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:

Angiogenesis

Tumorigenesis and the angiogenic switch

Nature Reviews Cancer volume 3, pages 401–410 (2003)Cite this article

Key Points

  • Tumour heterogeneity leads to heterogeneity in the tumour vasculature. Just as there are multiple phenotypes for any given tumour type, so can there be multiple phenotypes of the tumour angiogenic process.

  • The onset of angiogenesis, or the 'angiogenic switch', is a discrete step that can occur at any stage of tumour progression. It depends on the type of tumour and its microenvironment.

  • Tumour angiogenesis differs significantly from physiological angiogenesis. Differences include aberrant vascular structure, altered endothelial-cell–pericyte interactions, abnormal blood flow, increased permeability and delayed maturation.

  • The abnormal features of the tumour vasculature are believed to result from the disproportionate expression of angiogenic cytokines and inhibitors. Expression of these varies from tumour to tumour.

  • Tumour hypoxia complicates the angiogenic response, depending on the status of p53, which can regulate key angiogenic cytokines and inhibitors.

  • The angiogenic activity of a tumour does not necessarily correlate with tumour aggressiveness. Nonetheless, it can be a prognostic factor for certain tumour types.

  • Anti-angiogenic agents can be used not only for the treatment of cancer, but also for the prevention of cancer recurrence or metastasis. Given the heterogeneity of tumour and blood-vessel growth, a multidrug approach that targets various factors might be more successful than monotherapy in restraining cancer growth.

Abstract

It has become evident that we cannot understand tumour growth without considering components of the stromal microenvironment, such as the vasculature. At the same time, the tumour phenotype determines the nature of the tumour vasculature. Much research is now devoted to determining the impact of angiogenesis on tumour development and progression, and the reciprocal influences of tumour products on the microvasculature. A more detailed understanding of the complex parameters that govern the interactions between the tumour and vascular compartments will help to improve anti-angiogenic strategies — not only for cancer treatment, but also for preventing recurrence.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: The angiogenic balance.
Figure 2: The classical angiogenic switch.
Figure 3: New blood-vessel formation.
Figure 4: Blood vessel co-option precedes angiogenesis in astrocytoma progression.

Similar content being viewed by others

References

  1. Hahn, W. C. et al. Rules for making human tumor cells. N. Engl. J. Med. 347, 1593–603 (2002).

    CAS  PubMed  Google Scholar 

  2. Duesberg, P. et al. How aneuploidy may cause cancer and genetic instability. Anticancer Res. 19, 4887–4906 (1999).

    CAS  PubMed  Google Scholar 

  3. Pelengaris, S. et al. c-MYC: more than just a matter of life and death. Nature Rev. Cancer 2, 764–776 (2002).

    CAS  Google Scholar 

  4. Vogelstein, B. et al. Genetic alterations during colorectal-tumor development. N. Engl. J. Med. 319, 525–532 (1988).

    CAS  PubMed  Google Scholar 

  5. Hanahan, D. et al. The hallmarks of cancer. Cell 100, 57–70 (2000).

    Article  CAS  PubMed  Google Scholar 

  6. Folkman, J. in Cancer Medicine (Holland, M.D. et al.) 2546 (BC Decker, Hamilton, Ontario, 2000).

    Google Scholar 

  7. Papetti, M. et al. Mechanisms of normal and tumor-derived angiogenesis. Am. J. Physiol. Cell Physiol. 282, C497–C970 (2002).

    Google Scholar 

  8. Hlatky, L. et al. Clinical application of antiangiogenic therapy: microvessel density, what it does and doesn't tell us. J. Natl Cancer Inst. 94, 883–893 (2002). This important review discusses several misconceptions in the angiogenesis field. It specifically focuses on microvessel density and the information that can and cannot be gained from it.

    PubMed  Google Scholar 

  9. Dor, Y. et al. Vascular endothelial growth factor and vascular adjustments to perturbations in oxygen homeostasis. Am. J. Physiol. Cell Physiol. 280, C1367–C1374 (2001).

    CAS  PubMed  Google Scholar 

  10. Kerbel, R. et al. Clinical translation of angiogenesis inhibitors. Nature Rev. Cancer 2, 727–739 (2002). This is a recent and detailed review about anti-angiogenic therapy.

    CAS  Google Scholar 

  11. Hanahan, D. et al. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86, 353–364 (1996).

    CAS  PubMed  Google Scholar 

  12. Carmeliet, P. Mechanisms of angiogenesis and arteriogenesis. Nature Med. 6, 389–395 (2000).

    CAS  PubMed  Google Scholar 

  13. Dvorak, H. F. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N. Engl. J. Med. 315, 1650–1659 (1986).

    CAS  PubMed  Google Scholar 

  14. Benjamin, L. E. et al. Selective ablation of immature blood vessels in established human tumors follows vascular endothelial growth factor withdrawal. J. Clin. Invest. 103, 159–165 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  16. Folberg, R. et al. Vasculogenic mimicry and tumor angiogenesis. Am. J. Pathol. 156, 361–381 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. McDonald, D. M. et al. Vasculogenic mimicry: how convincing, how novel, and how significant? Am. J. Pathol. 156, 383–388 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Lyden, D. et al. Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nature Med. 7, 1194–1201 (2001).

    CAS  PubMed  Google Scholar 

  19. Rafii, S. et al. Efficient mobilization and recruitment of marrow-derived endothelial and hematopoietic stem cells by adenoviral vectors expressing angiogenic factors. Gene Ther. 9, 631–641 (2002).

    CAS  PubMed  Google Scholar 

  20. Hattori, K. et al. Vascular endothelial growth factor and angiopoietin-1 stimulate postnatal hematopoiesis by recruitment of vasculogenic and hematopoietic stem cells. J. Exp. Med. 193, 1005–1014 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Hattori, K. et al. Placental growth factor reconstitutes hematopoiesis by recruiting VEGFR1(+) stem cells from bone-marrow microenvironment. Nature Med. 8, 841–849 (2002).

    CAS  PubMed  Google Scholar 

  22. Pettersson, A. et al. Heterogeneity of the angiogenic response induced in different normal adult tissues by vascular permeability factor/vascular endothelial growth factor. Lab. Invest. 80, 99–115 (2000).

    CAS  PubMed  Google Scholar 

  23. Holash, J. et al. Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science 284, 1994–1998 (1999). The is the first report showing that tumours do not always start as avascular lesions, but can also initially grow by co-opting existing blood vessels. The co-opted host vasculature does not immediately undergo angiogenesis to support the tumour — it first regresses before hypoxia-induced neovascularization is initiated.

    CAS  PubMed  Google Scholar 

  24. Yancopoulos, G. D. et al. Vascular-specific growth factors and blood vessel formation. Nature 407, 242–248 (2000).

    CAS  PubMed  Google Scholar 

  25. Stone, J. et al. Development of retinal vasculature is mediated by hypoxia-induced vascular endothelial growth factor (VEGF) expression by neuroglia. J. Neurosci. 15, 4738–4747 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Hirschi, K. K. et al. Pericytes in the microvasculature. Cardiovasc. Res. 32, 687 (1996).

    CAS  PubMed  Google Scholar 

  27. Benjamin, L. E. et al. A plasticity window for blood vessel remodelling is defined by pericyte coverage of the preformed endothelial network and is regulated by PDGF-B and VEGF. Development 125, 1591–1598 (1998).

    CAS  PubMed  Google Scholar 

  28. Benjamin, L. E. et al. Conditional switching of vascular endothelial growth factor (VEGF) expression in tumors: induction of endothelial cell shedding and regression of hemangioblastoma-like vessels by VEGF withdrawal. Proc. Natl Acad. Sci. USA 94, 8761–8766 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Papapetropoulos, A. et al. Direct actions of angiopoietin-1 on human endothelium: evidence for network stabilization, cell survival, and interaction with other angiogenic growth factors. Lab. Invest. 79, 213–223 (1999).

    CAS  PubMed  Google Scholar 

  30. Adini, A. et al. Placental growth factor is a survival factor for tumor endothelial cells and macrophages. Cancer Res. 62, 2749–2752 (2002).

    CAS  PubMed  Google Scholar 

  31. Ferrara, N. VEGF and the quest for tumour angiogenesis factors. Nature Rev. Cancer 2, 795–803 (2002).

    CAS  Google Scholar 

  32. 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).

    CAS  PubMed  Google Scholar 

  33. Semenza, G. L. HIF-1 and tumor progression: pathophysiology and therapeutics. Trends Mol. Med. 8, S62–S67 (2002).

    CAS  PubMed  Google Scholar 

  34. Maxwell, P. H. et al. Activation of the HIF pathway in cancer. Curr. Opin. Genet. Dev. 11, 293–299 (2001).

    CAS  PubMed  Google Scholar 

  35. Black, W. C. et al. Advances in diagnostic imaging and overestimations of disease prevalence and the benefits of therapy. N. Engl. J. Med. 328, 1237–1243 (1993).

    CAS  PubMed  Google Scholar 

  36. O'Reilly, M. S. Angiostatin: an endogenous inhibitor of angiogenesis and of tumor growth. EXS. 79, 273–294 (1997).

    CAS  PubMed  Google Scholar 

  37. O'Reilly, M. S. et al. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 88, 277–285 (1997).

    CAS  PubMed  Google Scholar 

  38. Joseph, I. B. et al. Antiangiogenic treatment with linomide as chemoprevention for prostate, seminal vesicle, and breast carcinogenesis in rodents. Cancer Res. 56, 3404–3408 (1996).

    CAS  PubMed  Google Scholar 

  39. Subbaramaiah, K. et al. Cyclooxygenase 2: a molecular target for cancer prevention and treatment. Trends Pharmacol. Sci. 24, 96–102 (2003).

    CAS  PubMed  Google Scholar 

  40. Iniguez, M. A. et al. Cyclooxygenase-2: a therapeutic target in angiogenesis. Trends Mol. Med. 9, 73–78 (2003).

    CAS  PubMed  Google Scholar 

  41. Lieberman, R. Chemoprevention of prostate cancer: current status and future directions. Cancer Metastasis Rev. 21, 297–309 (2002).

    CAS  PubMed  Google Scholar 

  42. Hussain, T. et al. Cyclooxygenase-2 and prostate carcinogenesis. Cancer Lett. 191, 125–135 (2003).

    CAS  PubMed  Google Scholar 

  43. Chen, Y. J. et al. High cyclooxygenase-2 expression in cervical adenocarcinomas. Gynecol. Oncol. 88, 379–385 (2003).

    CAS  PubMed  Google Scholar 

  44. Folkman, J. et al. Induction of angiogenesis during the transition from hyperplasia to neoplasia. Nature 339, 58 (1989).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Bergers, G. et al. Angiogenesis and apoptosis are cellular parameters of neoplastic progression in transgenic mouse models of tumorigenesis. Int. J. Dev. Biol. 42, 995 (1998).

    CAS  PubMed  Google Scholar 

  48. Elson, D. A. et al. Sensitivity of the cervical transformation zone to estrogen-induced squamous carcinogenesis. Cancer Res. 60, 1267–1275 (2000).

    CAS  PubMed  Google Scholar 

  49. Inoue, M. et al. VEGF-A has a critical, nonredundant role in angiogenic switching and pancreatic beta cell carcinogenesis. Cancer Cell 1, 193–202 (2002).

    CAS  PubMed  Google Scholar 

  50. Rodriguez-Manzaneque, J. C. et al. Thrombospondin-1 suppresses spontaneous tumor growth and inhibits activation of matrix metalloproteinase-9 and mobilization of vascular endothelial growth factor. Proc. Natl Acad. Sci. USA 98, 12485–12490 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Weidner, N. Tumoural vascularity as a prognostic factor in cancer patients: the evidence continues to grow. J. Pathol. 184, 119–122 (1998).

    CAS  PubMed  Google Scholar 

  52. Zabrenetzky, V. et al. Expression of the extracellular matrix molecule thrombospondin inversely correlates with malignant progression in melanoma, lung and breast carcinoma cell lines. Int. J. Cancer 59, 191–195 (1994).

    CAS  PubMed  Google Scholar 

  53. Weinstat-Saslow, D. L. et al. Transfection of thrombospondin 1 complementary DNA into a human breast carcinoma cell line reduces primary tumor growth, metastatic potential, and angiogenesis. Cancer Res. 54, 6504–6511 (1994).

    CAS  PubMed  Google Scholar 

  54. Pelengaris, S. et al. Suppression of Myc-induced apoptosis in beta cells exposes multiple oncogenic properties of Myc and triggers carcinogenic progression. Cell 109, 321–334 (2002).

    CAS  PubMed  Google Scholar 

  55. Watnick, R. S. et al. Ras modulates Myc activity to repress thrombospondin-1 expression and increase tumor angiogenesis. Cancer Cell 3, 219–231 (2003). This study strengthens the proposition that the angiogenic switch is a crucial step in tumour progression and that is determined by the ultimate balance in pro- and anti-angiogenic factors.

    CAS  PubMed  Google Scholar 

  56. Vajkoczy, P. et al. Microtumor growth initiates angiogenic sprouting with simultaneous expression of VEGF, VEGF receptor-2, and angiopoietin-2. J. Clin. Invest. 109, 777–785 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Holash, J. et al. New model of tumor angiogenesis: dynamic balance between vessel regression and growth mediated by angiopoietins and VEGF. Oncogene 18, 5356–5362 (1999).

    CAS  PubMed  Google Scholar 

  58. Shweiki, D. et al. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 359, 843–845 (1992).

    CAS  PubMed  Google Scholar 

  59. Tomlinson, F. H. et al. The significance of atypia and histologic malignancy in pilocytic astrocytoma of the cerebellum: a clinicopathologic and flow cytometric study. J. Child Neurol. 9, 301–310 (1994).

    CAS  PubMed  Google Scholar 

  60. Brem, S. et al. Tumor angiogenesis: a quantitative method for histologic grading. J. Natl Cancer Inst. 48, 347–356 (1972).

    CAS  PubMed  Google Scholar 

  61. 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 

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

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Douglas, M. L. et al. Renal cell carcinoma may adapt to and overcome anti-angiogenic intervention with thalidomide. BJU Int. 89, 591–595 (2002).

    CAS  PubMed  Google Scholar 

  65. Yu, J. L. et al. Effect of p53 status on tumor response to antiangiogenic therapy. Science 295, 1526–1528 (2002).

    CAS  PubMed  Google Scholar 

  66. Gee, M. S. et al. Hypoxia-mediated apoptosis from angiogenesis inhibition underlies tumor control by recombinant interleukin 12. Cancer Res. 59, 4882–4889 (1999).

    CAS  PubMed  Google Scholar 

  67. Tran, J. et al. A role for survivin in chemoresistance of endothelial cells mediated by VEGF. Proc. Natl Acad. Sci. USA 99, 4349–4354 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Wang, J. H. et al. Hypoxia upregulates Bcl-2 expression and suppresses interferon-gamma induced antiangiogenic activity in human tumor derived endothelial cells. Cancer 94, 2745–2755 (2002).

    CAS  PubMed  Google Scholar 

  69. Zhang, X. S. et al. Multiple drug resistance phenotype of human endothelial cells induced by vascular endothelial growth factor 165. Acta Pharmacol. Sin. 22, 731–735 (2001).

    CAS  PubMed  Google Scholar 

  70. Forsythe, J. A. et al. Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol. Cell. Biol. 16, 4604–4613 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Stein, I. et al. Stabilization of vascular endothelial growth factor mRNA by hypoxia and hypoglycemia and coregulation with other ischemia-induced genes. Mol. Cell. Biol. 15, 5363–5368 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Laderoute, K. R. et al. Opposing effects of hypoxia on expression of the angiogenic inhibitor thrombospondin 1 and the angiogenic inducer vascular endothelial growth factor. Clin. Cancer Res. 6, 2941–2950 (2000).

    CAS  PubMed  Google Scholar 

  73. Royds, J. A. et al. Response of tumour cells to hypoxia: role of p53 and NFkB. Mol. Pathol. 51, 55–61 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Kwak, C. et al. Thrombospondin-1, vascular endothelial growth factor expression and their relationship with p53 status in prostate cancer and benign prostatic hyperplasia. BJU Int. 89, 303–309 (2002).

    CAS  PubMed  Google Scholar 

  75. Mukhopadhyay, D. et al. Wild-type p53 and v-Src exert opposing influences on human vascular endothelial growth factor gene expression. Cancer Res. 55, 6161–6165 (1995).

    CAS  PubMed  Google Scholar 

  76. Zhang, L. et al. Wild-type p53 suppresses angiogenesis in human leiomyosarcoma and synovial sarcoma by transcriptional suppression of vascular endothelial growth factor expression. Cancer Res. 60, 3655–3661 (2000).

    CAS  PubMed  Google Scholar 

  77. Ravi, R. et al. Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1alpha. Genes Dev. 14, 34–44 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Agani, F. et al. p53 does not repress hypoxia-induced transcription of the vascular endothelial growth factor gene. Cancer Res. 57, 4474–4477 (1997).

    CAS  PubMed  Google Scholar 

  79. Holmgren, L. et al. p53 induces angiogenesis-restricted dormancy in a mouse fibrosarcoma. Oncogene 17, 819–824 (1998).

    CAS  PubMed  Google Scholar 

  80. Gautam, A. et al. Aerosol delivery of PEI-p53 complexes inhibits B16-F10 lung metastases through regulation of angiogenesis. Cancer Gene Ther. 9, 28–36 (2002).

    CAS  PubMed  Google Scholar 

  81. Klement, G. et al. Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity. J. Clin. Invest. 105, R15–R24 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Browder, T. et al. Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res. 60, 1878–1886 (2000).

    CAS  PubMed  Google Scholar 

  83. Bergers, G. et al. Combining anti-angiogenic agents with metronomic chemotherapy enhances efficacy against late-stage pancreatic islet carcinomas in mice. CSH Symp. Quant. Biol. 67, 293–300 (2002).

    CAS  Google Scholar 

  84. Bergers, G. et al. Effects of angiogenesis inhibitors on multistage carcinogenesis in mice. Science 284, 808–812 (1999).

    CAS  PubMed  Google Scholar 

  85. Shigematsu, K. et al. Anti-angiogenic drug AGM1470 suppresses smooth muscle cell migration induced by endothelial PDGF. Eur. J. Vasc. Endovasc. Surg. 14, 290–298 (1997).

    CAS  PubMed  Google Scholar 

  86. Bergers, G. et al. Benefits of targeting both pericytes and endothelial cells in the tumor vasculature. J. Clin. Invest. 111, 1287–1295 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Cline, E. I. et al. Prediction of in vivo synergistic activity of antiangiogenic compounds by gene expression profiling. Cancer Res. 62, 7143–7148 (2002).

    CAS  PubMed  Google Scholar 

  88. Dancey, J. et al. Issues and progress with protein kinase inhibitors for cancer treatment. Nature Rev. Drug Discov. 2, 296–313 (2003).

    CAS  Google Scholar 

  89. Hu, Y. L. et al. Lysophosphatidic acid induction of vascular endothelial growth factor expression in human ovarian cancer cells. J. Natl Cancer Inst. 93, 762–768 (2001).

    CAS  PubMed  Google Scholar 

  90. Volpert, O. V. et al. The modulation of thrombospondin and other naturally occurring inhibitors of angiogenesis during tumor progression. Breast Cancer Res. Treat. 36, 119–126 (1995).

    CAS  PubMed  Google Scholar 

  91. Maeshima, Y. et al. Identification of the anti-angiogenic site within vascular basement membrane-derived tumstatin. J. Biol. Chem. 276, 15240–15248 (2001).

    CAS  PubMed  Google Scholar 

  92. Kamphaus, G. D. et al. Canstatin, a novel matrix-derived inhibitor of angiogenesis and tumor growth. J. Biol. Chem. 275, 1209–1215 (2000).

    CAS  PubMed  Google Scholar 

  93. Dameron, K. M. et al. Control of angiogenesis in fibroblasts by p53 regulation of thrombospondin-1. Science 265, 1582–1584 (1994).

    CAS  PubMed  Google Scholar 

  94. Lawler, J. et al. Thrombospondin-1 gene expression affects survival and tumor spectrum of p53-deficient mice. Am. J. Pathol. 159, 1949–1956 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Nishimori, H. et al. A novel brain-specific p53-target gene, BAI1, containing thrombospondin type 1 repeats inhibits experimental angiogenesis. Oncogene 15, 2145–2150 (1997).

    CAS  PubMed  Google Scholar 

  96. Bian, J. et al. Transcriptional activation by p53 of the human type IV collagenase (gelatinase A or matrix metalloproteinase 2) promoter. Mol. Cell. Biol. 17, 6330–6338 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Brantley, D. M. et al. Soluble Eph A receptors inhibit tumor angiogenesis and progression in vivo. Oncogene 21, 7011–7026 (2002).

    CAS  PubMed  Google Scholar 

  98. Dohn, M. et al. Receptor tyrosine kinase EphA2 is regulated by p53-family proteins and induces apoptosis. Oncogene 20, 6503–6515 (2001).

    CAS  PubMed  Google Scholar 

  99. Cheng, N. et al. Blockade of EphA receptor tyrosine kinase activation inhibits vascular endothelial cell growth factor-induced angiogenesis. Mol. Cancer Res. 1, 2–11 (2002).

    CAS  PubMed  Google Scholar 

  100. Sun, Y. et al. Human metalloproteinase-1 (collagenase-1) is a tumor suppressor protein p53 target gene. Ann. NY Acad. Sci. 878, 638–641 (1999).

    CAS  PubMed  Google Scholar 

  101. Zhou, Z. et al. Impaired endochondral ossification and angiogenesis in mice deficient in membrane-type matrix metalloproteinase I. Proc. Natl Acad. Sci. USA 97, 4052–4057 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Subbaramaiah, K. et al. Inhibition of cyclooxygenase-2 gene expression by p53. J. Biol. Chem. 274, 10911–10915 (1999).

    CAS  PubMed  Google Scholar 

  103. Pal, S. et al. Central role of p53 on regulation of vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) expression in mammary carcinoma. Cancer Res. 61, 6952–6957 (2001).

    CAS  PubMed  Google Scholar 

  104. Moser, T. Angiostatin binds ATP synthase on the surface of human endothelial cells. Proc. Natl Acad. Sci. USA 96, 2811–2816 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Troyanovsky, B. et al. Angiomotin: an angiostatin binding protein that regulates endothelial cell migration and tube formation. J. Cell. Biol. 152, 1247–1254 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Yeh, R. J. et al. The antiangiogenic agent TNP470 requires p53 and p21CIP/WAF for endothelial cell growth arrest. Proc. Natl Acad. Sci. USA 97, 12782–12787 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Sternlicht, M. D. et al. Matrix proteinases as emerging targets in anticancer therapy: status and prospects. ETT 4, 609–633 (2000).

    CAS  Google Scholar 

  108. Fong, T. A. et al. SU5416 is a potent and selective inhibitor of the vascular endothelial growth factor receptor (Flk–1/KDR) that inhibits tyrosine kinase catalysis, tumor vascularization, and growth of multiple tumor types. Cancer Res. 59, 99 (1999).

    CAS  PubMed  Google Scholar 

  109. Laird, A. D. et al. SU6668 is a potent antiangiogenic and antitumor agent that induces regression of established tumors. Cancer Res. 60, 4152–4160 (2000).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank T. Tihan (University of California San Francisco) for advising us on brain-tumour pathology.

Author information

Authors and Affiliations

  1. Department of Neurological Surgery, University of California San Francisco, Brain Tumor Research Center and Comprehensive Cancer Center, HSE 722, 513 Parnassus Avenue, San Francisco, 94143-0520, California, USA

    Gabriele Bergers

  2. Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, 02215, Massachusetts, USA

    Laura E. Benjamin

Authors
  1. Gabriele Bergers
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Laura E. Benjamin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gabriele Bergers.

Related links

Related links

DATABASES

Cancer.gov

astrocytoma

breast cancer

cervical cancer

colon cancer

glioblastoma

lung cancer

melanoma

prostate cancer

renal-cell carcinoma

GenBank

E1A

E6

E7

LocusLink

ANG1

ANG2

BCL2

BCL-XL

endostatin

FGF

HIF-1α

MDM2

MMP9

MYC

p53

PDGF

PDGFR

PlGF

RAS

RB

TERT

TIE2

TNF-α

TSP1

VEGFA

VEGFC

VEGFD

VEGFR1

VEGFR2

OMIM

familial adenomatous polyposis

FURTHER INFORMATION

National Cancer Institute — Understanding angiogenesis

Glossary

PERIVASCULAR CELLS

Mural cells that surround the endothelium. These cells are related to the vascular smooth-muscle lineage and share many markers with these cells.

ENDOTHELIAL PRECURSOR CELLS

Undifferentiated cells in the adult bone marrow that can travel through the blood to sites of ongoing angiogenesis, and differentiate into mature endothelial cells. They have recently been implicated in tumour angiogenesis. These cells are identified by co-expression of haematopoietic stem-cell markers (CD34 and AC133), and vascular endothelial-cell markers (VEGFR2 and TIE2).

PERICYTES

Cells that are related to vascular smooth muscle. These cells are adjacent to and surrounding the endothelium, share a common basement membrane with the endothelium, and have gap-junction connections with the endothelial cells. Whether these cells are multipotent, with the ability to differentiate into either vascular smooth muscle or even endothelium, is still unclear.

MURAL CELLS

Cells of the blood-vessel wall.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bergers, G., Benjamin, L. Tumorigenesis and the angiogenic switch. Nat Rev Cancer 3, 401–410 (2003). https://doi.org/10.1038/nrc1093

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc1093

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing