubMed  Google Scholar 

  92. Holash, J. et al. Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science 284, 1994–1998 (1999).

    Article  CAS  PubMed  Google Scholar 

  93. 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 

  94. Pezzella, F. et al. Non-small-cell lung carcinoma tumor growth without morphological evidence of neo-angiogenesis. Am. J. Pathol. 151, 1417–1423 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Offersen, B. V., Pfeiffer, P., Hamilton-Dutoit, S. & Overgaard, J. Patterns of angiogenesis in nonsmall-cell lung carcinoma. Cancer 91, 1500–1509 (2001).

    Article  CAS  PubMed  Google Scholar 

  96. Kim, E. S. et al. Potent VEGF blockade causes regression of coopted vessels in a model of neuroblastoma. Proc. Natl Acad. Sci. USA 99, 11399–11404 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Noguera-Troise, I. et al. Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis. Nature 444, 1032–1037 (2006).

    Article  CAS  PubMed  Google Scholar 

  98. Ridgway, J. et al. Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis. Nature 444, 1083–1087 (2006).

    Article  CAS  PubMed  Google Scholar 

  99. Kuhnert, F., Kirshner, J. R. & Thurston, G. Dll4-Notch signaling as a therapeutic target in tumor angiogenesis. Vasc. Cell 3, 20 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Li, J. L. et al. DLL4-Notch signaling mediates tumor resistance to anti-VEGF therapy in vivo. Cancer Res. 71, 6073–6083 (2011).

    Article  CAS  PubMed  Google Scholar 

  101. Yan, M. et al. Chronic DLL4 blockade induces vascular neoplasms. Nature 463, e6–e7 (2010).

    Article  CAS  PubMed  Google Scholar 

  102. Jubb, A. M. et al. Impact of exploratory biomarkers on the treatment effect of bevacizumab in metastatic breast cancer. Clin. Cancer Res. 17, 372–381 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Shojaei, F. & Ferrara, N. Role of the microenvironment in tumor growth and in refractoriness/resistance to anti-angiogenic therapies. Drug Resist. Updat. 11, 219–230 (2008).

    Article  CAS  PubMed  Google Scholar 

  104. Ko, J. S. et al. Direct and differential suppression of myeloid-derived suppressor cell subsets by sunitinib is compartmentally constrained. Cancer Res. 70, 3526–3536 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Squadrito, M. L. & De Palma, M. Macrophage regulation of tumor angiogenesis: implications for cancer therapy. Mol. Aspects Med. 32, 123–145 (2011).

    Article  CAS  PubMed  Google Scholar 

  106. Finke, J. et al. MDSC as a mechanism of tumor escape from sunitinib mediated anti-angiogenic therapy. Int. Immunopharmacol. 11, 856–861 (2011).

    Article  CAS  PubMed  Google Scholar 

  107. Allavena, P. & Mantovani, A. Immunology in the clinic review series; focus on cancer: tumour-associated macrophages: undisputed stars of the inflammatory tumour microenvironment. Clin. Exp. Immunol. 167, 195–205 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Kessenbrock, K., Plaks, V. & Werb, Z. Matrix metalloproteinases: regulators of the tumor microenvironment. Cell 141, 52–67 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Hanahan, D. & Coussens, L. M. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell 21, 309–322 (2012).

    Article  CAS  PubMed  Google Scholar 

  110. Shojaei, F. et al. Tumor refractoriness to anti-VEGF treatment is mediated by CD11b+Gr1+ myeloid cells. Nature Biotech. 25, 911–920 (2007).

    Article  CAS  Google Scholar 

  111. Orimo, A. et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 121, 335–348 (2005).

    Article  CAS  PubMed  Google Scholar 

  112. Huang, D. et al. Interleukin-8 mediates resistance to antiangiogenic agent sunitinib in renal cell carcinoma. Cancer Res. 70, 1063–1071 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Carbone, C. et al. Anti-VEGF treatment-resistant pancreatic cancers secrete proinflammatory factors that contribute to malignant progression by inducing an EMT cell phenotype. Clin. Cancer Res. 17, 5822–5832 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Facciabene, A. et al. Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and Treg cells. Nature 475, 226–230 (2011).

    Article  CAS  PubMed  Google Scholar 

  115. Crawford, Y. & Ferrara, N. Tumor and stromal pathways mediating refractoriness/resistance to anti-angiogenic therapies. Trends Pharmacol. Sci. 30, 624–630 (2009).

    Article  CAS  PubMed  Google Scholar 

  116. Wang, W., Ma, J. L., Jia, W. D. & Xu, G. L. Periostin: a putative mediator involved in tumour resistance to anti-angiogenic therapy? Cell Biol. Int. 35, 1085–1088 (2011).

    Article  CAS  PubMed  Google Scholar 

  117. Cirri, P. & Chiarugi, P. Cancer-associated-fibroblasts and tumour cells: a diabolic liaison driving cancer progression. Cancer Metastasis Rev. 31, 195–208 (2012).

    Article  PubMed  Google Scholar 

  118. Xu, L. et al. Direct evidence that bevacizumab, an anti-VEGF antibody, up-regulates SDF1α, CXCR4, CXCL6, and neuropilin 1 in tumors from patients with rectal cancer. Cancer Res. 69, 7905–7910 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Kioi, M. et al. Inhibition of vasculogenesis, but not angiogenesis, prevents the recurrence of glioblastoma after irradiation in mice. J. Clin. Invest. 120, 694–705 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Tseng, D., Vasquez-Medrano, D. A. & Brown, J. M. Targeting SDF-1/CXCR4 to inhibit tumour vasculature for treatment of glioblastomas. Br. J. Cancer 104, 1805–1809 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Priceman, S. J. et al. Targeting distinct tumor-infiltrating myeloid cells by inhibiting CSF-1 receptor: combating tumor evasion of antiangiogenic therapy. Blood 115, 1461–1471 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Ebos, J. M. et al. Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell 15, 232–239 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Paez-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  CAS  PubMed  PubMed Central  Google Scholar 

  124. Maione, F. et al. Semaphorin 3A overcomes cancer hypoxia and metastatic dissemination induced by antiangiogenic treatment in mice. J. Clin. Invest. 122, 1832–1848 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. 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 

  126. 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 

  127. Casazza, A. et al. Tumour growth inhibition and anti-metastatic activity of a mutated furin-resistant Semaphorin 3E isoform. EMBO Mol. Med. 4, 234–250 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Conley, S. J. et al. Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia. Proc. Natl Acad. Sci. USA 109, 2784–2789 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Cooke, V. G. et al. Pericyte depletion results in hypoxia-associated epithelial-to-mesenchymal transition and metastasis mediated by Met signaling pathway. Cancer Cell 21, 66–81 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Grepin, R. et al. Acceleration of clear cell renal cell carcinoma growth in mice following bevacizumab/Avastin treatment: the role of CXCL cytokines. Oncogene 31, 1683–1694 (2012).

    Article  CAS  PubMed  Google Scholar 

  131. He, S. et al. Neutrophil-mediated experimental metastasis is enhanced by VEGFR inhibition in a zebrafish xenograft model. J. Pathol. 227, 431–445 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Shojaei, F., Simmons, B. H., Lee, J. H., Lappin, P. B. & Christensen, J. G. HGF/c-Met pathway is one of the mediators of sunitinib-induced tumor cell type-dependent metastasis. Cancer Lett. 320, 48–55 (2012).

    Article  CAS  PubMed  Google Scholar 

  133. Singh, M. et al. Anti-VEGF antibody therapy does not promote metastasis in genetically engineered mouse tumor models. J. Pathol. 227, 417–430 (2012).

    Article  CAS  PubMed  Google Scholar 

  134. Chung, A. S. et al. Differential drug-class specific metastatic effects following treatment with a panel of angiogenesis inhibitors. J. Pathol. 227, 404–416 (2012).

    Article  CAS  PubMed  Google Scholar 

  135. Lai, A. Z., Abella, J. V. & Park, M. Crosstalk in Met receptor oncogenesis. Trends Cell Biol. 19, 542–551 (2009).

    Article  CAS  PubMed  Google Scholar 

  136. Jones, M. C. et al. VEGFR1 (Flt1) regulates Rab4 recycling to control fibronectin polymerization and endothelial vessel branching. Traffic 10, 754–766 (2009).

    Article  CAS  PubMed  Google Scholar 

  137. Caswell, P. T., Vadrevu, S. & Norman, J. C. Integrins: masters and slaves of endocytic transport. Nature Rev. Mol. Cell Biol. 10, 843–853 (2009).

    Article  CAS  Google Scholar 

  138. Muller, P. A. et al. Mutant p53 enhances MET trafficking and signalling to drive cell scattering and invasion. Oncogene 14 May 2012 (doi:10.1038/onc.2012.148).

  139. Ou, G. et al. Usefulness of HIF-1 imaging for determining optimal timing of combining bevacizumab and radiotherapy. Int. J. Radiat. Oncol. Biol. Phys. 75, 463–467 (2009).

    Article  CAS  PubMed  Google Scholar 

  140. Semenza, G. L. Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene 29, 625–634 (2010).

    Article  CAS  PubMed  Google Scholar 

  141. Blouw, B. et al. The hypoxic response of tumors is dependent on their microenvironment. Cancer Cell 4, 133–146 (2003).

    Article  CAS  PubMed  Google Scholar 

  142. Rapisarda, A. & Melillo, G. Role of the hypoxic tumor microenvironment in the resistance to anti-angiogenic therapies. Drug Resist. Updat. 12, 74–80 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Wilson, W. R. & Hay, M. P. Targeting hypoxia in cancer therapy. Nature Rev. Cancer 11, 393–410 (2011).

    Article  CAS  Google Scholar 

  144. Rapisarda, A. et al. Topoisomerase I-mediated inhibition of hypoxia-inducible factor 1: mechanism and therapeutic implications. Cancer Res. 64, 1475–1482 (2004).

    Article  CAS  PubMed  Google Scholar 

  145. Sapra, P. et al. Potent and sustained inhibition of HIF-1α and downstream genes by a polyethyleneglycol-SN38 conjugate, EZN-2208, results in anti-angiogenic effects. Angiogenesis 14, 245–253 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Zelzer, E. et al. Insulin induces transcription of target genes through the hypoxia-inducible factor HIF-1α/ARNT. EMBO J. 17, 5085–5094 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Li, H. et al. Insulin-like growth factor-I receptor blockade reduces tumor angiogenesis and enhances the effects of bevacizumab for a human gastric cancer cell line, MKN45. Cancer 117, 3135–3147 (2011).

    Article  CAS  PubMed  Google Scholar 

  148. Lopez, T. & Hanahan, D. Elevated levels of IGF-1 receptor convey invasive and metastatic capability in a mouse model of pancreatic islet tumorigenesis. Cancer Cell 1, 339–353 (2002).

    Article  CAS  PubMed  Google Scholar 

  149. Ulanet, D. B., Ludwig, D. L., Kahn, C. R. & Hanahan, D. Insulin receptor functionally enhances multistage tumor progression and conveys intrinsic resistance to IGF-1R targeted therapy. Proc. Natl Acad. Sci. USA 107, 10791–10798 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Schioppa, T. et al. Regulation of the chemokine receptor CXCR4 by hypoxia. J. Exp. Med. 198, 1391–1402 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Pennacchietti, S. et al. Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell 3, 347–361 (2003).

    Article  PubMed  Google Scholar 

  152. Erler, J. T. et al. Lysyl oxidase is essential for hypoxia-induced metastasis. Nature 440, 1222–1226 (2006).

    Article  CAS  PubMed  Google Scholar 

  153. Gherardi, E., Birchmeier, W., Birchmeier, C. & Vande Woude, G. Targeting MET in cancer: rationale and progress. Nature Rev. Cancer 12, 89–103 (2012).

    Article  CAS  Google Scholar 

  154. Thiery, J. P., Acloque, H., Huang, R. Y. & Nieto, M. A. Epithelial-mesenchymal transitions in development and disease. Cell 139, 871–890 (2009).

    Article  CAS  PubMed  Google Scholar 

  155. Yilmaz, M. & Christofori, G. Mechanisms of motility in metastasizing cells. Mol. Cancer Res. 8, 629–642 (2010).

    Article  CAS  PubMed  Google Scholar 

  156. Narayana, A. et al. Antiangiogenic therapy using bevacizumab in recurrent high-grade glioma: impact on local control and patient survival. J. Neurosurg. 110, 173–180 (2009).

    Article  PubMed  Google Scholar 

  157. Ye, X. et al. An anti-Axl monoclonal antibody attenuates xenograft tumor growth and enhances the effect of multiple anticancer therapies. Oncogene 29, 5254–5264 (2010).

    Article  CAS  PubMed  Google Scholar 

  158. You, W. K. et al. VEGF and c-Met blockade amplify angiogenesis inhibition in pancreatic islet cancer. Cancer Res. 71, 4758–4768 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Yakes, F. M. et al. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol. Cancer Ther. 10, 2298–2308 (2011).

    Article  CAS  PubMed  Google Scholar 

  160. Gjerdrum, C. et al. Axl is an essential epithelial-to-mesenchymal transition-induced regulator of breast cancer metastasis and patient survival. Proc. Natl Acad. Sci. USA 107, 1124–1129 (2010).

    Article  CAS  PubMed  Google Scholar 

  161. Linger, R. M., Keating, A. K., Earp, H. S. & Graham, D. K. TAM receptor tyrosine kinases: biologic functions, signaling, and potential therapeutic targeting in human cancer. Adv. Cancer Res. 100, 35–83 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Holland, S. J. et al. R428, a selective small molecule inhibitor of Axl kinase, blocks tumor spread and prolongs survival in models of metastatic breast cancer. Cancer Res. 70, 1544–1554 (2010).

    Article  CAS  PubMed  Google Scholar 

  163. Hussain, M. et al. Cabozantinib (XL184) in metastatic castration-resistant prostate cancer (mCRPC): results from a phase II randomized discontinuation trial. J. Clin. Oncol. Abstr. 29, 4516 (2011).

    Article  Google Scholar 

  164. Kurzrock, R. et al. Activity of XL184 (Cabozantinib), an oral tyrosine kinase inhibitor, in patients with medullary thyroid cancer. J. Clin. Oncol. 29, 2660–2666 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Aftab, D. T. & McDonald, D. M. MET and VEGF: synergistic targets in castration-resistant prostate cancer. Clin. Transl. Oncol. 13, 703–709 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Brown, M. S. et al. Computer-aided quantitative bone scan assessment of prostate cancer treatment response. Nucl. Med. Commun. 33, 384–394 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  167. Polyak, K. & Weinberg, R. A. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nature Rev. Cancer 9, 265–273 (2009).

    Article  CAS  Google Scholar 

  168. Frank, N. Y., Schatton, T. & Frank, M. H. The therapeutic promise of the cancer stem cell concept. J. Clin. Invest. 120, 41–50 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Mehlen, P. & Puisieux, A. Metastasis: a question of life or death. Nature Rev. Cancer 6, 449–458 (2006).

    Article  CAS  Google Scholar 

  170. Allegra, C. J. et al. Phase III trial assessing bevacizumab in stages II and III carcinoma of the colon: results of NSABP protocol C-08. J. Clin. Oncol. 29, 11–16 (2011).

    Article  CAS  PubMed  Google Scholar 

  171. Rhim, A. D. et al. EMT and dissemination precede pancreatic tumor formation. Cell 148, 349–361 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Mancuso, M. R. et al. Rapid vascular regrowth in tumors after reversal of VEGF inhibition. J. Clin. Invest. 116, 2610–2621 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Cacheux, W. et al. Reversible tumor growth acceleration following bevacizumab interruption in metastatic colorectal cancer patients scheduled for surgery. Ann. Oncol. 19, 1659–1661 (2008).

    Article  CAS  PubMed  Google Scholar 

  174. O'Connor, J. P. et al. DCE-MRI biomarkers of tumour heterogeneity predict CRC liver metastasis shrinkage following bevacizumab and FOLFOX-6. Br. J. Cancer 105, 139–145 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Dingemans, A. M. et al. First-line erlotinib and bevacizumab in patients with locally advanced and/or metastatic non-small-cell lung cancer: a phase II study including molecular imaging. Ann. Oncol. 22, 559–566 (2011).

    Article  PubMed  Google Scholar 

  176. Kawai, N. et al. Correlation of biological aggressiveness assessed by 11C-methionine PET and hypoxic burden assessed by 18F-fluoromisonidazole PET in newly diagnosed glioblastoma. Eur. J. Nucl. Med. Mol. Imaging 38, 441–450 (2011).

    Article  CAS  PubMed  Google Scholar 

  177. Harris, R. J. et al. 18F-FDOPA and 18F-FLT positron emission tomography parametric response maps predict response in recurrent malignant gliomas treated with bevacizumab. Neuro Oncol. 14, 1079–1089 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Dewdney, A., Cunningham, D., Barbachano, Y. & Chau, I. Correlation of bevacizumab-induced hypertension and outcome in the BOXER study, a phase II study of capecitabine, oxaliplatin (CAPOX) plus bevacizumab as peri-operative treatment in 45 patients with poor-risk colorectal liver-only metastases unsuitable for upfront resection. Br. J. Cancer 106, 1718–1721 (2011).

    Article  CAS  Google Scholar 

  179. Mir, O. et al. An observational study of bevacizumab-induced hypertension as a clinical biomarker of antitumor activity. Oncologist 16, 1325–1332 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Osterlund, P. et al. Hypertension and overall survival in metastatic colorectal cancer patients treated with bevacizumab-containing chemotherapy. Br. J. Cancer 104, 599–604 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. DePrimo, S. E. et al. Circulating protein biomarkers of pharmacodynamic activity of sunitinib in patients with metastatic renal cell carcinoma: modulation of VEGF and VEGF-related proteins. J. Transl. Med. 5, 32 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  182. Burstein, H. J. et al. VEGF as a marker for outcome among advanced breast cancer patients receiving anti-VEGF therapy with bevacizumab and vinorelbine chemotherapy. Clin. Cancer Res. 14, 7871–7877 (2008).

    Article  CAS  PubMed  Google Scholar 

  183. Pena, C., Lathia, C., Shan, M., Escudier, B. & Bukowski, R. M. Biomarkers predicting outcome in patients with advanced renal cell carcinoma: results from sorafenib phase III treatment approaches in renal cancer global evaluation trial. Clin. Cancer Res. 16, 4853–4863 (2010).

    Article  CAS  PubMed  Google Scholar 

  184. Nikolinakos, P. G. et al. Plasma cytokine and angiogenic factor profiling identifies markers associated with tumor shrinkage in early-stage non-small cell lung cancer patients treated with pazopanib. Cancer Res. 70, 2171–2179 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Kopetz, S. et al. Phase II trial of infusional fluorouracil, irinotecan, and bevacizumab for metastatic colorectal cancer: efficacy and circulating angiogenic biomarkers associated with therapeutic resistance. J. Clin. Oncol. 28, 453–459 (2010).

    Article  CAS  PubMed  Google Scholar 

  186. Dellapasqua, S. et al. Metronomic cyclophosphamide and capecitabine combined with bevacizumab in advanced breast cancer. J. Clin. Oncol. 26, 4899–4905 (2008).

    Article  CAS  PubMed  Google Scholar 

  187. Ronzoni, M. et al. Circulating endothelial cells and endothelial progenitors as predictive markers of clinical response to bevacizumab-based first-line treatment in advanced colorectal cancer patients. Ann. Oncol. 21, 2382–2389 (2010).

    Article  CAS  PubMed  Google Scholar 

  188. Rugo, H. S. et al. A phase II study of lapatinib and bevacizumab as treatment for HER2-overexpressing metastatic breast cancer. Breast Cancer Res. Treat. 134, 13–20 (2012).

    Article  CAS  PubMed  Google Scholar 

  189. Wedam, S. B. et al. Antiangiogenic and antitumor effects of bevacizumab in patients with inflammatory and locally advanced breast cancer. J. Clin. Oncol. 24, 769–777 (2006).

    Article  CAS  PubMed  Google Scholar 

  190. Denduluri, N. et al. Circulating biomarkers of bevacizumab activity in patients with breast cancer. Cancer Biol. Ther. 7, 15–20 (2008).

    Article  CAS  PubMed  Google Scholar 

  191. Yang, S. X., Steinberg, S.M., Nguyen, D. & Swain, S.M. p53, HER2 and tumor cell apoptosis correlate with clinical outcome after neoadjuvant bevacizumab plus chemotherapy in breast cancer. Int. J. Oncol. 38, 1445–1452 (2011).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported in part by US National Institutes of Health (NIH) grants HL24136 and HL59157 from the National Heart, Lung, and Blood Institute, and funding from AngelWorks Foundation (to D.McD.).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Donald M. McDonald.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sennino, B., McDonald, D. Controlling escape from angiogenesis inhibitors. Nat Rev Cancer 12, 699–709 (2012). https://doi.org/10.1038/nrc3366

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc3366

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