Tumor Angiogenesis

  • Domenico Ribatti


In 1907, Goldman described the characteristics of tumor vessels including their dilatation, accelerated proliferation and irregular arrangement. In 1939, Ide et al. were the first to suggest that tumors release specific factors capable of stimulating the growth of blood vessels. In 1945, Algire and Chalkley were the first to appreciate that growing malignancies could continuously elicit new capillary growth from the host. They used a transparent chamber implanted in a cat’s skin to study the vasoproliferative reaction secondary to a wound or implantation of normal or neoplastic tissues. They showed that the vasoproliferative response induced by tumor tissues was more substantial and earlier than that induced by normal tissues or following a wound. They found that capillaries arose from the host and that endothelial proliferation appeared as early as 3 days after implantation, weheras in wounds it did not begin for 6 days. Moreover, differentiation of vessels in vessels into arterioles and venules was not evident and the authors believe that an oustainding characteristic of the tumor cells was its capacity to elicit continued growth of new capillaries from the host: “This characteristic of the tumor cell, rather than some hypothetical capacity for autonomous growth inherent within the cell, is, from the standpoint of the host, an important expression of neoplastic change”. They concluded that the growth of a tumor is closely connected to the development of an intrinsic vascular network.


  1. Algire GH, Chalkley HW (1945) Vascular reactions of mice to wound and to normal and neoplastic transplants. J Natl Cancer Inst 6:73–85CrossRefGoogle Scholar
  2. Aterton A (1977) Growth stimulation of endothelial cells by simultaneous culture with sarcoma 180 cells in diffusion chambers. Cancer Res 37:3619–3622Google Scholar
  3. Ausprunk DH, Knighton DR, Folkman J (1974) Differentiation of vascular endothelium in the chick chorioallantois: a structural and autoradiographic study. Dev Biol 38:237–248CrossRefPubMedGoogle Scholar
  4. Ausprunk DH, Knighton DR, Folkman J (1975) Vascularization of normal and neoplastic tissues grafted to the chick chorioallantois. Role of host and preexisting graft blood vessels. Am J Pathol 79:597–618PubMedPubMedCentralGoogle Scholar
  5. Bergers G, Song S, Mayer-Morse N et al (2003) Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J Clin Invest 111:1287–1295CrossRefPubMedPubMedCentralGoogle Scholar
  6. Brem S, Cotran R, Folkman J (1972) Tumor angiogenesis: a quantitative method for histologic grading. J Natl Cancer Inst 48:347–356PubMedGoogle Scholar
  7. Brem S, Brem H, Folkman J et al (1976) Prolonged tumor dormancy by prevention of neovascularization in the vitreous. Cancer Res 36:2807–2812PubMedGoogle Scholar
  8. Brem S, Gullino PM, Medina D (1977) Angiogenesis: a marker for neoplastic transformation of mammary papillary hyperplasia. Science 195:880–882CrossRefPubMedGoogle Scholar
  9. Brem S, Jensen HM, Gullino PM (1978) Angiogenesis as a marker of preneoplastic lesions of the human breast. Cancer 41:239–244CrossRefPubMedGoogle Scholar
  10. Cairns RA, Khokha R, Hill RP (2003) Molecular mechanisms of tumor growth and metastasis: an integrated view. Curr Mol Med 3:659–671CrossRefPubMedGoogle Scholar
  11. Cao Y (2010) Angiogenesis: what can it offer for future medicine? Exp Cell Res 316:1304–1308CrossRefPubMedGoogle Scholar
  12. Casanovas O, Hicklin DJ, Bergers et al (2005) Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell 8:299–309CrossRefPubMedGoogle Scholar
  13. Castellani P, Boris L, Caremolla A et al (2002) Differentiation between high- and low-grade astrocytoma using a human recombinant antibody to the extra domain-B of fibronectin. American J Pathol 161:1695–1700CrossRefGoogle Scholar
  14. Cavallo T, Sade R, Folkman J et al (1972) Tumor angiogenesis: rapid induction of endothelial mitosis demonstrated by autoradiography. J Cell Biol 54:408–420CrossRefPubMedPubMedCentralGoogle Scholar
  15. Cavallo T, Sade R, Folkman J et al (1973) Ultrastructural autoradiographic studies of the early vasoproliferative response in tumor angiogenesis. Am J Pathol 70:345–362PubMedPubMedCentralGoogle Scholar
  16. Chodak GW, Haudenschild C, Gittes RF et al (1980) Angiogenic activity as a marker of neoplastic and preneoplastic lesions of the human bladder. Ann Surg 192:762–771CrossRefPubMedPubMedCentralGoogle Scholar
  17. Denekamp J, Hobson B (1982) Endothelial cell proliferation in experimental tumors. Br J Cancer 46:711–720CrossRefPubMedPubMedCentralGoogle Scholar
  18. Ebos JM, Lee CR, Christensen JG et al (2007) Multiple circulating proangiogenic factors induced by sunitinib malate are tumor-independent and correlate with antitumor efficacy. Proc Natl Acad Sci U S A 104:17069–17074CrossRefPubMedPubMedCentralGoogle Scholar
  19. Ebos JM, Lee CR, Cruz-Munoz W et al (2009) Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell 15:232–239CrossRefPubMedPubMedCentralGoogle Scholar
  20. Ehrman RL, Knoth M (1968) Choriocarcinoma: transfilter stimulation of vasoproliferation in the hamster cheek pouch studied by light and electron microscopy. J Natl Cancer Inst 41:1329–1341Google Scholar
  21. Erber R, Thurnher A, Katsen AD et al (2004) Combined inhibition of VEGF and PDGF signaling enforces tumor vessel regression by interfering with pericyte-mediated endothelial cell survival mechanisms. FASEB J 18:338–340CrossRefPubMedGoogle Scholar
  22. Folkman J (1971) Tumor angiogenesis. Therapeutic implications. N Engl J Med 285:1182–1186CrossRefPubMedPubMedCentralGoogle Scholar
  23. Folkman J (1990) Whas is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst 82:4–6CrossRefGoogle Scholar
  24. Folkman J (2002) Clinical application of antiangiogenic therapy: microvessel density, what it does and doesn’t tell us. J Natl Cancer Inst 94:883–893CrossRefPubMedGoogle Scholar
  25. Folkman J, Cotran R (1976) Relation of vascular proliferation to tumor growth. Int Rev Exp Pathol 16:207–248PubMedGoogle Scholar
  26. Folkman J, Hochberg M (1983) Self-regulation of growth in three dimensions. J Exp Med 138:745–753CrossRefGoogle Scholar
  27. Folkman MJ, Long DM, Becker FF (1963) Growth and metastasis of tumor in organ culture. Cancer 16:453–467CrossRefPubMedGoogle Scholar
  28. Folkman J, Watson K, Ingber D et al (1989) Induction of angiogenesis during the transition from hyperplasia to neoplasia. Nature 339:58–61CrossRefPubMedGoogle Scholar
  29. Gimbrone MA Jr, Gullino PM (1976a) Angiogenesis capacity of preneoplastic lesions of the murine mammary gland as a marker of neoplastic transformation. Cancer Res 36:2611–2620PubMedGoogle Scholar
  30. Gimbrone MA Jr, Gullino PM (1976b) Neovascularization induced by intraocular xenografts of normal, preneoplastic and neoplastic mouse mammary tissue. J Natl Cancer Inst 56:305–318CrossRefPubMedGoogle Scholar
  31. Gimbrone MA Jr, Aster RH, Cotran RS et al (1969) Preservation of vascular integrity in organs perfused in vitro with a platelet-rich medium. Nature 222:33–36CrossRefPubMedGoogle Scholar
  32. Gimbrone MA Jr, Cotran RS, Folkman J (1974a) Human vascular endothelial cells in culture. Growth and DNA synthesis. J Cell Biol 60:673–684CrossRefPubMedPubMedCentralGoogle Scholar
  33. Gimbrone MA Jr, Cotran RS, Folkman J (1974b) Tumor growth and neovascularization: an experimental model using rabbit cornea. J Natl Cancer Inst 52:413–427CrossRefPubMedGoogle Scholar
  34. Gimbrone MA, Leapman SB, Cotran RS et al (1972) Tumor dormancy in vivo by prevention of neovascularization. J Exp Med 136:261–276CrossRefPubMedPubMedCentralGoogle Scholar
  35. Gimbrone MA, Leapman S, Cotran RS et al (1973) Tumor angiogenesis: iris neovascularization at a distance from experimental intraocular tumors. J Natl Cancer Inst 50:219–228CrossRefGoogle Scholar
  36. Goldman E (1907) The growth of malignant disease in man and the lower animals with special reference to the vascular system. Lancet 2:1236–1237CrossRefGoogle Scholar
  37. Greenblatt M, Shubik P (1968) Tumor angiogenesis: transfilter diffusion studied in the hamster by the transparent chamber technique. J Natl Cancer Inst 41:1111–1124Google Scholar
  38. Greene HSN (1941) Heterologous transplantation of mammalian tumors: I. The transfer of rabbit tumors to alien species. J Exp Med 73:461–474CrossRefPubMedPubMedCentralGoogle Scholar
  39. Gullino PM, Grantham FH (1961) Studies on the exchange of fluids between host and tumor. The blood flow of hepatomas and other tumors in rats and mice. J Natl Cancer Inst 27:1465–1491PubMedGoogle Scholar
  40. Hanahan D, Folkman J (1996) Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86:353–364CrossRefPubMedGoogle Scholar
  41. Holmgren L, O’Reilly MS, Folkman J (1995) Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nat Med 1:149–153CrossRefGoogle Scholar
  42. Hu-Lowe DD, Zou HY, Grazzini ML et al (2008) Non-clinical antiangiogenesis and antitumor activities of axitinib (AG-013736), an oral, potent, and selective inhibitor of vascular endothelial growth factor receptor tyrosine kinase 1, 2, 3. Clin Cancer Res 14:7272–7283CrossRefPubMedGoogle Scholar
  43. Ide AG, Baker NH, Warren SL (1939) Vascularization of the Brown-Pearce rabbit epithelioma transplant as seen in the transparent ear chamber. Am J Roentg 32:891–899Google Scholar
  44. Inai T, Mancuso M, Hashizume H et al (2004) Inhibition of vascular endothelial growth factor (VEGF) signaling in cancer causes loss of endothelial fenestrations, regression of tumor vessels, and appearance of basement membrane ghosts. Am J Pathol 165:35–52CrossRefPubMedPubMedCentralGoogle Scholar
  45. Jain RK (2001) Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat Med 7:987–989CrossRefPubMedGoogle Scholar
  46. Kandell J, Bossy-Wetzel E, Radvanyi F et al (1991) Neovascularization is associated with switch to the export of bFGF in the multispep development of fibrosarcoma. Cell 66:1095–1104CrossRefGoogle Scholar
  47. Knighton D, Ausprunk D, Tapper D et al (1977) Avascular and vascular phases of tumour growth in the chick embryo. Br J Cancer 35:347–356CrossRefPubMedPubMedCentralGoogle Scholar
  48. Kunkel P, Ulbricht U, Bohlen P et al (2001) Inhibition of glioma angiogenesis and growth in vivo by systemic treatment with a monoclonal antibody against vascular endothelial growth factor receptor-2. Cancer Res 61:6624–6628PubMedGoogle Scholar
  49. Lewis WH (1927) The vascular pattern of tumours. John Hopkins Hosp Bull 41:156–173Google Scholar
  50. McCulloch P, Choy A, Martin L (1995) Association between tumour angiogenesis and tumour cell shedding into effluent venous blood during breast cancer surgery. Lancet 346:1334–1335CrossRefPubMedGoogle Scholar
  51. Melwin RM, Algire GH (1956) The role of graft and host vessels in vascularization of grafts of normal and neoplastic tissues. J Natl Cancer Inst 17:23–33Google Scholar
  52. Narayana A, Kelly P, Golfinos PJ et al (2008) Antiangiogenic therapy using bevacizumab in recurrent high-grade glioma: impact on local control and patient survival. J Neurosurg 110:173–180CrossRefGoogle Scholar
  53. Nordern AD, Young GS, Setayesh K et al (2008) Bevacizumab for recurrent malignant gliomas: efficacy, toxicity and patterns of recurrence. Neurology 70:779–787CrossRefGoogle Scholar
  54. O’Reilly MS, Holmgren L, Shing Y et al (1994) Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastasis by a Lewis lung carcinoma. Cell 79:315–328CrossRefGoogle Scholar
  55. Padera TP, Kuo AH, Hoshida T et al (2008) Differential response of primary tumor versus lymphatic metastasis to VEGFR-2 and VEGFR-3 kinase inhibitors cediranib and vandetanib. Mol. Cancer Res 7:2272–2279Google Scholar
  56. Paez-Ribes M, Allen A, Hudock J et al (2009) Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 15:222–231CrossRefGoogle Scholar
  57. Pennacchietti S, Michieli P, Galluzzo M et al (2003) Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell 3:347–361CrossRefPubMedGoogle Scholar
  58. Roskoski R Jr (2007) Sunitinib: a VEGF and PDGF receptor protein kinase and angiogenesis inhibitor. Biochem Biophys Res Commun. 356:323–328CrossRefPubMedGoogle Scholar
  59. Saidi A, Hagedorn M, Allain N et al (2009) Combined targeting of interleukin 6 and vascular endothelial growth factor potently inhibits glioma growth and invasiveness. Int J Cancer 125:1054–1064CrossRefPubMedGoogle Scholar
  60. Srivastava A, Ladler P, Davies R et al (1989) The prognostic significance of tumor vascularity in intermediate thickness (0.76-4.0 mm) skin melanoma. Am J Pathol 133:419–423Google Scholar
  61. St Croix B, Ragio C, Velculescu V et al (2000) Genes expressed in human tumor endothelium. Science 18:1197–1202CrossRefGoogle Scholar
  62. Urbach F (1961) The blood suplly of tumors. In: Montagna W, Ellis RA (eds) Advances of biology of the skin. Pergamon Press, New York, pp 123–149Google Scholar
  63. Weidner N, Semple JP, Welch WR et al (1991) Tumor angiogenesis and metastasis– correlation in invasive breast carcinoma. N Engl J Med 324:1–8CrossRefGoogle Scholar
  64. Weidner N, Folkman J, Pozza F et al (1992) Tumor angiogenesis: a new significant and independent prognostic indicator in early-stage breast cancer. J Natl Cancer Inst 84:1875–1887CrossRefPubMedGoogle Scholar
  65. Weidner N, Carroll PR, Flax J et al (1993) Tumor angiogenesis correlates with metastasis in invasive prostate carcinoma. Am J Pathol 143:401–409PubMedPubMedCentralGoogle Scholar
  66. Weinstat-Saslow D, Steeg PS (1994) Angiogenesis and colonization in the tumor metastatc process: basic and applied advances. FASEB J 8:401–407CrossRefPubMedGoogle Scholar
  67. Wilhelm SM, Adnane L, Newell P et al (2008) Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling. Mol Cancer Ther 7:3129–3140CrossRefPubMedGoogle Scholar
  68. Xian X, Hakansson J, Stahlberg A et al (2006) Pericytes limit tumor cell metastasis. J Clin Invest 116:642–651CrossRefPubMedPubMedCentralGoogle Scholar

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© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Domenico Ribatti
    • 1
  1. 1.Department of Basic Medical Sciences, Neurosciences and Sensory OrgansUniversity of Bari Medical SchoolBariItaly

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