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.

  • Review Article
  • Published:

Molecular mechanisms and clinical applications of angiogenesis

Nature volume 473, pages 298–307 (2011)Cite this article

Subjects

Abstract

Blood vessels deliver oxygen and nutrients to every part of the body, but also nourish diseases such as cancer. Over the past decade, our understanding of the molecular mechanisms of angiogenesis (blood vessel growth) has increased at an explosive rate and has led to the approval of anti-angiogenic drugs for cancer and eye diseases. So far, hundreds of thousands of patients have benefited from blockers of the angiogenic protein vascular endothelial growth factor, but limited efficacy and resistance remain outstanding problems. Recent preclinical and clinical studies have shown new molecular targets and principles, which may provide avenues for improving the therapeutic benefit from anti-angiogenic strategies.

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

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Figure 1: Modes of vessel formation.
Figure 2: Molecular basis of vessel branching.
Figure 3: Potential mechanisms of resistance to targeted VEGF therapy in cancer.

Similar content being viewed by others

References

  1. Folkman, J. Angiogenesis: an organizing principle for drug discovery? Nature Rev. Drug Discov. 6, 273–286 (2007).

    Article  CAS  Google Scholar 

  2. Carmeliet, P. Angiogenesis in health and disease. Nature Med. 9, 653–660 (2003).

    Article  CAS  PubMed  Google Scholar 

  3. Swift, M. R. & Weinstein, B. M. Arterial–venous specification during development. Circ. Res. 104, 576–588 (2009).

    Article  PubMed  CAS  Google Scholar 

  4. Wang, R. et al. Glioblastoma stem-like cells give rise to tumour endothelium. Nature 468, 829–833 (2010).

    Article  ADS  PubMed  CAS  Google Scholar 

  5. Schaper, W. Collateral circulation: past and present. Basic Res. Cardiol. 104, 5–21 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Jain, R. K., Duda, D. G., Clark, J. W. & Loeffler, J. S. Lessons from phase III clinical trials on anti-VEGF therapy for cancer. Nature Clin. Pract. Oncol. 3, 24–40 (2006).

    Article  CAS  Google Scholar 

  7. Ferrara, N. VEGF-A: a critical regulator of blood vessel growth. Eur. Cytokine Netw. 20, 158–163 (2009).

    Article  PubMed  CAS  Google Scholar 

  8. Nagy, J. A., Dvorak, A. M. & Dvorak, H. F. VEGF-A and the induction of pathological angiogenesis. Annu. Rev. Pathol. 2, 251–275 (2007).

    Article  PubMed  CAS  Google Scholar 

  9. Neufeld, G. & Kessler, O. The semaphorins: versatile regulators of tumour progression and tumour angiogenesis. Nature Rev. Cancer 8, 632–645 (2008).

    Article  CAS  Google Scholar 

  10. Phng, L. K. & Gerhardt, H. Angiogenesis: a team effort coordinated by Notch. Dev. Cell 16, 196–208 (2009).

    Article  PubMed  CAS  Google Scholar 

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

    Article  ADS  PubMed  PubMed Central  CAS  Google Scholar 

  12. Lee, S. et al. Autocrine VEGF signaling is required for vascular homeostasis. Cell 130, 691–703 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Lanahan, A. A. et al. VEGF receptor 2 endocytic trafficking regulates arterial morphogenesis. Dev. Cell 18, 713–724 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Jain, R. K. et al. Biomarkers of response and resistance to antiangiogenic therapy. Nature Rev. Clin. Oncol. 6, 327–338 (2009). This review highlights the importance of various types of biomarker to personalize anti-angiogenic medicine, distinguish responders from non-responders and monitor treatment efficacy and adverse effects.

    Article  CAS  Google Scholar 

  15. Buysschaert, I., Schmidt, T., Roncal, C., Carmeliet, P. & Lambrechts, D. Genetics, epigenetics and pharmaco-(epi)genomics in angiogenesis. J. Cell. Mol. Med. 12, 2533–2551 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Tvorogov, D. et al. Effective suppression of vascular network formation by combination of antibodies blocking VEGFR ligand binding and receptor dimerization. Cancer Cell 18, 630–640 (2010).

    Article  PubMed  CAS  Google Scholar 

  17. Tammela, T. & Alitalo, K. Lymphangiogenesis: molecular mechanisms and future promise. Cell 140, 460–476 (2010).

    Article  PubMed  CAS  Google Scholar 

  18. Herbert, S. P. et al. Arterial–venous segregation by selective cell sprouting: an alternative mode of blood vessel formation. Science 326, 294–298 (2009).

    Article  ADS  PubMed  PubMed Central  CAS  Google Scholar 

  19. 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 

  20. Carmeliet, P. et al. Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions. Nature Med. 7, 575–583 (2001).

    Article  PubMed  CAS  Google Scholar 

  21. 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  PubMed  CAS  Google Scholar 

  22. 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  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  24. Hagberg, C. E. et al. Vascular endothelial growth factor B controls endothelial fatty acid uptake. Nature 464, 917–921 (2010).

    Article  ADS  PubMed  CAS  Google Scholar 

  25. Bry, M. et al. Vascular endothelial growth factor-B acts as a coronary growth factor in transgenic rats without inducing angiogenesis, vascular leak, or inflammation. Circulation 122, 1725–1733 (2010).

    Article  PubMed  CAS  Google Scholar 

  26. Schwartz, J. D., Rowinsky, E. K., Youssoufian, H., Pytowski, B. & Wu, Y. Vascular endothelial growth factor receptor-1 in human cancer. Cancer 116, 1027–1032 (2010).

    Article  PubMed  CAS  Google Scholar 

  27. Lichtenberger, B. M. et al. Autocrine VEGF signaling synergizes with EGFR in tumor cells to promote epithelial cancer development. Cell 140, 268–279 (2010).

    Article  PubMed  CAS  Google Scholar 

  28. Duda, D. G. & Jain, R. K. Premetastatic lung 'niche': is vascular endothelial growth factor receptor 1 activation required? Cancer Res. 70, 5670–5673 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Kaplan, R. N. et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438, 820–827 (2005).

    Article  ADS  PubMed  PubMed Central  CAS  Google Scholar 

  30. Jain, R. K. Molecular regulation of vessel maturation. Nature Med. 9, 685–693 (2003).

    Article  PubMed  CAS  Google Scholar 

  31. Hellberg, C., Ostman, A. & Heldin, C. H. PDGF and vessel maturation. Recent Results Cancer Res. 180, 103–114 (2010).

    Article  PubMed  CAS  Google Scholar 

  32. Gaengel, K., Genove, G., Armulik, A. & Betsholtz, C. Endothelial-mural cell signaling in vascular development and angiogenesis. Arterioscler. Thromb. Vasc. Biol. 29, 630–638 (2009). This article discusses the role of pericytes in tumour angiogenesis, and highlights the possible pro-metastatic effects of blocking pericyte coverage.

    Article  PubMed  CAS  Google Scholar 

  33. Quaegebeur, A., Segura, I. & Carmeliet, P. Pericytes: blood–brain barrier safeguards against neurodegeneration? Neuron 68, 321–323 (2010).

    Article  PubMed  CAS  Google Scholar 

  34. Song, S., Ewald, A. J., Stallcup, W., Werb, Z. & Bergers, G. PDGFRβ+ perivascular progenitor cells in tumours regulate pericyte differentiation and vascular survival. Nature Cell Biol. 7, 870–879 (2005).

    Article  PubMed  CAS  Google Scholar 

  35. 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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. McCarty, M. F. et al. Overexpression of PDGF-BB decreases colorectal and pancreatic cancer growth by increasing tumor pericyte content. J. Clin. Invest. 117, 2114–2122 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Sennino, B. et al. Cellular source and amount of vascular endothelial growth factor and platelet-derived growth factor in tumors determine response to angiogenesis inhibitors. Cancer Res. 69, 4527–4536 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Nisancioglu, M. H., Betsholtz, C. & Genove, G. The absence of pericytes does not increase the sensitivity of tumor vasculature to vascular endothelial growth factor-A blockade. Cancer Res. 70, 5109–5115 (2010).

    Article  PubMed  CAS  Google Scholar 

  39. Gerhardt, H. & Semb, H. Pericytes: gatekeepers in tumour cell metastasis? J. Mol. Med. 86, 135–144 (2008).

    Article  PubMed  Google Scholar 

  40. Lebrin, F. et al. Thalidomide stimulates vessel maturation and reduces epistaxis in individuals with hereditary hemorrhagic telangiectasia. Nature Med. 16, 420–428 (2010).

    Article  ADS  PubMed  CAS  Google Scholar 

  41. 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  PubMed  CAS  Google Scholar 

  42. di Tomaso, E. et al. PDGF-C induces maturation of blood vessels in a model of glioblastoma and attenuates the response to anti-VEGF treatment. PLoS ONE 4, e5123 (2009).

    Article  ADS  PubMed  PubMed Central  CAS  Google Scholar 

  43. Pardali, E., Goumans, M. J. & ten Dijke, P. Signaling by members of the TGF-β family in vascular morphogenesis and disease. Trends Cell Biol. 20, 556–567 (2010).

    Article  PubMed  CAS  Google Scholar 

  44. Beenken, A. & Mohammadi, M. The FGF family: biology, pathophysiology and therapy. Nature Rev. Drug Discov. 8, 235–253 (2009).

    Article  CAS  Google Scholar 

  45. Murakami, M. et al. The FGF system has a key role in regulating vascular integrity. J. Clin. Invest. 118, 3355–3366 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  47. Augustin, H. G., Koh, G. Y., Thurston, G. & Alitalo, K. Control of vascular morphogenesis and homeostasis through the angiopoietin–Tie system. Nature Rev. Mol. Cell Biol. 10, 165–177 (2009).

    Article  CAS  Google Scholar 

  48. Saharinen, P. et al. Angiopoietins assemble distinct Tie2 signalling complexes in endothelial cell–cell and cell–matrix contacts. Nature Cell Biol. 10, 527–537 (2008).

    Article  PubMed  CAS  Google Scholar 

  49. 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).

    Article  PubMed  CAS  Google Scholar 

  50. Falcon, B. L. et al. Contrasting actions of selective inhibitors of angiopoietin-1 and angiopoietin-2 on the normalization of tumor blood vessels. Am. J. Pathol. 175, 2159–2170 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Koh, Y. J. et al. Double antiangiogenic protein, DAAP, targeting VEGF-A and angiopoietins in tumor angiogenesis, metastasis, and vascular leakage. Cancer Cell 18, 171–184 (2010).

    Article  PubMed  CAS  Google Scholar 

  52. Benedito, R. et al. The Notch ligands Dll4 and Jagged1 have opposing effects on angiogenesis. Cell 137, 1124–1135 (2009).

    Article  PubMed  CAS  Google Scholar 

  53. Phng, L. K. et al. Nrarp coordinates endothelial Notch and Wnt signaling to control vessel density in angiogenesis. Dev. Cell 16, 70–82 (2009).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  54. Jakobsson, L. et al. Endothelial cells dynamically compete for the tip cell position during angiogenic sprouting. Nature Cell Biol. 12, 943–953 (2010).

    Article  PubMed  CAS  Google Scholar 

  55. Thurston, G., Noguera-Troise, I. & Yancopoulos, G. D. The Delta paradox: DLL4 blockade leads to more tumour vessels but less tumour growth. Nature Rev. Cancer 7, 327–331 (2007). References 10 and 55 discuss the molecular model of vessel branching, and the role of DLL4 and NOTCH signalling in tip- and stalk-cell formation.

    Article  CAS  Google Scholar 

  56. Yan, M. et al. Chronic DLL4 blockade induces vascular neoplasms. Nature 463, E6–E7 (2010).

    Article  ADS  PubMed  CAS  Google Scholar 

  57. Corada, M. et al. The Wnt/β-catenin pathway modulates vascular remodeling and specification by upregulating Dll4/Notch signaling. Dev. Cell 18, 938–949 (2010).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  58. Dejana, E. The role of Wnt signaling in physiological and pathological angiogenesis. Circ. Res. 107, 943–952 (2010).

    Article  PubMed  CAS  Google Scholar 

  59. Desgrosellier, J. S. & Cheresh, D. A. Integrins in cancer: biological implications and therapeutic opportunities. Nature Rev. Cancer 10, 9–22 (2010).

    Article  CAS  Google Scholar 

  60. Hodivala-Dilke, K. αvβ3 integrin and angiogenesis: a moody integrin in a changing environment. Curr. Opin. Cell Biol. 20, 514–519 (2008).

    Article  PubMed  CAS  Google Scholar 

  61. Contois, L., Akalu, A. & Brooks, P. C. Integrins as 'functional hubs' in the regulation of pathological angiogenesis. Semin. Cancer Biol. 19, 318–328 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Deryugina, E. I. & Quigley, J. P. Pleiotropic roles of matrix metalloproteinases in tumor angiogenesis: contrasting, overlapping and compensatory functions. Biochim. Biophys. Acta 1803, 103–120 (2010).

    Article  PubMed  CAS  Google Scholar 

  63. Bergers, G. et al. Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nature Cell Biol. 2, 737–744 (2000).

    Article  PubMed  CAS  Google Scholar 

  64. Iruela-Arispe, M. L. & Davis, G. E. Cellular and molecular mechanisms of vascular lumen formation. Dev. Cell 16, 222–231 (2009).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  65. Du, R. et al. HIF1α induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion. Cancer Cell 13, 206–220 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Heissig, B. et al. Role of neutrophil-derived matrix metalloproteinase-9 in tissue regeneration. Histol. Histopathol. 25, 765–770 (2010).

    PubMed  CAS  Google Scholar 

  67. Heissig, B. et al. Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand. Cell 109, 625–637 (2002).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Blasi, F. & Carmeliet, P. uPAR: a versatile signalling orchestrator. Nature Rev. Mol. Cell Biol. 3, 932–943 (2002).

    Article  CAS  Google Scholar 

  69. Pries, A. R., Hopfner, M., le Noble, F., Dewhirst, M. W. & Secomb, T. W. The shunt problem: control of functional shunting in normal and tumour vasculature. Nature Rev. Cancer 10, 587–593 (2010).

    Article  CAS  Google Scholar 

  70. Dejana, E., Tournier-Lasserve, E. & Weinstein, B. M. The control of vascular integrity by endothelial cell junctions: molecular basis and pathological implications. Dev. Cell 16, 209–221 (2009).

    Article  PubMed  CAS  Google Scholar 

  71. Strilic, B. et al. The molecular basis of vascular lumen formation in the developing mouse aorta. Dev. Cell 17, 505–515 (2009).

    Article  PubMed  CAS  Google Scholar 

  72. Mazzone, M. et al. Heterozygous deficiency of PHD2 restores tumor oxygenation and inhibits metastasis via endothelial normalization. Cell 136, 839–851 (2009). This article provides genetic evidence of a role for the oxygen-sensor PHD2 in tumour vessel normalization through its regulation of endothelial cell phalanx formation.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Duda, D. G. et al. CXCL12 (SDF1α) — CXCR4/CXCR7 pathway inhibition: an emerging sensitizer for anti-cancer therapies? Clin. Cancer Res. 17, 2074–2080 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Visentin, B. et al. Validation of an anti-sphingosine-1-phosphate antibody as a potential therapeutic in reducing growth, invasion, and angiogenesis in multiple tumor lineages. Cancer Cell 9, 225–238 (2006).

    Article  PubMed  CAS  Google Scholar 

  75. Kuhnert, F. et al. Essential regulation of CNS angiogenesis by the orphan G protein-coupled receptor GPR124. Science 330, 985–989 (2010).

    Article  ADS  PubMed  PubMed Central  CAS  Google Scholar 

  76. Escudier, B. et al. Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overall survival. J. Clin. Oncol. 28, 2144–2150 (2010).

    Article  PubMed  CAS  Google Scholar 

  77. 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  PubMed  CAS  Google Scholar 

  78. 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  PubMed  PubMed Central  CAS  Google Scholar 

  79. 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). References 78 and 79 provide preclinical evidence that VEGF or VEGFR blockade can enhance metastasis, whereas references 87 and 88 provide preclinical and clinical evidence that VEGF or VEGFR blockade has no effect on metastasis.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Carmeliet, P. Angiogenesis in life, disease and medicine. Nature 438, 932–936 (2005).

    Article  ADS  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  82. Ferrara, N. Pathways mediating VEGF-independent tumor angiogenesis. Cytokine Growth Factor Rev. 21, 21–26 (2010). References 46 and 82 discuss the mechanisms of resistance to VEGF or VEGFR blockade.

    Article  PubMed  CAS  Google Scholar 

  83. Nagengast, W. B. et al. VEGF-PET imaging is a noninvasive biomarker showing differential changes in the tumor during sunitinib treatment. Cancer Res. 71, 143–153 (2011).

    Article  PubMed  CAS  Google Scholar 

  84. Joyce, J. A. & Pollard, J. W. Microenvironmental regulation of metastasis. Nature Rev. Cancer 9, 239–252 (2009).

    Article  CAS  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. di Tomaso, E. et al. Glioblastoma recurrence after cediranib therapy in patients: lack of “rebound” revascularization as mode of escape. Cancer Res. 71, 19–28 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Padera, T. P. et al. Differential response of primary tumor versus lymphatic metastasis to VEGFR-2 and VEGFR-3 kinase inhibitors cediranib and vandetanib. Mol. Cancer Ther. 7, 2272–2279 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Miles, D. et al. Disease course patterns after discontinuation of bevacizumab: pooled analysis of randomized phase III trials. J. Clin. Oncol. 29, 83–88 (2010).

    Article  PubMed  CAS  Google Scholar 

  89. Jain, R. K. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307, 58–62 (2005). This review presents evidence for vascular abnormalities in tumours, and the therapeutic potential to normalize these vessels for treatment of cancer and other diseases characterized by abnormal vessels.

    Article  ADS  PubMed  CAS  Google Scholar 

  90. Jain, R. K. Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nature Med. 7, 987–989 (2001).

    Article  PubMed  CAS  Google Scholar 

  91. Plotkin, S. R. et al. Hearing improvement after bevacizumab in patients with neurofibromatosis type 2. N. Engl. J. Med. 361, 358–367 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Butler, J. M., Kobayashi, H. & Rafii, S. Instructive role of the vascular niche in promoting tumour growth and tissue repair by angiocrine factors. Nature Rev. Cancer 10, 138–146 (2010). This review discusses the emerging concept that endothelial cells produce instructive signals for organ development, repair and even cancer. It also highlights the importance of hypoxia-mediated signalling in angiogenesis.

    Article  CAS  Google Scholar 

  93. Adams, R. H. & Eichmann, A. Axon guidance molecules in vascular patterning. Cold Spring Harb. Perspect. Biol. 2, a001875 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Mosch, B., Reissenweber, B., Neuber, C. & Pietzsch, J. Eph receptors and ephrin ligands: important players in angiogenesis and tumor angiogenesis. J. Oncol. 2010, 135285 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Sawamiphak, S. et al. Ephrin-B2 regulates VEGFR2 function in developmental and tumour angiogenesis. Nature 465, 487–491 (2010).

    Article  ADS  PubMed  CAS  Google Scholar 

  96. Majmundar, A. J., Wong, W. J. & Simon, M. C. Hypoxia-inducible factors and the response to hypoxic stress. Mol. Cell 40, 294–309 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Fraisl, P., Mazzone, M., Schmidt, T. & Carmeliet, P. Regulation of angiogenesis by oxygen and metabolism. Dev. Cell 16, 167–179 (2009).

    Article  PubMed  CAS  Google Scholar 

  98. Arany, Z. et al. HIF-independent regulation of VEGF and angiogenesis by the transcriptional coactivator PGC-1α. Nature 451, 1008–1112 (2008). References 24, 97 and 98 discuss the link between metabolism and angiogenesis, and show that metabolic regulators control angiogenesis.

    Article  ADS  PubMed  CAS  Google Scholar 

  99. Ohtani, K. & Dimmeler, S. Control of cardiovascular differentiation by microRNAs. Basic Res. Cardiol. 106, 5–11 (2010). This review discusses the emerging evidence for regulation of angiogenesis by epigenetic mechanisms.

    Article  PubMed  CAS  Google Scholar 

  100. Nicoli, S. et al. MicroRNA-mediated integration of haemodynamics and Vegf signalling during angiogenesis. Nature 464, 1196–1200 (2010).

    Article  ADS  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgements

We would like to acknowledge the late J. Folkman for inspiring us and others to work in the area of tumour angiogenesis. We would like to thank L. Claeson-Welch, H. Augustin, E. Dejana, S. Kozin, D. G. Duda, S. Goel, L. L. Munn, G. Sledge, R. Stupp and H. D. Suit for their comments, and L. Notebaert for help with the illustrations. We apologize to the authors whose work we could not cite because of the limit on the number of references. The work of P.C. is supported by a Federal Government Belgium grant (IUAP06/30), long-term structural Methusalem funding by the Flemish Government, a Concerted Research Activities Belgium grant (GOA2006/11), Leducq Transatlantic Network ARTEMIS and a grant from Flanders Research Foundation (FWO G.0673.08). The research of R.K.J. is supported by US National Institutes of Health grants P01-CA80124, R01-CA85140, R01-CA115767 and R01-CA126642, Federal Share/NCI Proton Beam Program Income, the National Foundation for Cancer Research and a Department of Defense Breast Cancer Research Innovator Award (W81XWH-10-1-0016).

Author information

Authors and Affiliations

  1. Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, Leuven, B-3000, Belgium

    Peter Carmeliet

  2. Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, K. U. Leuven, Leuven, B-3000, Belgium

    Peter Carmeliet

  3. Department of Radiation Oncology, Edwin L. Steele Laboratory for Tumor Biology, Massachusetts General Hospital and Harvard Medical School, Boston, 02114, Massachusetts, USA

    Rakesh K. Jain

Authors
  1. Peter Carmeliet
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rakesh K. Jain
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Peter Carmeliet or Rakesh K. Jain.

Ethics declarations

Competing interests

R.K.J. reports receiving consulting fees from Astellas, AstraZeneca, Dyax, Enlight Biosciences, Genzyme, Millenium, MorphoSys, Noxxon and SynDevRx; lecture fees from Alnylam, Genzyme, Pfizer and MPM Capital; and grant support from Dyax, AstraZeneca, MedImmune and Roche; and owns equity in Enlight Biosciences and SynDevRx. P.C. reports receiving recent consulting fees from Roche, ThromboGenics and Astellas; lecture fees from Roche and Novartis; and grant support from ThromboGenics; and owns equity in ThromboGenics.

Additional information

Reprints and permissions information is available at http://www.nature.com/reprints.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Carmeliet, P., Jain, R. Molecular mechanisms and clinical applications of angiogenesis. Nature 473, 298–307 (2011). https://doi.org/10.1038/nature10144

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature10144

This article is cited by

Search

Advanced 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