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  • Review Article
  • Published:

Microenvironmental regulation of tumour angiogenesis

Nature Reviews Cancer volume 17, pages 457–474 (2017)Cite this article

Subjects

Key Points

  • Malignant progression of benign tumours is typically associated with an angiogenic switch — the transition from a quiescent to a proliferative vasculature. The de novo recruitment of various innate immune cells was shown to trigger the angiogenic switch in mouse tumour models.

  • Macrophages are important pro-angiogenic cells in the tumour microenvironment. They promote tumour angiogenesis mainly by secreting pro-angiogenic growth factors and facilitating the degradation of the perivascular extracellular matrix.

  • Neutrophils and immature myeloid cells have important roles during the initial angiogenic switch in experimental tumour models. They were also found to sustain tumour revascularization in the context of anti-angiogenic therapy.

  • B cells and T cells may either promote or limit tumour angiogenesis depending on the specific subtype and activation state. In the context of immunotherapy, they may induce the regression of tumour blood vessels.

  • Tumour blood vessels typically display scant pericyte coverage. However, pericytes provide pro-survival cues to angiogenic blood vessels, and their pharmacological targeting improves tumour response to anti-angiogenic therapy.

  • Cancer-associated fibroblasts produce the extracellular matrix and are an important source of pro-angiogenic factors and myeloid cell chemoattractants in the tumour microenvironment.

  • Adipocytes stimulate peri-tumoural angiogenesis by secreting pro-inflammatory and pro-angiogenic cytokines, and by releasing fatty acids that are consumed by angiogenic endothelial cells.

  • The extracellular matrix conveys both pro-angiogenic and angiostatic signals to tumour blood vessels.

  • The metabolic properties of cancer cells and tumour-associated stromal cells influence angiogenesis in many ways (for example, by regulating glucose bioavailability to angiogenic blood vessels).

  • Vascular heterogeneity is a hallmark of cancer and is determined by multiple factors, including the specific organ and tissue in which the tumour arises, the composition of tumour-associated stromal cells, as well as the nature, diversity and relative abundance of pro- and anti-angiogenic mediators.

  • Tumour-associated stromal cells modulate tumour responses to anti-angiogenic therapy.

Abstract

Tumours display considerable variation in the patterning and properties of angiogenic blood vessels, as well as in their responses to anti-angiogenic therapy. Angiogenic programming of neoplastic tissue is a multidimensional process regulated by cancer cells in concert with a variety of tumour-associated stromal cells and their bioactive products, which encompass cytokines and growth factors, the extracellular matrix and secreted microvesicles. In this Review, we discuss the extrinsic regulation of angiogenesis by the tumour microenvironment, highlighting potential vulnerabilities that could be targeted to improve the applicability and reach of anti-angiogenic cancer therapies.

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Figure 1: Angiogenesis during malignant progression.
Figure 2: Myeloid cell regulation of tumour angiogenesis.
Figure 3: Cross-talk between lymphocytes and myeloid cells regulates tumour angiogenesis.
Figure 4: Chronic wound-healing response promotes tumour angiogenesis.
Figure 5: Metabolic regulation of tumour angiogenesis.
Figure 6: Mechanisms of tumour escape from angiogenesis inhibition.

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References

  1. Potente, M., Gerhardt, H. & Carmeliet, P. Basic and therapeutic aspects of angiogenesis. Cell 146, 873–887 (2011).

    Article  CAS  PubMed  Google Scholar 

  2. LaGory, E. L. & Giaccia, A. J. The ever-expanding role of HIF in tumour and stromal biology. Nat. Cell Biol. 18, 356–365 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Bossi, P. et al. Angiogenesis in colorectal tumors: microvessel quantitation in adenomas and carcinomas with clinicopathological correlations. Cancer Res. 55, 5049–5053 (1995).

    CAS  PubMed  Google Scholar 

  4. Bluff, J. E. et al. Angiogenesis is associated with the onset of hyperplasia in human ductal breast disease. Br. J. Cancer 101, 666–672 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Bergers, G. & Benjamin, L. E. Tumorigenesis and the angiogenic switch. Nat. Rev. Cancer 3, 401–410 (2003).

    Article  CAS  PubMed  Google Scholar 

  6. Fukumura, D., Yuan, F., Monsky, W. L., Chen, Y. & Jain, R. K. Effect of host microenvironment on the microcirculation of human colon adenocarcinoma. Am. J. Pathol. 151, 679–688 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Monsky, W. L. et al. Role of host microenvironment in angiogenesis and microvascular functions in human breast cancer xenografts: mammary fat pad versus cranial tumors. Clin. Cancer Res. 8, 1008–1013 (2002).

    CAS  PubMed  Google Scholar 

  8. 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 

  9. Morrissey, C. et al. Differential expression of angiogenesis associated genes in prostate cancer bone, liver and lymph node metastases. Clin. Exp. Metastasis 25, 377–388 (2008).

    Article  CAS  PubMed  Google Scholar 

  10. Jubb, A. M. et al. Vascular phenotypes in primary non-small cell lung carcinomas and matched brain metastases. Br. J. Cancer 104, 1877–1881 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Morikawa, S. et al. Abnormalities in pericytes on blood vessels and endothelial sprouts in tumors. Am. J. Pathol. 160, 985–1000 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Inoue, M., Hager, J. H., Ferrara, N., Gerber, H. P. & Hanahan, D. VEGF-A has a critical, nonredundant role in angiogenic switching and pancreatic beta cell carcinogenesis. Cancer Cell 1, 193–202 (2002).

    Article  CAS  PubMed  Google Scholar 

  13. Bergers, G. et al. Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat. Cell Biol. 2, 737–744 (2000). This study implicated myeloid-cell derived MMP9 as a key regulator of the angiogenic switch in a GEMM of cancer.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Egeblad, M., Nakasone, E. S. & Werb, Z. Tumors as organs: complex tissues that interface with the entire organism. Dev. Cell 18, 884–901 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. De Palma, M. & Hanahan, D. The biology of personalized cancer medicine: facing individual complexities underlying hallmark capabilities. Mol. Oncol. 6, 111–127 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Cortez, E., Roswall, P. & Pietras, K. Functional subsets of mesenchymal cell types in the tumor microenvironment. Semin. Cancer Biol. 25, 3–9 (2014).

    Article  CAS  PubMed  Google Scholar 

  17. Kalluri, R. The biology and function of fibroblasts in cancer. Nat. Rev. Cancer 16, 582–598 (2016).

    Article  CAS  PubMed  Google Scholar 

  18. Qian, B. Z. & Pollard, J. W. Macrophage diversity enhances tumor progression and metastasis. Cell 141, 39–51 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Fang, S. & Salven, P. Stem cells in tumor angiogenesis. J. Mol. Cell. Cardiol. 50, 290–295 (2011).

    Article  CAS  PubMed  Google Scholar 

  20. Lahmar, Q. et al. Tissue-resident versus monocyte-derived macrophages in the tumor microenvironment. Biochim. Biophys. Acta 1865, 23–34 (2016).

    CAS  PubMed  Google Scholar 

  21. Leek, R. D. et al. Association of macrophage infiltration with angiogenesis and prognosis in invasive breast carcinoma. Cancer Res. 56, 4625–4629 (1996). This report identified a positive correlation between macrophage infiltration and a high vascular grade in human breast cancers.

    CAS  PubMed  Google Scholar 

  22. Koh, Y. W., Park, C. S., Yoon, D. H., Suh, C. & Huh, J. CD163 expression was associated with angiogenesis and shortened survival in patients with uniformly treated classical Hodgkin lymphoma. PLoS ONE 9, e870666 (2014).

    Google Scholar 

  23. Clear, A. J. et al. Increased angiogenic sprouting in poor prognosis FL is associated with elevated numbers of CD163+ macrophages within the immediate sprouting microenvironment. Blood 115, 5053–5056 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Lin, E. Y. et al. Macrophages regulate the angiogenic switch in a mouse model of breast cancer. Cancer Res. 66, 11238–11246 (2006).

    Article  CAS  PubMed  Google Scholar 

  25. Zeisberger, S. M. et al. Clodronate-liposome-mediated depletion of tumour-associated macrophages: a new and highly effective antiangiogenic therapy approach. Br. J. Cancer 95, 272–281 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. 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 

  27. Lohela, M. et al. Intravital imaging reveals distinct responses of depleting dynamic tumor-associated macrophage and dendritic cell subpopulations. Proc. Natl Acad. Sci. USA 111, E5086–E5095 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. 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 

  29. Baer, C., Squadrito, M. L., Iruela-Arispe, M. L. & De Palma, M. Reciprocal interactions between endothelial cells and macrophages in angiogenic vascular niches. Exp. Cell Res. 319, 1626–1634 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Lewis, J. S., Landers, R. J., Underwood, J. C., Harris, A. L. & Lewis, C. E. Expression of vascular endothelial growth factor by macrophages is up-regulated in poorly vascularized areas of breast carcinomas. J. Pathol. 192, 150–158 (2000).

    Article  CAS  PubMed  Google Scholar 

  31. Stockmann, C. et al. Deletion of vascular endothelial growth factor in myeloid cells accelerates tumorigenesis. Nature 456, 814–818 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Hughes, R. et al. Perivascular M2 macrophages stimulate tumor relapse after chemotherapy. Cancer Res. 75, 3479–3491 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Harney, A. S. et al. Real-time imaging reveals local, transient vascular permeability, and tumor cell intravasation stimulated by TIE2hi macrophage-derived VEGFA. Cancer Discov. 5, 932–943 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Murdoch, C., Muthana, M., Coffelt, S. B. & Lewis, C. E. The role of myeloid cells in the promotion of tumour angiogenesis. Nat. Rev. Cancer 8, 618–631 (2008).

    Article  CAS  PubMed  Google Scholar 

  35. Yeo, E. J. et al. Myeloid WNT7b mediates the angiogenic switch and metastasis in breast cancer. Cancer Res. 74, 2962–2973 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Lewis, C. E., Harney, A. S. & Pollard, J. W. The multifaceted role of perivascular macrophages in tumors. Cancer Cell 30, 18–25 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Olson, O. C. & Joyce, J. A. Cysteine cathepsin proteases: regulators of cancer progression and therapeutic response. Nat. Rev. Cancer 15, 712–729 (2015).

    Article  CAS  PubMed  Google Scholar 

  38. 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 

  39. Huang, S. et al. Contributions of stromal metalloproteinase-9 to angiogenesis and growth of human ovarian carcinoma in mice. J. Natl Cancer Inst. 94, 1134–1142 (2002).

    Article  CAS  PubMed  Google Scholar 

  40. Giraudo, E., Inoue, M. & Hanahan, D. An amino-bisphosphonate targets MMP-9-expressing macrophages and angiogenesis to impair cervical carcinogenesis. J. Clin. Invest. 114, 623–633 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Joyce, J. A. et al. Cathepsin cysteine proteases are effectors of invasive growth and angiogenesis during multistage tumorigenesis. Cancer Cell 5, 443–453 (2004).

    Article  CAS  PubMed  Google Scholar 

  42. De Palma, M., Venneri, M. A., Roca, C. & Naldini, L. Targeting exogenous genes to tumor angiogenesis by transplantation of genetically modified hematopoietic stem cells. Nat. Med. 9, 789–795 (2003).

    Article  CAS  PubMed  Google Scholar 

  43. De Palma, M. et al. Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors. Cancer Cell 8, 211–226 (2005). References 42 and 43 illustrated that the conditional elimination of bone marrow-derived, perivascular monocytes was sufficient to impair angiogenesis and delay tumour growth in transplant cancer models.

    Article  CAS  PubMed  Google Scholar 

  44. Matsubara, T. et al. TIE2-expressing monocytes as a diagnostic marker for hepatocellular carcinoma correlates with angiogenesis. Hepatology 57, 1416–1425 (2013).

    Article  CAS  PubMed  Google Scholar 

  45. Mazzieri, R. et al. Targeting the ANG2/TIE2 axis inhibits tumor growth and metastasis by impairing angiogenesis and disabling rebounds of proangiogenic myeloid cells. Cancer Cell 19, 512–526 (2011).

    Article  CAS  PubMed  Google Scholar 

  46. 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 

  47. Kozin, S. V. et al. Recruitment of myeloid but not endothelial precursor cells facilitates tumor regrowth after local irradiation. Cancer Res. 70, 5679–5685 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Welford, A. F. et al. TIE2-expressing macrophages limit the therapeutic efficacy of the vascular-disrupting agent combretastatin A4 phosphate in mice. J. Clin. Invest. 121, 1969–1973 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Chen, L. et al. Tie2 expression on macrophages is required for blood vessel reconstruction and tumor relapse after chemotherapy. Cancer Res. 76, 6828–6838 (2016).

    Article  CAS  PubMed  Google Scholar 

  50. Dou, G. R. et al. Myeloid-specific blockade of Notch signaling attenuates choroidal neovascularization through compromised macrophage infiltration and polarization in mice. Sci. Rep. 6, 28617 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Tamagnone, L. Emerging role of semaphorins as major regulatory signals and potential therapeutic targets in cancer. Cancer Cell 22, 145–152 (2012).

    Article  CAS  PubMed  Google Scholar 

  52. Barnett, F. H. et al. Macrophages form functional vascular mimicry channels in vivo. Sci. Rep. 6, 36659 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Moldovan, N. I., Goldschmidt-Clermont, P. J., Parker-Thornburg, J., Shapiro, S. D. & Kolattukudy, P. E. Contribution of monocytes/macrophages to compensatory neovascularization: the drilling of metalloelastase-positive tunnels in ischemic myocardium. Circ. Res. 87, 378–384 (2000).

    Article  CAS  PubMed  Google Scholar 

  54. Coffelt, S. B., Wellenstein, M. D. & de Visser, K. E. Neutrophils in cancer: neutral no more. Nat. Rev. Cancer 16, 431–446 (2016).

    Article  CAS  PubMed  Google Scholar 

  55. Liang, W. & Ferrara, N. The complex role of neutrophils in tumor angiogenesis and metastasis. Cancer Immunol. Res. 4, 83–91 (2016).

    Article  CAS  PubMed  Google Scholar 

  56. Kujawski, M. et al. Stat3 mediates myeloid cell-dependent tumor angiogenesis in mice. J. Clin. Invest. 118, 3367–3377 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Gaudry, M. et al. Intracellular pool of vascular endothelial growth factor in human neutrophils. Blood 90, 4153–4161 (1997).

    Article  CAS  PubMed  Google Scholar 

  58. Qu, X., Zhuang, G., Yu, L., Meng, G. & Ferrara, N. Induction of Bv8 expression by granulocyte colony-stimulating factor in CD11b+Gr1+ cells: key role of Stat3 signaling. J. Biol. Chem. 287, 19574–19584 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Shojaei, F. et al. Bv8 regulates myeloid-cell-dependent tumour angiogenesis. Nature 450, 825–831 (2007).

    Article  CAS  PubMed  Google Scholar 

  60. Jablonska, J., Leschner, S., Westphal, K., Lienenklaus, S. & Weiss, S. Neutrophils responsive to endogenous IFN-beta regulate tumor angiogenesis and growth in a mouse tumor model. J. Clin. Invest. 120, 1151–1164 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Nozawa, H., Chiu, C. & Hanahan, D. Infiltrating neutrophils mediate the initial angiogenic switch in a mouse model of multistage carcinogenesis. Proc. Natl Acad. Sci. USA 103, 12493–12498 (2006). This study highlighted the contribution of neutrophils to angiogenesis in the early stages of tumour progression in a mouse model of PNET.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Rivera, L. B. et al. Intratumoral myeloid cells regulate responsiveness and resistance to antiangiogenic therapy. Cell Rep. 11, 577–591 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Nakasone, E. S. et al. Imaging tumor-stroma interactions during chemotherapy reveals contributions of the microenvironment to resistance. Cancer Cell 21, 488–503 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Deryugina, E. I. et al. Tissue-infiltrating neutrophils constitute the major in vivo source of angiogenesis-inducing MMP-9 in the tumor microenvironment. Neoplasia 16, 771–788 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Ardi, V. C. et al. Neutrophil MMP-9 proenzyme, unencumbered by TIMP-1, undergoes efficient activation in vivo and catalytically induces angiogenesis via a basic fibroblast growth factor (FGF-2)/FGFR-2 pathway. J. Biol. Chem. 284, 25854–25866 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Kumar, V., Patel, S., Tcyganov, E. & Gabrilovich, D. I. The nature of myeloid-derived suppressor cells in the tumor microenvironment. Trends Immunol. 37, 208–220 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Coffelt, S. B. et al. Elusive identities and overlapping phenotypes of proangiogenic myeloid cells in tumors. Am. J. Pathol. 176, 1564–1576 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  68. Motz, G. T. & Coukos, G. The parallel lives of angiogenesis and immunosuppression: cancer and other tales. Nat. Rev. Immunol. 11, 702–711 (2011).

    Article  CAS  PubMed  Google Scholar 

  69. Dirkx, A. E. et al. Tumor angiogenesis modulates leukocyte-vessel wall interactions in vivo by reducing endothelial adhesion molecule expression. Cancer Res. 63, 2322–2329 (2003).

    CAS  PubMed  Google Scholar 

  70. Johansson, A., Hamzah, J. & Ganss, R. More than a scaffold: stromal modulation of tumor immunity. Biochim. Biophys. Acta 1865, 3–13 (2016).

    CAS  PubMed  Google Scholar 

  71. Kessler, D. A., Langer, R. S., Pless, N. A. & Folkman, J. Mast cells and tumor angiogenesis. Int. J. Cancer 18, 703–709 (1976).

    Article  CAS  PubMed  Google Scholar 

  72. Coussens, L. M. et al. Inflammatory mast cells up-regulate angiogenesis during squamous epithelial carcinogenesis. Genes Dev. 13, 1382–1397 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Gounaris, E. et al. Mast cells are an essential hematopoietic component for polyp development. Proc. Natl Acad. Sci. USA 104, 19977–19982 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Soucek, L. et al. Mast cells are required for angiogenesis and macroscopic expansion of Myc-induced pancreatic islet tumors. Nat. Med. 13, 1211–1218 (2007). References 72–74 revealed unexpected roles for mast cells as pro-angiogenic cells in different GEMMs of cancer.

    Article  CAS  PubMed  Google Scholar 

  75. Movahedi, K. et al. Different tumor microenvironments contain functionally distinct subsets of macrophages derived from Ly6C(high) monocytes. Cancer Res. 70, 5728–5739 (2010).

    Article  CAS  PubMed  Google Scholar 

  76. Cormier, S. A. et al. Pivotal advance: eosinophil infiltration of solid tumors is an early and persistent inflammatory host response. J. Leukoc. Biol. 79, 1131–1139 (2006).

    Article  CAS  PubMed  Google Scholar 

  77. Davis, B. P. & Rothenberg, M. E. Eosinophils and cancer. Cancer Immunol. Res. 2, 1–8 (2014).

    Article  CAS  PubMed  Google Scholar 

  78. Yang, C. et al. B cells promote tumor progression via STAT3 regulated-angiogenesis. PLoS ONE 8, e64159 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Andreu, P. et al. FcRgamma activation regulates inflammation-associated squamous carcinogenesis. Cancer Cell 17, 121–134 (2010). This study illustrated a role for B cells and secreted IgG in promoting pro-angiogenic myeloid cell programming in a mouse model of skin cancer.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Tian, L. et al. Mutual regulation of tumour vessel normalization and immunostimulatory reprogramming. Nature 544, 250–254 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Fathallah-Shaykh, H. M., Zhao, L. J., Kafrouni, A. I., Smith, G. M. & Forman, J. Gene transfer of IFN-gamma into established brain tumors represses growth by antiangiogenesis. J. Immunol. 164, 217–222 (2000).

    Article  CAS  PubMed  Google Scholar 

  82. Kammertoens, T. et al. Tumour ischaemia by interferon-gamma resembles physiological blood vessel regression. Nature 545, 98–102 (2017). References 80–82 showed that T cells regulate the tumour-associated vasculature by limiting angiogenesis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Biswas, S. K. & Mantovani, A. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat. Immunol. 11, 889–896 (2010).

    Article  CAS  PubMed  Google Scholar 

  84. DeNardo, D. G. et al. CD4+ T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages. Cancer Cell 16, 91–102 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Baer, C. et al. Suppression of microRNA activity amplifies IFN-gamma-induced macrophage activation and promotes anti-tumour immunity. Nat. Cell Biol. 18, 790–802 (2016).

    Article  CAS  PubMed  Google Scholar 

  86. 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 

  87. Bruno, A., Ferlazzo, G., Albini, A. & Noonan, D. M. A think tank of TINK/TANKs: tumor-infiltrating/tumor-associated natural killer cells in tumor progression and angiogenesis. J. Natl Cancer Inst. 106, dju200 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  88. Gotthardt, D. et al. STAT5 Is a key regulator in NK cells and acts as a molecular switch from tumor surveillance to tumor promotion. Cancer Discov. 6, 414–429 (2016).

    Article  CAS  PubMed  Google Scholar 

  89. Sharma, D., Brummel-Ziedins, K. E., Bouchard, B. A. & Holmes, C. E. Platelets in tumor progression: a host factor that offers multiple potential targets in the treatment of cancer. J. Cell. Physiol. 229, 1005–1015 (2014).

    Article  CAS  PubMed  Google Scholar 

  90. Sabrkhany, S., Griffioen, A. W. & Oude Egbrink, M. G. The role of blood platelets in tumor angiogenesis. Biochim. Biophys. Acta 1815, 189–196 (2011).

    CAS  PubMed  Google Scholar 

  91. Chatterjee, M. et al. Distinct platelet packaging, release, and surface expression of proangiogenic and antiangiogenic factors on different platelet stimuli. Blood 117, 3907–3911 (2011).

    Article  CAS  PubMed  Google Scholar 

  92. Jonnalagadda, D., Izu, L. T. & Whiteheart, S. W. Platelet secretion is kinetically heterogeneous in an agonist-responsive manner. Blood 120, 5209–5216 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Yan, M., Lesyk, G., Radziwon-Balicka, A. & Jurasz, P. Pharmacological regulation of platelet factors that influence tumor angiogenesis. Semin. Oncol. 41, 370–377 (2014).

    Article  CAS  PubMed  Google Scholar 

  94. Ho- Tin-Noe, B., Goerge, T., Cifuni, S. M., Duerschmied, D. & Wagner, D. D. Platelet granule secretion continuously prevents intratumor hemorrhage. Cancer Res. 68, 6851–6858 (2008).

    Article  CAS  Google Scholar 

  95. Klement, G. L. et al. Platelets actively sequester angiogenesis regulators. Blood 113, 2835–2842 (2009).

    Article  CAS  PubMed  Google Scholar 

  96. Peterson, J. E. et al. VEGF, PF4 and PDGF are elevated in platelets of colorectal cancer patients. Angiogenesis 15, 265–273 (2012).

    Article  CAS  PubMed  Google Scholar 

  97. Salven, P., Orpana, A. & Joensuu, H. Leukocytes and platelets of patients with cancer contain high levels of vascular endothelial growth factor. Clin. Cancer Res. 5, 487–491 (1999). References 95–97 showed that platelets could sequester, and become a reservoir of, pro-angiogenic mediators in patients with cancer.

    CAS  PubMed  Google Scholar 

  98. Kuznetsov, H. S. et al. Identification of luminal breast cancers that establish a tumor-supportive macroenvironment defined by proangiogenic platelets and bone marrow-derived cells. Cancer Discov. 2, 1150–1165 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Feng, W. et al. A novel role for platelet secretion in angiogenesis: mediating bone marrow-derived cell mobilization and homing. Blood 117, 3893–3902 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Armulik, A., Genove, G. & Betsholtz, C. Pericytes: developmental, physiological, and pathological perspectives, problems, and promises. Dev. Cell 21, 193–215 (2011).

    Article  CAS  PubMed  Google Scholar 

  101. Eberhard, A. et al. Heterogeneity of angiogenesis and blood vessel maturation in human tumors: implications for antiangiogenic tumor therapies. Cancer Res. 60, 1388–1393 (2000).

    CAS  PubMed  Google Scholar 

  102. Saharinen, P., Eklund, L. & Alitalo, K. Therapeutic targeting of the angiopoietin-TIE pathway. Nat. Rev. Drug Discov. https://doi.org/10.1038/nrd.2016.278 (2017).

  103. Thurston, G. et al. Leakage-resistant blood vessels in mice transgenically overexpressing angiopoietin-1. Science 286, 2511–2514 (1999).

    Article  CAS  PubMed  Google Scholar 

  104. Xian, X. et al. Pericytes limit tumor cell metastasis. J. Clin. Invest. 116, 642–651 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. You, W. K., Yotsumoto, F., Sakimura, K., Adams, R. H. & Stallcup, W. B. NG2 proteoglycan promotes tumor vascularization via integrin-dependent effects on pericyte function. Angiogenesis 17, 61–76 (2014).

    Article  CAS  PubMed  Google Scholar 

  106. Nasarre, P. et al. Host-derived angiopoietin-2 affects early stages of tumor development and vessel maturation but is dispensable for later stages of tumor growth. Cancer Res. 69, 1324–1333 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Holopainen, T. et al. Effects of angiopoietin-2-blocking antibody on endothelial cell-cell junctions and lung metastasis. J. Natl Cancer Inst. 104, 461–475 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Rigamonti, N. et al. Role of angiopoietin-2 in adaptive tumor resistance to VEGF signaling blockade. Cell Rep. 8, 696–706 (2014).

    Article  CAS  PubMed  Google Scholar 

  109. Park, J. S. et al. Normalization of tumor vessels by Tie2 activation and Ang2 inhibition enhances drug delivery and produces a favorable tumor microenvironment. Cancer Cell 30, 953–967 (2016).

    Article  CAS  PubMed  Google Scholar 

  110. Birbrair, A. et al. Type-2 pericytes participate in normal and tumoral angiogenesis. Am. J. Physiol. Cell Physiol. 307, C25–C38 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. 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 

  112. Keskin, D. et al. Targeting vascular pericytes in hypoxic tumors increases lung metastasis via angiopoietin-2. Cell Rep. 10, 1066–1081 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Erber, R. et al. Combined inhibition of VEGF and PDGF signaling enforces tumor vessel regression by interfering with pericyte-mediated endothelial cell survival mechanisms. FASEB J. 18, 338–340 (2004).

    Article  CAS  PubMed  Google Scholar 

  114. Bergers, G., Song, S., Meyer-Morse, N., Bergsland, E. & Hanahan, D. Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J. Clin. Invest. 111, 1287–1295 (2003). References 113 and 114 highlighted the anti-tumoural benefits of co-targeting pericytes and ECs in mouse cancer models, paving the way to the clinical testing of non-selective VEGFR and PDGFR inhibitors in PNETs and other cancer types.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Egeblad, M., Rasch, M. G. & Weaver, V. M. Dynamic interplay between the collagen scaffold and tumor evolution. Curr. Opin. Cell Biol. 22, 697–706 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Tuxhorn, J. A., McAlhany, S. J., Dang, T. D., Ayala, G. E. & Rowley, D. R. Stromal cells promote angiogenesis and growth of human prostate tumors in a differential reactive stroma (DRS) xenograft model. Cancer Res. 62, 3298–3307 (2002).

    CAS  PubMed  Google Scholar 

  117. 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 

  118. Gerber, H. P., Kowalski, J., Sherman, D., Eberhard, D. A. & Ferrara, N. Complete inhibition of rhabdomyosarcoma xenograft growth and neovascularization requires blockade of both tumor and host vascular endothelial growth factor. Cancer Res. 60, 6253–6258 (2000).

    CAS  PubMed  Google Scholar 

  119. Fukumura, D. et al. Tumor induction of VEGF promoter activity in stromal cells. Cell 94, 715–725 (1998). References 117–119 implicated CAFs as an important source of VEGFA and myeloid-cell chemoattractants in mouse tumour models.

    Article  CAS  PubMed  Google Scholar 

  120. Crawford, Y. et al. PDGF-C mediates the angiogenic and tumorigenic properties of fibroblasts associated with tumors refractory to anti-VEGF treatment. Cancer Cell 15, 21–34 (2009).

    Article  CAS  PubMed  Google Scholar 

  121. Pietras, K., Pahler, J., Bergers, G. & Hanahan, D. Functions of paracrine PDGF signaling in the proangiogenic tumor stroma revealed by pharmacological targeting. PLoS Med. 5, e19 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  122. Anderberg, C. et al. Paracrine signaling by platelet-derived growth factor-CC promotes tumor growth by recruitment of cancer-associated fibroblasts. Cancer Res. 69, 369–378 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Hou, X. et al. PDGF-CC blockade inhibits pathological angiogenesis by acting on multiple cellular and molecular targets. Proc. Natl Acad. Sci. USA 107, 12216–12221 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Kaur, A. et al. sFRP2 in the aged microenvironment drives melanoma metastasis and therapy resistance. Nature 532, 250–254 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Filleur, S. et al. In vivo mechanisms by which tumors producing thrombospondin 1 bypass its inhibitory effects. Genes Dev. 15, 1373–1382 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Dirat, B. et al. Cancer-associated adipocytes exhibit an activated phenotype and contribute to breast cancer invasion. Cancer Res. 71, 2455–2465 (2011).

    Article  CAS  PubMed  Google Scholar 

  127. Lim, S., Hosaka, K., Nakamura, M. & Cao, Y. Co-option of pre-existing vascular beds in adipose tissue controls tumor growth rates and angiogenesis. Oncotarget 7, 38282–38291 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  128. Cao, Y. Angiogenesis and vascular functions in modulation of obesity, adipose metabolism, and insulin sensitivity. Cell Metab. 18, 478–489 (2013).

    Article  CAS  PubMed  Google Scholar 

  129. Renehan, A. G., Zwahlen, M. & Egger, M. Adiposity and cancer risk: new mechanistic insights from epidemiology. Nat. Rev. Cancer 15, 484–498 (2015).

    Article  CAS  PubMed  Google Scholar 

  130. Bougaret, L. et al. Supernatants of adipocytes from obese versus normal weight women and breast cancer cells: in vitro impact on angiogenesis. J. Cell. Physiol. 232, 1808–1816 (2016).

    Article  PubMed  CAS  Google Scholar 

  131. Arendt, L. M. et al. Obesity promotes breast cancer by CCL2-mediated macrophage recruitment and angiogenesis. Cancer Res. 73, 6080–6093 (2013).

    Article  CAS  PubMed  Google Scholar 

  132. Hagiwara, A. et al. Milky spots as the implantation site for malignant cells in peritoneal dissemination in mice. Cancer Res. 53, 687–692 (1993).

    CAS  PubMed  Google Scholar 

  133. Wagner, M. et al. Inflamed tumor-associated adipose tissue is a depot for macrophages that stimulate tumor growth and angiogenesis. Angiogenesis 15, 481–495 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Nieman, K. M. et al. Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nat. Med. 17, 1498–1503 (2011). References 133 and 134 showed that cancer cells could reprogramme peri-tumoural adipocytes to sustain tumour inflammation, angiogenesis and growth.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Harjes, U., Bridges, E., McIntyre, A., Fielding, B. A. & Harris, A. L. Fatty acid-binding protein 4, a point of convergence for angiogenic and metabolic signaling pathways in endothelial cells. J. Biol. Chem. 289, 23168–23176 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Schoors, S. et al. Fatty acid carbon is essential for dNTP synthesis in endothelial cells. Nature 520, 192–197 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Dvorak, H. F. Tumor stroma, tumor bood vessels, and antiangiogenesis therapy. Cancer J. 21, 237–243 (2015).

    Article  CAS  PubMed  Google Scholar 

  138. Bonnans, C., Chou, J. & Werb, Z. Remodelling the extracellular matrix in development and disease. Nat. Rev. Mol. Cell Biol. 15, 786–8014 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Arroyo, A. G. & Iruela-Arispe, M. L. Extracellular matrix, inflammation, and the angiogenic response. Cardiovasc. Res. 86, 226–235 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Baluk, P., Morikawa, S., Haskell, A., Mancuso, M. & McDonald, D. M. Abnormalities of basement membrane on blood vessels and endothelial sprouts in tumors. Am. J. Pathol. 163, 1801–1815 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  141. Sorokin, L. The impact of the extracellular matrix on inflammation. Nat. Rev. Immunol. 10, 712–723 (2010).

    Article  CAS  PubMed  Google Scholar 

  142. Shao, R. et al. Acquired expression of periostin by human breast cancers promotes tumor angiogenesis through up-regulation of vascular endothelial growth factor receptor 2 expression. Mol. Cell. Biol. 24, 3992–4003 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Van Obberghen-Schilling, E. et al. Fibronectin and tenascin-C: accomplices in vascular morphogenesis during development and tumor growth. Int. J. Dev. Biol. 55, 511–525 (2011).

    Article  CAS  PubMed  Google Scholar 

  144. Klenotic, P. A., Zhang, C. & Lin, Z. Emerging roles of CCN proteins in vascular development and pathology. J. Cell Commun. Signal. 10, 251–257 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  145. Saupe, F. et al. Tenascin-C downregulates wnt inhibitor dickkopf-1, promoting tumorigenesis in a neuroendocrine tumor model. Cell Rep. 5, 482–492 (2013).

    Article  CAS  PubMed  Google Scholar 

  146. Lawler, P. R. & Lawler, J. Molecular basis for the regulation of angiogenesis by thrombospondin-1 and -2. Cold Spring Harb. Perspect. Med. 2, a006627 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  147. Rivera, L. B., Bradshaw, A. D. & Brekken, R. A. The regulatory function of SPARC in vascular biology. Cell. Mol. Life Sci. 68, 3165–3173 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Mammoto, A. et al. A mechanosensitive transcriptional mechanism that controls angiogenesis. Nature 457, 1103–1108 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Rivron, N. C. et al. Tissue deformation spatially modulates VEGF signaling and angiogenesis. Proc. Natl Acad. Sci. USA 109, 6886–6891 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Mason, B. N., Starchenko, A., Williams, R. M., Bonassar, L. J. & Reinhart-King, C. A. Tuning three-dimensional collagen matrix stiffness independently of collagen concentration modulates endothelial cell behavior. Acta Biomater. 9, 4635–4644 (2013).

    Article  CAS  PubMed  Google Scholar 

  151. Yun, H., Lee, M., Kim, S. S. & Ha, J. Glucose deprivation increases mRNA stability of vascular endothelial growth factor through activation of AMP-activated protein kinase in DU145 prostate carcinoma. J. Biol. Chem. 280, 9963–9972 (2005).

    Article  CAS  PubMed  Google Scholar 

  152. Shi, Q. et al. Regulation of vascular endothelial growth factor expression by acidosis in human cancer cells. Oncogene 20, 3751–3756 (2001).

    Article  CAS  PubMed  Google Scholar 

  153. Vegran, F., Boidot, R., Michiels, C., Sonveaux, P. & Feron, O. Lactate influx through the endothelial cell monocarboxylate transporter MCT1 supports an NF-kappaB/IL-8 pathway that drives tumor angiogenesis. Cancer Res. 71, 2550–2560 (2011).

    Article  CAS  PubMed  Google Scholar 

  154. Sonveaux, P. et al. Targeting the lactate transporter MCT1 in endothelial cells inhibits lactate-induced HIF-1 activation and tumor angiogenesis. PLoS ONE 7, e33418 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Casazza, A. et al. Impeding macrophage entry into hypoxic tumor areas by Sema3A/Nrp1 signaling blockade inhibits angiogenesis and restores antitumor immunity. Cancer Cell 24, 695–709 (2013).

    Article  CAS  PubMed  Google Scholar 

  156. Laoui, D. et al. Tumor hypoxia does not drive differentiation of tumor-associated macrophages but rather fine-tunes the M2-like macrophage population. Cancer Res. 74, 24–30 (2014).

    Article  CAS  PubMed  Google Scholar 

  157. Colegio, O. R. et al. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 513, 559–563 (2014). References 155–157 illustrated the effects of tumour hypoxia on the pro-angiogenic macrophage phenotype.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Biswas, S. K. Metabolic reprogramming of immune cells in cancer progression. Immunity 43, 435–449 (2015).

    Article  CAS  PubMed  Google Scholar 

  159. Wenes, M. et al. Macrophage metabolism controls tumor blood vessel morphogenesis and metastasis. Cell Metab. 24, 701–715 (2016).

    Article  CAS  PubMed  Google Scholar 

  160. Potente, M. & Carmeliet, P. The link between angiogenesis and endothelial metabolism. Annu. Rev. Physiol. 79, 43–66 (2017).

    Article  CAS  PubMed  Google Scholar 

  161. Gorrini, C., Harris, I. S. & Mak, T. W. Modulation of oxidative stress as an anticancer strategy. Nat. Rev. Drug Discov. 12, 931–947 (2013).

    Article  CAS  PubMed  Google Scholar 

  162. Xia, C. et al. Reactive oxygen species regulate angiogenesis and tumor growth through vascular endothelial growth factor. Cancer Res. 67, 10823–10830 (2007).

    Article  CAS  PubMed  Google Scholar 

  163. West, X. Z. et al. Oxidative stress induces angiogenesis by activating TLR2 with novel endogenous ligands. Nature 467, 972–976 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Garrido-Urbani, S. et al. Targeting vascular NADPH oxidase 1 blocks tumor angiogenesis through a PPARalpha mediated mechanism. PLoS ONE 6, e14665 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Warren, C. M., Ziyad, S., Briot, A., Der, A. & Iruela-Arispe, M. L. A ligand-independent VEGFR2 signaling pathway limits angiogenic responses in diabetes. Sci. Signal. 7, ra1 (2014).

    PubMed  PubMed Central  Google Scholar 

  166. Okuno, Y., Nakamura-Ishizu, A., Otsu, K., Suda, T. & Kubota, Y. Pathological neoangiogenesis depends on oxidative stress regulation by ATM. Nat. Med. 18, 1208–1216 (2012).

    Article  CAS  PubMed  Google Scholar 

  167. Rak, J. et al. Oncogenes and tumor angiogenesis: differential modes of vascular endothelial growth factor up-regulation in ras-transformed epithelial cells and fibroblasts. Cancer Res. 60, 490–498 (2000).

    CAS  PubMed  Google Scholar 

  168. Sparmann, A. & Bar-Sagi, D. Ras-induced interleukin-8 expression plays a critical role in tumor growth and angiogenesis. Cancer Cell 6, 447–458 (2004). This study showed that a mutant RAS oncogene fostered myeloid-cell infiltration and tumour angiogenesis by activating the transcription of Cxcl8 in cancer cells.

    Article  CAS  PubMed  Google Scholar 

  169. Bottos, A. et al. Targeting oncogenic serine/threonine-protein kinase BRAF in cancer cells inhibits angiogenesis and abrogates hypoxia. Proc. Natl Acad. Sci. USA 109, E353–E359 (2012).

    Article  CAS  PubMed  Google Scholar 

  170. Sharma, A. et al. Mutant V599EB-Raf regulates growth and vascular development of malignant melanoma tumors. Cancer Res. 65, 2412–2421 (2005).

    Article  CAS  PubMed  Google Scholar 

  171. Phan, V. T. et al. Oncogenic RAS pathway activation promotes resistance to anti-VEGF therapy through G-CSF-induced neutrophil recruitment. Proc. Natl Acad. Sci. USA 110, 6079–6084 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Pylayeva-Gupta, Y., Lee, K. E., Hajdu, C. H., Miller, G. & Bar-Sagi, D. Oncogenic Kras-induced GM-CSF production promotes the development of pancreatic neoplasia. Cancer Cell 21, 836–847 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Cremolini, C. et al. FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic colorectal cancer: updated overall survival and molecular subgroup analyses of the open-label, phase 3 TRIBE study. Lancet Oncol. 16, 1306–1315 (2015).

    Article  CAS  PubMed  Google Scholar 

  174. Tabernero, J. et al. Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol. 16, 499–508 (2015).

    Article  CAS  PubMed  Google Scholar 

  175. Becker, A. et al. Extracellular vesicles in cancer: cell-to-cell mediators of metastasis. Cancer Cell 30, 836–848 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Kholia, S. et al. Extracellular vesicles as new players in angiogenesis. Vascul. Pharmacol. 86, 64–70 (2016).

    Article  CAS  PubMed  Google Scholar 

  177. Skog, J. et al. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat. Cell Biol. 10, 1470–1476 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Taraboletti, G. et al. Bioavailability of VEGF in tumor-shed vesicles depends on vesicle burst induced by acidic pH. Neoplasia 8, 96–103 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Graves, L. E. et al. Proinvasive properties of ovarian cancer ascites-derived membrane vesicles. Cancer Res. 64, 7045–7049 (2004).

    Article  CAS  PubMed  Google Scholar 

  180. Squadrito, M. L. et al. Endogenous RNAs modulate microRNA sorting to exosomes and transfer to acceptor cells. Cell Rep. 8, 1432–1446 (2014).

    Article  CAS  PubMed  Google Scholar 

  181. Janowska-Wieczorek, A. et al. Microvesicles derived from activated platelets induce metastasis and angiogenesis in lung cancer. Int. J. Cancer 113, 752–760 (2005).

    Article  CAS  PubMed  Google Scholar 

  182. Sheldon, H. et al. New mechanism for Notch signaling to endothelium at a distance by Delta-like 4 incorporation into exosomes. Blood 116, 2385–2394 (2010).

    Article  CAS  PubMed  Google Scholar 

  183. Lombardo, G. et al. Activated Stat5 trafficking via endothelial cell-derived extracellular vesicles controls IL-3 pro-angiogenic paracrine action. Sci. Rep. 6, 25689 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Tkach, M. & Thery, C. Communication by extracellular vesicles: where we are and where we need to go. Cell 164, 1226–1232 (2016).

    Article  CAS  PubMed  Google Scholar 

  185. Nazarenko, I. et al. Cell surface tetraspanin Tspan8 contributes to molecular pathways of exosome-induced endothelial cell activation. Cancer Res. 70, 1668–1678 (2010).

    Article  CAS  PubMed  Google Scholar 

  186. Zhuang, G. et al. Tumour-secreted miR-9 promotes endothelial cell migration and angiogenesis by activating the JAK-STAT pathway. EMBO J. 31, 3513–3523 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Al-Nedawi, K., Meehan, B., Kerbel, R. S., Allison, A. C. & Rak, J. Endothelial expression of autocrine VEGF upon the uptake of tumor-derived microvesicles containing oncogenic EGFR. Proc. Natl Acad. Sci. USA 106, 3794–3799 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  188. Umezu, T. et al. Exosomal miR-135b shed from hypoxic multiple myeloma cells enhances angiogenesis by targeting factor-inhibiting HIF-1. Blood 124, 3748–3757 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Ferrara, N. & Adamis, A. P. Ten years of anti-vascular endothelial growth factor therapy. Nat. Rev. Drug Discov. 15, 385–403 (2016).

    Article  CAS  PubMed  Google Scholar 

  190. Bridgeman, V. L. et al. Vessel co-option is common in human lung metastases and mediates resistance to anti-angiogenic therapy in preclinical lung metastasis models. J. Pathol. 241, 362–374 (2017).

    Article  CAS  PubMed  Google Scholar 

  191. Frentzas, S. et al. Vessel co-option mediates resistance to anti-angiogenic therapy in liver metastases. Nat. Med. 22, 1294–1302 (2016). References 190 and 191 highlighted the potential clinical implications of vascular co-option for resistance to anti-angiogenic therapy in metastatic disease.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. 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 

  193. Bonapace, L. et al. Cessation of CCL2 inhibition accelerates breast cancer metastasis by promoting angiogenesis. Nature 515, 130–133 (2014).

    Article  CAS  PubMed  Google Scholar 

  194. Gordon-Weeks, A. N. et al. Neutrophils promote hepatic metastasis growth through fibroblast growth factor 2-dependent angiogenesis in mice. Hepatology 65, 1920–1935 (2017).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Hu, Y. L. et al. Hypoxia-induced autophagy promotes tumor cell survival and adaptation to antiangiogenic treatment in glioblastoma. Cancer Res. 72, 1773–1783 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Sounni, N. E. et al. Blocking lipid synthesis overcomes tumor regrowth and metastasis after antiangiogenic therapy withdrawal. Cell Metab. 20, 280–294 (2014).

    Article  CAS  PubMed  Google Scholar 

  198. Allen, E. et al. Metabolic symbiosis enables adaptive resistance to anti-angiogenic therapy that is dependent on mTOR signaling. Cell Rep. 15, 1144–1160 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Jimenez-Valerio, G. et al. Resistance to antiangiogenic therapies by metabolic symbiosis in renal cell carcinoma PDX models and patients. Cell Rep. 15, 1134–1143 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Pisarsky, L. et al. Targeting metabolic symbiosis to overcome resistance to anti-angiogenic therapy. Cell Rep. 15, 1161–1174 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Bensaad, K. et al. Fatty acid uptake and lipid storage induced by HIF-1alpha contribute to cell growth and survival after hypoxia-reoxygenation. Cell Rep. 9, 349–365 (2014). References 196–201 highlighted distinct mechanisms whereby tumours escape the inhibitory effects of anti-angiogenic therapy through metabolic reprogramming.

    Article  CAS  PubMed  Google Scholar 

  202. 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 

  203. Scholz, A. et al. Endothelial cell-derived angiopoietin-2 is a therapeutic target in treatment-naive and bevacizumab-resistant glioblastoma. EMBO Mol. Med. 8, 39–57 (2016).

    Article  CAS  PubMed  Google Scholar 

  204. 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 

  205. 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 

  206. Gabrusiewicz, K. et al. Anti-vascular endothelial growth factor therapy-induced glioma invasion is associated with accumulation of Tie2-expressing monocytes. Oncotarget 5, 2208–2220 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  207. De Palma, M. & Lewis, C. E. Macrophage regulation of tumor responses to anticancer therapies. Cancer Cell 23, 277–286 (2013).

    Article  CAS  PubMed  Google Scholar 

  208. Huang, H. et al. Specifically targeting angiopoietin-2 inhibits angiogenesis, Tie2-expressing monocyte infiltration, and tumor growth. Clin. Cancer Res. 17, 1001–1011 (2011).

    Article  CAS  PubMed  Google Scholar 

  209. Kloepper, J. et al. Ang-2/VEGF bispecific antibody reprograms macrophages and resident microglia to anti-tumor phenotype and prolongs glioblastoma survival. Proc. Natl Acad. Sci. USA 113, 4476–4481 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Schmittnaegel, M. et al. Dual angiopoietin-2 and VEGFA inhibition elicits antitumor immunity that is enhanced by PD-1 checkpoint blockade. Sci. Transl Med. 9, aak9670 (2017).

    Article  CAS  Google Scholar 

  211. Pahler, J. C. et al. Plasticity in tumor-promoting inflammation: impairment of macrophage recruitment evokes a compensatory neutrophil response. Neoplasia 10, 329–340 (2008). This study suggested that the genetic impairment of macrophages could exacerbate the tumour-promoting functions of neutrophils in a mouse model of cervical cancer.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. von Tresckow, B. et al. An open-label, multicenter, phase I/II study of JNJ-40346527, a CSF-1R inhibitor, in patients with relapsed or refractory Hodgkin lymphoma. Clin. Cancer Res. 21, 1843–1850 (2015).

    Article  CAS  PubMed  Google Scholar 

  213. Butowski, N. et al. Orally administered colony stimulating factor 1 receptor inhibitor PLX3397 in recurrent glioblastoma: an Ivy Foundation Early Phase Clinical Trials Consortium phase II study. Neuro Oncol. 18, 557–564 (2016).

    Article  PubMed  Google Scholar 

  214. Kaneda, M. M. et al. PI3Kgamma is a molecular switch that controls immune suppression. Nature 539, 437–4424 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. De Palma, M. et al. Tumor-targeted interferon-alpha delivery by Tie2-expressing monocytes inhibits tumor growth and metastasis. Cancer Cell 14, 299–311 (2008).

    Article  CAS  PubMed  Google Scholar 

  216. 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 

  217. Raymond, E. et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N. Engl. J. Med. 364, 501–513 (2011).

    Article  CAS  PubMed  Google Scholar 

  218. Ebos, J. M. et al. Neoadjuvant antiangiogenic therapy reveals contrasts in primary and metastatic tumor efficacy. EMBO Mol. Med. 6, 1561–1576 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Chung, A. S. et al. An interleukin-17-mediated paracrine network promotes tumor resistance to anti-angiogenic therapy. Nat. Med. 19, 1114–1123 (2013).

    Article  CAS  PubMed  Google Scholar 

  220. Carmeliet, P. & Jain, R. K. Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases. Nat. Rev. Drug Discov. 10, 417–427 (2011).

    Article  CAS  PubMed  Google Scholar 

  221. De Palma, M. & Jain, R. K. CD4+ T cell activation and vascular normalization: two sides of the same coin? Immunity 46, 773–775 (2017).

    Article  CAS  PubMed  Google Scholar 

  222. Schoenfeld, J. et al. Active immunotherapy induces antibody responses that target tumor angiogenesis. Cancer Res. 70, 10150–10160 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. Wu, X. et al. Angiopoietin-2 as a biomarker and target for immune checkpoint therapy. Cancer Immunol. Res. 5, 17–28 (2017). References 222 and 223 revealed that the anti-tumoural effects of certain cancer immunotherapies may also involve immune-mediated anti-angiogenic or angiostatic mechanisms.

    Article  CAS  PubMed  Google Scholar 

  224. Aird, W. C. Endothelial cell heterogeneity. Cold Spring Harb. Perspect. Med. 2, a006429 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  225. Hida, K., Maishi, N., Torii, C. & Hida, Y. Tumor angiogenesis — characteristics of tumor endothelial cells. Int. J. Clin. Oncol. 21, 206–212 (2016).

    Article  CAS  PubMed  Google Scholar 

  226. Chaudhary, A. & St Croix, B. Selective blockade of tumor angiogenesis. Cell Cycle 11, 2253–2259 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  227. Pasqualini, R., Moeller, B. J. & Arap, W. Leveraging molecular heterogeneity of the vascular endothelium for targeted drug delivery and imaging. Semin. Thromb. Hemost. 36, 343–351 (2010).

    Article  CAS  PubMed  Google Scholar 

  228. Amin, D. N., Hida, K., Bielenberg, D. R. & Klagsbrun, M. Tumor endothelial cells express epidermal growth factor receptor (EGFR) but not ErbB3 and are responsive to EGF and to EGFR kinase inhibitors. Cancer Res. 66, 2173–2180 (2006).

    Article  CAS  PubMed  Google Scholar 

  229. Xiong, Y. Q. et al. Human hepatocellular carcinoma tumor-derived endothelial cells manifest increased angiogenesis capability and drug resistance compared with normal endothelial cells. Clin. Cancer Res. 15, 4838–4846 (2009).

    Article  CAS  PubMed  Google Scholar 

  230. Akiyama, K. et al. Tumor endothelial cells acquire drug resistance by MDR1 up-regulation via VEGF signaling in tumor microenvironment. Am. J. Pathol. 180, 1283–1293 (2012).

    Article  CAS  PubMed  Google Scholar 

  231. Hida, K. et al. Tumor-associated endothelial cells with cytogenetic abnormalities. Cancer Res. 64, 8249–8255 (2004).

    Article  CAS  PubMed  Google Scholar 

  232. Kim, Y. W. & Byzova, T. V. Oxidative stress in angiogenesis and vascular disease. Blood 123, 625–631 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. Soda, Y. et al. Transdifferentiation of glioblastoma cells into vascular endothelial cells. Proc. Natl Acad. Sci. USA 108, 4274–4280 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  234. Williamson, S. C. et al. Vasculogenic mimicry in small cell lung cancer. Nat. Commun. 7, 13322 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Work in the authors' laboratories is mainly supported by the European Research Council (to M.D.P.), the Swiss National Science Foundation (grants 31003A-165963 to M.D.P.; 31003A-156266, 31ER30-160674 and 316030-164119 to T.V.P.), the Swiss Cancer League (grants KFS-3759-08-2015 to M.D.P.; KLS-3406-02-2014 to T.V.P.), the Leenaards Foundation, the San Salvatore Foundation, and the Swiss Bridge Foundation (to M.D.P. and T.V.P.).

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Authors and Affiliations

  1. The Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, 1015, Switzerland

    Michele De Palma & Daniela Biziato

  2. Department of Fundamental Oncology, Ludwig Institute for Cancer Research and Division of Experimental Pathology, University of Lausanne and University of Lausanne Hospital, Lausanne, 1066, Switzerland

    Tatiana V. Petrova

Authors
  1. Michele De Palma
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  2. Daniela Biziato
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  3. Tatiana V. Petrova
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Contributions

M.D.P. conceived and wrote the article and display items. T.V.P. contributed to discussions of the content and writing of the article. M.D.P., D.B. and T.V.P. researched the data for the article. M.D.P., D.B. and T.V.P. reviewed and edited the article before submission.

Corresponding authors

Correspondence to Michele De Palma or Tatiana V. Petrova.

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Competing interests

M.D.P. and T.V.P. have received research grants from Hoffmann-La Roche to investigate angiogenesis and macrophage inhibitors.

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Glossary

Hypoxia

The condition of low oxygen availability. In tumours, hypoxia is observed in cancer cells that reside more than 70–150 μm away from a perfused blood vessel.

Pro-angiogenic factors

Biological molecules that stimulate endothelial cell proliferation and angiogenesis.

Anti-angiogenic factors

Biological molecules that block angiogenesis or promote the regression of angiogenic blood vessels.

Pericyte

Cell that enwraps and promotes the survival of endothelial cells, stabilizing small blood vessels.

Tumour microenvironment

(TME). The complex and dynamic ensemble of cancer cells, tumour-associated stromal cells (TASCs; comprising primarily leukocytes, fibroblasts and vascular cells) and their extracellular products.

Progenitors

Undifferentiated cells capable of producing lineage-committed cellular progeny.

Damage-associated molecular patterns

(DAMPs). Biological molecules that can initiate an inflammatory response independently of infection.

Clodronate liposomes

A formulation of small lipid vesicles containing a bisphosphonate that is capable of inducing macrophage death upon engulfment.

Angiostatic functions

Properties that promote endothelial cell quiescence and limit angiogenesis.

RIP1–Tag2 transgenic mice

Expression of the SV40 large T antigen (Tag) under the control of the rat insulin promoter (RIP) causes β-cell hyperplasia, which progresses through a series of rate-limiting stages to invasive pancreatic neuroendocrine tumour (PNET).

Vascular guidance

The guided, directional growth of blood vessels.

Vascular mimicry

The process whereby vascular-like channels are formed by non-endothelial cells in certain tumours, namely melanomas.

Non-thrombogenic EC-like surfaces

Cellular surfaces capable of preventing the formation of a clot (or thrombus) when in contact with blood.

Type I interferon

A family of secreted proteins with antiviral and immunomodulatory functions, which bind to a common receptor.

Genetically engineered mouse models (GEMMs) of cancer

Transgenic mice in which cancer is initiated and driven by defined genetic alterations, such as the expression of oncogene(s) and/or the inactivation of tumour suppressor gene(s), or both.

Immunocompetent mice

Mice that have an intact immune system. They are permissive to the growth of transplanted tumours with matched genetic background (syngeneic tumours).

T helper 1 (TH1) cells

T cells that can stimulate other immune cells, such as macrophages and cytotoxic T lymphocytes, to kill infected or cancer cells. They do so primarily through the release of the TH1 cytokine interferon-γ.

TH2 cells

T cells that stimulate B cells to produce immunoglobulins. They do so through the release of TH2 cytokines, such as interleukin-4.

Cytotoxic T lymphocytes

(CTLs). T cells capable of killing other cells, including cancer cells, generally through the recognition of specific antigens.

Cancer immunosurveillance

The process whereby immune cells, namely lymphocytes and natural killer cells, recognize initiated cancer cells and eliminate them; it may also lead to the selection of less immunogenic cancer cell clones.

Lipolysis

The process whereby triglycerides are resolved into glycerol and free fatty acids through hydrolysis.

β-Oxidation

The process that occurs in the mitochondrion and that uses fatty acids to generate acetyl-CoA, which is essential for producing ATP through oxidative phosphorylation.

Glycolysis

The metabolic process that occurs in the cell cytoplasm and that uses glucose to generate pyruvate and the high-energy molecules ATP and NADH; in the presence of oxygen, pyruvate may enter the mitochondrion to sustain oxidative metabolism.

Reactive oxygen species

(ROS). Chemically reactive molecular species that contain oxygen; by reacting with biological molecules, ROS can alter their structure and function.

Oxidative metabolism

The metabolic processes that converge on oxidative phosphorylation to produce ATP.

Extracellular vesicles

(EVs). The heterogeneous assortment of secreted vesicles produced by virtually any cell type through diverse biogenesis processes.

Tetraspanins

A family of transmembrane proteins that organize microdomains enriched in membrane-bound signalling proteins.

Orthotopic tumour transplant

An experimental tumour that results from the injection of cancer cells into the tissue or organ from which the cancer cells were originally derived.

Ectopic tumour transplant

An experimental tumour that results from the injection of cancer cells into an anatomical site that is different from the one from which the cancer cells were originally derived. Generally, ectopic tumours are inoculated in the subcutaneous space.

TH17 cells

T cells that have roles in protecting organ surfaces, in particular the gut mucosa, from pathogens. They produce interleukin-17 and stimulate B cell-mediated humoral immunity.

Immune checkpoint

A ligand–receptor pair that either activates or inhibits a stimulatory signal for lymphocytes, resulting in the activation or suppression of an immune response.

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Cite this article

De Palma, M., Biziato, D. & Petrova, T. Microenvironmental regulation of tumour angiogenesis. Nat Rev Cancer 17, 457–474 (2017). https://doi.org/10.1038/nrc.2017.51

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