International Journal of Clinical Oncology

, Volume 21, Issue 2, pp 206–212 | Cite as

Tumor angiogenesis—characteristics of tumor endothelial cells

  • Kyoko Hida
  • Nako Maishi
  • Chisaho Torii
  • Yasuhiro Hida
Invited Review Article


Tumor blood vessels provide nutrition and oxygen to the tumor, resulting in tumor progression. They also act as gatekeepers, inducing tumor metastasis. Thus, targeting tumor blood vessels is an important strategy in cancer therapy. Tumor endothelial cells (TECs), which line the inner layer of blood vessels of the tumor stromal tissue, are the main targets of anti-angiogenic therapy. Because new tumor blood vessels generally sprout from pre-existing vasculature, they have been considered to be the same as normal blood vessels. However, tumor blood vessels demonstrate a markedly abnormal phenotype that includes several important morphological changes. The degree of angiogenesis is determined by the balance between the angiogenic stimulators and inhibitors released by the tumor and host cells. Recent studies have revealed that TECs also exhibit altered characteristics which depend on the tumor microenvironment. Here, we review recent studies on TEC abnormalities and heterogeneity with respect to tumor progression and consider their therapeutic implications.


Tumor angiogenesis Anti-angiogenic therapy Tumor endothelial cell Blood vessel Metastasis 



We thank the members of the Department of Vascular Biology, Institute for Genetic Medicine, Hokkaido University, and Dr. Shindoh for helpful discussions.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Science, and Culture of Japan (to K. Hida, Y. Hida, and N. Maishi) and by grants from the Suhara Foundation and Naito Foundation (to K. Hida).


  1. 1.
    Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285(21):1182–1186CrossRefPubMedGoogle Scholar
  2. 2.
    Folkman J, Kerbel R (2002) Role of angiogenesis in tumor growth and metastasis. Clinical translation of angiogenesis inhibitors. Semin Oncol 29(6 Suppl 16):15–18CrossRefPubMedGoogle Scholar
  3. 3.
    Folkman J (2007) Angiogenesis: an organizing principle for drug discovery? Nat Rev Drug Discov 6(4):273–286CrossRefPubMedGoogle Scholar
  4. 4.
    Johnson DH, Fehrenbacher L, Novotny WF et al (2004) Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 22(11):2184–2191CrossRefPubMedGoogle Scholar
  5. 5.
    Keedy VL, Sandler AB (2007) Inhibition of angiogenesis in the treatment of non-small cell lung cancer. Cancer Sci 98(12):1825–1830CrossRefPubMedGoogle Scholar
  6. 6.
    Kindler HL, Friberg G, Singh DA et al (2005) Phase II trial of bevacizumab plus gemcitabine in patients with advanced pancreatic cancer. J Clin Oncol 23(31):8033–8040CrossRefPubMedGoogle Scholar
  7. 7.
    Saif MW, Elfiky A, Salem RR (2007) Gastrointestinal perforation due to bevacizumab in colorectal cancer. Ann Surg Oncol 14(6):1860–1869CrossRefPubMedGoogle Scholar
  8. 8.
    Winkler F, Kozin SV, Tong RT et al (2004) Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell 6(6):553–563PubMedGoogle Scholar
  9. 9.
    Zhang L, Takara K, Yamakawa D, et al (2015) Apelin as a marker for monitoring the tumor vessel normalization window during antiangiogenic therapy. Cancer Sci 107(1):36–44Google Scholar
  10. 10.
    Bergers G, Benjamin LE (2003) Tumorigenesis and the angiogenic switch. Nat Rev Cancer 3(6):401–410CrossRefPubMedGoogle Scholar
  11. 11.
    Goh PP, Sze DM, Roufogalis BD (2007) Molecular and cellular regulators of cancer angiogenesis. Curr Cancer Drug Targets 7(8):743–758CrossRefPubMedGoogle Scholar
  12. 12.
    McDonald DM, Choyke PL (2003) Imaging of angiogenesis: from microscope to clinic. Nat Med 9(6):713–725CrossRefPubMedGoogle Scholar
  13. 13.
    Hashizume H, Baluk P, Morikawa S et al (2000) Openings between defective endothelial cells explain tumor vessel leakiness. Am J Pathol 156(4):1363–1380CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Kalluri R (2003) Basement membranes: structure, assembly and role in tumour angiogenesis. Nat Rev Cancer 3(6):422–433CrossRefPubMedGoogle Scholar
  15. 15.
    Baluk P, Hashizume H, McDonald DM (2005) Cellular abnormalities of blood vessels as targets in cancer. Curr Opin Genet Dev 15(1):102–111CrossRefPubMedGoogle Scholar
  16. 16.
    McDonald DM, Baluk P (2002) Significance of blood vessel leakiness in cancer. Cancer Res 62(18):5381–5385PubMedGoogle Scholar
  17. 17.
    Jain RK (2005) Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307(5706):58–62CrossRefPubMedGoogle Scholar
  18. 18.
    Chang YS, di Tomaso E, McDonald DM et al (2000) Mosaic blood vessels in tumors: frequency of cancer cells in contact with flowing blood. Proc Natl Acad Sci USA 97(26):14608–14613CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Langenkamp E, Molema G (2009) Microvascular endothelial cell heterogeneity: general concepts and pharmacological consequences for anti-angiogenic therapy of cancer. Cell Tissue Res 335(1):205–222CrossRefPubMedGoogle Scholar
  20. 20.
    Arap W, Kolonin MG, Trepel M et al (2002) Steps toward mapping the human vasculature by phage display. Nat Med 8(2):121–127CrossRefPubMedGoogle Scholar
  21. 21.
    Trepel M, Arap W, Pasqualini R (2002) In vivo phage display and vascular heterogeneity: implications for targeted medicine. Curr Opin Chem Biol 6(3):399–404CrossRefPubMedGoogle Scholar
  22. 22.
    Hida K, Hida Y, Amin DN et al (2004) Tumor-associated endothelial cells with cytogenetic abnormalities. Cancer Res 64(22):8249–8255CrossRefPubMedGoogle Scholar
  23. 23.
    Arbiser JL, Raab G, Rohan RM et al (1999) Isolation of mouse stromal cells associated with a human tumor using differential diphtheria toxin sensitivity. Am J Pathol 155(3):723–729CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Croix BS, Rago C, Velculescu V et al (2000) Genes expressed in human tumor endothelium. Science 289(5482):1197–1202CrossRefGoogle Scholar
  25. 25.
    Seaman S, Stevens J, Yang MY et al (2007) Genes that distinguish physiological and pathological angiogenesis. Cancer Cell 11(6):539–554CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Carson-Walter EB, Watkins DN, Nanda A et al (2001) Cell surface tumor endothelial markers are conserved in mice and humans. Cancer Res 61(18):6649–6655PubMedGoogle Scholar
  27. 27.
    Nanda A, Croix BS (2004) Tumor endothelial markers: new targets for cancer therapy. Curr Opin Oncol 16(1):44–49CrossRefPubMedGoogle Scholar
  28. 28.
    Buckanovich RJ, Sasaroli D, O’Brien-Jenkins A et al (2007) Tumor vascular proteins as biomarkers in ovarian cancer. J Clin Oncol 25(7):852–861CrossRefPubMedGoogle Scholar
  29. 29.
    Lu C, Bonome T, Li Y et al (2007) Gene alterations identified by expression profiling in tumor-associated endothelial cells from invasive ovarian carcinoma. Cancer Res 67(4):1757–1768CrossRefPubMedGoogle Scholar
  30. 30.
    Hida K, Klagsbrun M (2005) A new perspective on tumor endothelial cells: unexpected chromosome and centrosome abnormalities. Cancer Res 65(7):2507–2510CrossRefPubMedGoogle Scholar
  31. 31.
    Amin DN, Hida K, Bielenberg DR et al (2006) 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(4):2173–2180CrossRefPubMedGoogle Scholar
  32. 32.
    Tsuchiya K, Hida K, Hida Y et al (2010) Adrenomedullin antagonist suppresses tumor formation in renal cell carcinoma through inhibitory effects on tumor endothelial cells and endothelial progenitor mobilization. Int J Oncol 36(6):1379–1386PubMedGoogle Scholar
  33. 33.
    Matsuda K, Ohga N, Hida Y et al (2010) Isolated tumor endothelial cells maintain specific character during long-term culture. Biochem Biophys Res Commun 394(4):947–954CrossRefPubMedGoogle Scholar
  34. 34.
    Kurosu T, Ohga N, Hida Y et al (2011) HuR keeps an angiogenic switch on by stabilising mRNA of VEGF and COX-2 in tumour endothelium. Br J Cancer 104(5):819–829CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Bussolati B, Deambrosis I, Russo S et al (2003) Altered angiogenesis and survival in human tumor-derived endothelial cells. Faseb J 17(9):1159–1161PubMedGoogle Scholar
  36. 36.
    Matsuda K, Ohga N, Hida Y, et al (2010) Isolated tumor endothelial cells maintain specific character during long-term culture. Biochem Biophys Res Commun 394(4):947–954Google Scholar
  37. 37.
    Bussolati B, Grange C, Bruno S et al (2006) Neural-cell adhesion molecule (NCAM) expression by immature and tumor-derived endothelial cells favors cell organization into capillary-like structures. Exp Cell Res 312(6):913–924CrossRefPubMedGoogle Scholar
  38. 38.
    Fonsato V, Buttiglieri S, Deregibus MC et al (2006) Expression of Pax2 in human renal tumor-derived endothelial cells sustains apoptosis resistance and angiogenesis. Am J Pathol 168(2):706–713CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Akino T, Hida K, Hida Y et al (2009) Cytogenetic abnormalities of tumor-associated endothelial cells in human malignant tumors. Am J Pathol 175(6):2657–2667CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Ricci-Vitiani L, Pallini R, Biffoni M et al (2010) Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells. Nature 468(7325):824–828CrossRefPubMedGoogle Scholar
  41. 41.
    Wang R, Chadalavada K, Wilshire J et al (2010) Glioblastoma stem-like cells give rise to tumour endothelium. Nature 468(7325):829–833CrossRefPubMedGoogle Scholar
  42. 42.
    Xiong YQ, Sun HC, Zhang W et al (2009) Human hepatocellular carcinoma tumor-derived endothelial cells manifest increased angiogenesis capability and drug resistance compared with normal endothelial cells. Clin Cancer Res 15(15):4838–4846CrossRefPubMedGoogle Scholar
  43. 43.
    Akiyama K, Ohga N, Hida Y et al (2012) Tumor endothelial cells acquire drug resistance by MDR1 up-regulation via VEGF signaling in tumor microenvironment. Am J Pathol 180(3):1283–1293CrossRefPubMedGoogle Scholar
  44. 44.
    Mundhekar AN, Bullard DC, Kucik DF (2006) Intracellular heterogeneity in adhesiveness of endothelium affects early steps in leukocyte adhesion. Am J Physiol Cell Physiol 291(1):C130–C137CrossRefPubMedGoogle Scholar
  45. 45.
    Molema G (2010) Heterogeneity in endothelial responsiveness to cytokines, molecular causes, and pharmacological consequences. Semin Thromb Hemost 36(3):246–264CrossRefPubMedGoogle Scholar
  46. 46.
    Saubamea B, Cochois-Guegan V, Cisternino S et al (2012) Heterogeneity in the rat brain vasculature revealed by quantitative confocal analysis of endothelial barrier antigen and P-glycoprotein expression. J Cereb Blood Flow Metab 32(1):81–92CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Dudley AC, Khan ZA, Shih SC et al (2008) Calcification of multipotent prostate tumor endothelium. Cancer Cell 14(3):201–211CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Ohga N, Ishikawa S, Maishi N et al (2012) Heterogeneity of tumor endothelial cells: comparison between tumor endothelial cells isolated from high- and low-metastatic tumors. Am J Pathol 180(3):1294–1307CrossRefPubMedGoogle Scholar
  49. 49.
    Bussolati B, Assenzio B, Deregibus MC et al (2006) The proangiogenic phenotype of human tumor-derived endothelial cells depends on thrombospondin-1 downregulation via phosphatidylinositol 3-kinase/Akt pathway. J Mol Med (Berl) 84(10):852–863CrossRefGoogle Scholar
  50. 50.
    Adya R, Tan BK, Punn A et al (2008) Visfatin induces human endothelial VEGF and MMP-2/9 production via MAPK and PI3 K/Akt signalling pathways: novel insights into visfatin-induced angiogenesis. Cardiovasc Res 78(2):356–365CrossRefPubMedGoogle Scholar
  51. 51.
    Naito H, Kidoya H, Sakimoto S et al (2011) Identification and characterization of a resident vascular stem/progenitor cell population in preexisting blood vessels. EMBO J 31(4):842–855CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Ohmura-Kakutani H, Akiyama K, Maishi N et al (2014) Identification of tumor endothelial cells with high aldehyde dehydrogenase activity and a highly angiogenic phenotype. PLoS One 9(12):e113910CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Sato Y (2011) Persistent vascular normalization as an alternative goal of anti-angiogenic cancer therapy. Cancer Sci 102(7):1253–1256CrossRefPubMedGoogle Scholar
  54. 54.
    Helfrich I, Scheffrahn I, Bartling S et al (2010) Resistance to antiangiogenic therapy is directed by vascular phenotype, vessel stabilization, and maturation in malignant melanoma. J Exp Med 207(3):491–503CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Taylor SM, Nevis KR, Park HL et al (2010) Angiogenic factor signaling regulates centrosome duplication in endothelial cells of developing blood vessels. Blood 116(16):3108–3117CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Gao D, Nolan D, McDonnell K, et al (2009) Bone marrow-derived endothelial progenitor cells contribute to the angiogenic switch in tumor growth and metastatic progression. Biochim Biophys Acta 1796(1):33–40Google Scholar

Copyright information

© Japan Society of Clinical Oncology 2016

Authors and Affiliations

  • Kyoko Hida
    • 1
  • Nako Maishi
    • 1
  • Chisaho Torii
    • 1
    • 2
  • Yasuhiro Hida
    • 3
  1. 1.Vascular Biology, Frontier Research Unit, Institute for Genetic MedicineHokkaido UniversitySapporoJapan
  2. 2.Department of Oral and Maxillofacial SurgeryHokkaido University Graduate School of Dental MedicineSapporoJapan
  3. 3.Department of Cardiovascular and Thoracic SurgeryHokkaido University Graduate School of MedicineSapporoJapan

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