Mechanisms of tumour vascularisation

Review article


Tissue growth is highly dependent on the supply of oxygen and nutrients. This regulatory mechanism does not only apply to normal tissue but also to tumour tissue. In contrast to normal tissue, a tumour at the initial stage is not vascularised. Thus, further expansion requires that the tumour creates its own blood vessel supply. In this context, it is well established that tumours can induce capillary sprouting from pre-existing, surrounding vessels. For many years, it was believed that tumour vascularisation is exclusively due to this process. However, recent studies have revealed complementary mechanisms and processes, such as intussusceptive angiogenesis and postnatal vasculogenesis, as well as alternative mechanisms, like vessel co-option and vasculogenic mimicry. Furthermore, several cellular and molecular mechanisms mediating the switch from a non-angiogenic to an angiogenic phenotype have meanwhile been identified and targeting key molecules has become a novel strategy to treat malignant diseases. This review briefly summarises the current knowledge on molecular and cellular aspects of tumour vascularisation to emphasise the complexity of the vascularisation process.


Angiogenesis Intussusception Vasculogenesis Vessel co-option Vasculogenic mimicry 


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  1. Folkman J. Tumor angiogenesis: therapeutic implications. New Engl J Med, 285: 1182–1186, 1971PubMedGoogle Scholar
  2. Folkman J, Shing Y. Angiogenesis. J Biol Chem, 267: 10931–10934, 1992PubMedGoogle Scholar
  3. Risau W. Mechanisms of angiogenesis. Nature, 386: 671–674, 1997PubMedCrossRefGoogle Scholar
  4. Auguste P, Lemiere S, Larrieu-Lahargue F, et al. Molecular mechanisms of tumor vascularization. Cr Re in Oncol/Haematol, 54: 53–61, 2005CrossRefGoogle Scholar
  5. Otrock ZK, Mahfouz RAR, Makarem JA, et al. Understanding the biology of angiogenesis: review of the most important molecular mechanisms. Blood Cells Mol Diseases, 39: 212–220, 2007CrossRefGoogle Scholar
  6. Pugh CW, Ratcliffe PJ. Regulation of angiogenesis by hypoxia: role of the HIF system. Nature Med, 9: 677–684, 2003PubMedCrossRefGoogle Scholar
  7. Folkman J. Angiogenesis: an organizing principle? Nature Rev, 6: 273–286, 2007CrossRefGoogle Scholar
  8. Ergun S, Tilki D, Oliveira-Ferrer L, et al. Significance of vascular stabilization for tumor growth and metastasis. Cancer Lett, 238: 180–187, 2006PubMedCrossRefGoogle Scholar
  9. Mc Donald DM, Baluk P. Significance of blood vessel leakiness in cancer. Cancer Res, 62: 5381–5385, 2002Google Scholar
  10. Ergün S, Kilic N, Ziegeler G, et al. CEA-related adhesion molecule 1: a potent angiogenic factor and a major effector of vascular endothelial growth factor. Mol Cell, 5: 311–320, 2000PubMedCrossRefGoogle Scholar
  11. Kilic N, Oliveira-Ferrer L, Wurmbach JH, et al. Pro-angiogenic signaling by the endothelial presence of CEACAM1. J Biol Chem, 280: 2361–2369, 2005PubMedCrossRefGoogle Scholar
  12. Chantrain CF, Henriet P, Jodele S, et al. Mechanisms of pericyte recruitment in tumour angiogeneis: a new role for metalloproteases. Eur J Cancer, 42: 310–318, 2006PubMedCrossRefGoogle Scholar
  13. Thurston G, Rudge JS, Ioffe E, et al. Angiopoietin-1 protects the adult vasculature against plasma leakage. Nat Med, 6: 460–463, 2000PubMedCrossRefGoogle Scholar
  14. Tilki D, Kilic N, Sevinc S, et al. Zone-specific remodeling of tumour blood vessels affects tumor growth. Cancer, 110: 2347–2362, 2007PubMedCrossRefGoogle Scholar
  15. Djonov V, Baum O, Burri PH. Vascular remodeling by intussusceptive angiogenesis. Cell Tissue Res, 314: 107–117, 2003PubMedCrossRefGoogle Scholar
  16. Risau W, Flamme I. Vasculogenesis. Ann Rev Cell Dev Biol, 11: 73–91, 1995CrossRefGoogle Scholar
  17. Asahara T, Murohara T, Sullivan A, et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science, 275: 964–967, 1997PubMedCrossRefGoogle Scholar
  18. Peichev M, Naijer AJ, Pereira D, et al. Expression of VEGFR-2 and AC133 by circulating human CD34(+) cells identifies a population of functional endothelial precursors. Blood, 95: 952–958, 2000PubMedGoogle Scholar
  19. Gehling UM, Ergün S, Schumacher U, et al. In vitro differentiation of endothelial cells from AC133-positive progenitor cells. Blood, 95: 3106–3112, 2000PubMedGoogle Scholar
  20. Sangai T, Adams V, Gielen S, et al. Effect of differences in cancer cells and tumor growth sites on recruiting bone marrow-derived endothelial cells and myofibroblats in cancer-induced stroma. Int J Cancer, 115: 885–892, 2005PubMedCrossRefGoogle Scholar
  21. Ingram DA, Mead LE, Moore DB, et al. Vessel wall-derived endothelial cells rapidly proliferate because they contain a complete hierarchy of endothelial progenitor cells. Blood, 105: 2783–2786, 2005PubMedCrossRefGoogle Scholar
  22. Zengin E, Chalajour F, Gehling UM, et al. Vascular wall resident progenitor cells: a source for postnatal vasculogenesis. Development, 133: 1543–1551, 2006PubMedCrossRefGoogle Scholar
  23. Ergün S, Tilki D, Hohn HP, et al. Potential implications of vascular wall resident endothelial progenitor cells. Thromb Haemost, 98: 930–939, 2007PubMedGoogle Scholar
  24. Holash J, Maisonpierre PC, Compton D, et al. Vessel cooption, regression and growth in tumors mediated by angiopoietins and VEGF. Science, 284: 1994–1998, 1999PubMedCrossRefGoogle Scholar
  25. Döme B, Paku S, Somlai B, et al. Vascularization of cutaneous melanoma involves vessel co-option and has clinical significance. J Pathol, 197: 355–362, 2002PubMedCrossRefGoogle Scholar
  26. Maniotis AJFR, Hess A, Seftor EA, et al. Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry. Am J Pathol, 155: 739–752, 1999PubMedGoogle Scholar
  27. Zhang S, Zhang D, Sun B. Vasculogenic mimicry: Current status and future prospects. Cancer Lett, 254: 157–164, 2007PubMedCrossRefGoogle Scholar
  28. Kalluri R, Zeisberg M. Fibroblasts in cancer. Nature, 6: 392–401, 2006Google Scholar
  29. Jin DK, Shido K, Kopp HG, et al. Cytokine-mediated deployment of SDF-1 induces revascularization through recruitment of CXCR4 (+) hemangiocytes. Nat Med, 12: 557–567, 2006PubMedCrossRefGoogle Scholar
  30. Lyden D, Hattori K, Dias S, et al. Impaired recruitment of bone marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and tumor growth. Nat Med, 7: 1194–1201, 2001PubMedCrossRefGoogle Scholar
  31. Italiano JE Jr, Richardson JL, Patel-Hett S, et al. Angiogenesis is regulated by a novel mechanism: pro- and anti-angiogenic proteins are organized into separate platelet alpha-granules and differentially released. Blood, 111 (2007 Oct 25): 1227–1233, 2008PubMedCrossRefGoogle Scholar
  32. Sawano A, Iwai S, Sakurai Y, et al. Flt-1, vascular endothelial growth factor-1, is novel surface marker for the lineage of monocyte-macrophages in humans. Blood, 97: 785–791, 2001PubMedCrossRefGoogle Scholar
  33. De Palma M, Naldini L. Role of haematopoietic cells and endothelial progenitors in tumour angiogenesis. Biochim Biophys Acta, 1766: 159–166, 2006PubMedGoogle Scholar
  34. Okamoto R, Ueno M, Yamada Y, et al. Haematopoietic cells regulate the angiogenic switch during tumorigenesis. Blood, 105: 2757–2763, 2005PubMedCrossRefGoogle Scholar
  35. Kopp HG, Hooper AT, Broekmann MJ et al. Thrombospondins deployed by thrombopoietic cells determine angiogeneic switch and extent of revascularization. J Clin Invest, 116: 3277–3291, 2006PubMedCrossRefGoogle Scholar
  36. Fernandez Pujol B, Lucibello FC, Gehling UM, et al. Endothelial like cells derived from CD14 positive monocytes. Differentiation, 65: 287–300, 2000PubMedCrossRefGoogle Scholar
  37. Conejo-Garcia JR, Benecia F, Courreges MC, et al. Tumour-infiltrating dendritic cell precursors recruited by a beta-defensin contribute to vasculogenesis under the influence of Vegf-A. Nat Med, 10: 950–958, 2004PubMedCrossRefGoogle Scholar
  38. Yang L, DeBusk LM, Fukada B, et al. Expansion of myeloid immune suppressor Gr-1+CD11b+ cells in tumour-bearing host directly promotes tumor angiogenesis. Cancer Cell, 6: 409–421, 2004PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  1. 1.Department of Hepatobiliary Surgery and Transplant SurgeryUniversity Hospital Hamburg-EppendorfHamburgGermany
  2. 2.Institute of AnatomyUniversity Hospital EssenEssenGermany

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