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:

The multifaceted circulating endothelial cell in cancer: towards marker and target identification

Nature Reviews Cancer volume 6, pages 835–845 (2006)Cite this article

Key Points

  • Circulating endothelial cells (CECs) with a mature phenotype, which are probably derived from blood vessel wall turnover, are increased in patients with some types of cancer and in various other conditions including mechanical, inflammatory, infective, ischaemic and autoimmune states.

  • A subpopulation of CECs shows a progenitor-like phenotype. Preclinical and clinical data indicate that these circulating endothelial progenitors (CEPs) can incorporate in cancer vessels, albeit usually at low frequencies. Some preclinical studies suggest that CEPs have a key role in promoting cancer vasculogenesis and in late stages of cancer development. Therefore, CEP-targeting drugs (including many anti-angiogenic agents) might, in principle, inhibit cancer growth.

  • CEC and CEP numbers, kinetics and viability can be measured by different approaches, including positive enrichment by immunobeads and flow cytometry. However, so far no single antigen has been successfully exploited to discriminate between endothelial and haematopoietic cells; consequently, a multiparametric investigation at the single-cell level is mandatory at present.

  • CEC measurement has been found to correlate well with well-known preclinical assays of angiogenesis, such as the corneal micropocket assay, which cannot be adapted for use in patients. In addition, CEC kinetics and viability have been found to correlate with clinical outcomes in cancer patients treated with anti-angiogenic therapeutic approaches.

  • CECs and/or CEPs might, in the future, be used to deliver drugs to cancer vessels.

Abstract

Increases in the number of circulating endothelial cells (CECs) and progenitors (CEPs) have been reported in various pathological conditions including cancer. Preclinical studies have shown that CEC and CEP kinetics correlate well with several standard laboratory angiogenesis assays, which cannot be used in humans. At the clinical level, evidence is emerging that CEC kinetics and viability might correlate with clinical outcomes in cancer patients who undergo anti-angiogenic treatment. Therefore, CEC and CEP measurement has potential as a surrogate marker for monitoring anti-angiogenic treatment and drug activity, and could help to determine the optimal biological dose of anti-angiogenic drugs, which are being used with increasing frequency in medical oncology.

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: Antigen expression in circulating endothelial cells, microparticles and progenitors, platelets and haematopoietic cells.
Figure 2: Representative CEC and CEP counting by flow cytometry.
Figure 3: The role of CECs and CEPs in cancer.
Figure 4: Effects of anti-angiogenic treatment.
Figure 5: Possible mechanisms to explain the finding in cancer patients that CECs and CEPs carry genetic lesions similar to those found in cancer cells.

Similar content being viewed by others

References

  1. Schrag, D. The price tag on progress — chemotherapy for colorectal cancer. N. Engl. J. Med. 351, 317–319 (2004).

    Article  CAS  PubMed  Google Scholar 

  2. 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. Onco. 3, 24–40 (2006).

    Article  CAS  Google Scholar 

  3. Schneider, M., Tjwa, M. & Carmeliet, P. A surrogate marker to monitor angiogenesis at last. Cancer Cell 7, 3–4 (2005).

    Article  CAS  PubMed  Google Scholar 

  4. Kerbel, R. S. & Folkman, J. Clinical translation of angiogenesis inhibitors. Nature Rev. Cancer 2, 727–739 (2002).

    Article  CAS  Google Scholar 

  5. Hlatky, L., Hahnfeldt, P. & Folkman, J. Clinical application of antiangiogenic therapy: microvessel density, what it does and doesn't tell us. J. Natl Cancer Inst. 94, 883–893 (2002).

    Article  PubMed  Google Scholar 

  6. Jain, R. K. Tumor angiogenesis and accessibility: role of vascular endothelial growth factor. Semin. Oncol. 29 (Suppl. 16), 3–9 (2002).

    Article  CAS  PubMed  Google Scholar 

  7. Motzer, R. J. et al. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J. Clin. Oncol. 24, 16–24 (2006).

    Article  CAS  PubMed  Google Scholar 

  8. Morgan, B. et al. Dynamic contrast-enhanced magnetic resonance imaging as a biomarker for the pharmacological response of PTK787/ZK 222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases, in patients with advanced colorectal cancer and liver metastases: results from two phase I studies. J. Clin. Oncol. 2, 3955–3964 (2003).

    Article  CAS  Google Scholar 

  9. Hladovec, J. & Rossamn, P. Circulating endothelial cells isolated together with platelets and the experimental modification of their counts in rats. Thromb. Res. 3, 665–674 (1973).

    Article  Google Scholar 

  10. Blann, A. D . et al. Circulating endothelial cells. Biomarker of vascular disease. Thromb. Haemost. 93, 228–235 (2005).

    Article  CAS  PubMed  Google Scholar 

  11. Cines, D. B. et al. Endothelial cells in physiology and in the pathophysiology of vascular disorders. Blood 91, 3527–3561 (1998).

    CAS  PubMed  Google Scholar 

  12. Solovey A. et al. Circulating activated endothelial cells in sickle cell anemia. N. Engl. J. Med. 337, 1584–1590 (1997).

    Article  CAS  PubMed  Google Scholar 

  13. Moldovan, N. I., Moldovan, L. & Simionescu, N. Binding of vascular anticoagulant alpha (annexin V) to the aortic intima of the hypercholesterolemic rabbit. An autoradiographic study. Blood Coagul. Fibrinolysis. 5, 921–928 (1994).

    Article  CAS  PubMed  Google Scholar 

  14. Rajagopalan, S. et al. Endothelial cell apoptosis in systemic lupus erythematosus: a common pathway for abnormal vascular function and thrombosis propensity. Blood 103, 3677–3683 (2004).

    Article  CAS  PubMed  Google Scholar 

  15. Rabascio, C. et al. Assessing tumor angiogenesis: increased circulating VE-cadherin RNA in patients with cancer indicates viability of circulating endothelial cells. Cancer Res. 64, 4373–4377 (2004).

    Article  CAS  PubMed  Google Scholar 

  16. Mancuso, P. et al. Resting and activated endothelial cells are increased in the peripheral blood of cancer patients. Blood 97, 3658–3661 (2001).

    Article  CAS  PubMed  Google Scholar 

  17. Lin, Y., Weisdorf, D. J., Solovey, A. & Hebbel, R. P. Origins of circulating endothelial cells and endothelial outgrowth from blood. J. Clin. Invest. 105, 71–77 (2000). Suggested for the first time that most CECs originate from vessel walls and have limited growth capability, whereas a tiny CEC subpopulation — probably from the bone marrow — is responsible for most endothelial cell proliferative potential.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Asahara, T. et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science 275, 964–967 (1997).

    Article  CAS  PubMed  Google Scholar 

  19. Shi, Q. et al. Evidence for circulating bone marrow-derived endothelial cells. Blood 92, 362–367 (1998). References 18 and 19 demonstrated the presence of CEPs able to generate new vessels in adult mammals.

    CAS  PubMed  Google Scholar 

  20. Goon, P. K., Lip, G. Y., Boos, C. J., Stonelake, P. S. & Blann, A. D. Circulating endothelial cells, endothelial progenitor cells, and endothelial microparticles in cancer. Neoplasia 8, 79–88 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Solovey, A. N. et al. Identification and functional assessment of endothelial P1H12. J. Lab. Clin. Med. 5, 322–331 (2001).

    Article  Google Scholar 

  22. Elshal, M. F., Khan, S. S., Takahashi, Y., Solomon, M. A. & McCoy, J. P. Jr. CD146 (Mel-CAM), an adhesion marker of endothelial cells, is a novel marker of lymphocyte subset activation in normal peripheral blood. Blood 106, 2923–2924 (2005).

    Article  CAS  PubMed  Google Scholar 

  23. Duda, D. G. et al. Differential CD146 expression on circulating versus tissue endothelial cells in rectal cancer patients: implications for circulating endothelial and progenitor cells as biomarkers for antiangiogenic therapy. J. Clin. Oncol. 24, 1449–1453 (2006).

    Article  CAS  PubMed  Google Scholar 

  24. Kim, I., Yilmaz, O. H. & Morrison, S. J. CD144 (VE-cadherin) is transiently expressed by fetal liver hematopoietic stem cells. Blood 106, 903–905 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Shaked, Y. et al. Genetic heterogeneity of the vasculogenic phenotype parallels angiogenesis; implications for cellular surrogate marker analysis of antiangiogenesis. Cancer Cell 7, 101–111 (2005). Showed a correlation between CECs/CEPs and 'gold standard' preclinical angiogenesis assays, and indicated how CEC and/or CEP measurement can help to define the OBD of anti-angiogenic drugs.

    CAS  PubMed  Google Scholar 

  26. Mancuso, P. et al. Circulating endothelial cell kinetics and viability predict survival in breast cancer patients receiving metronomic chemotherapy. Blood 108, 452–459 (2006). Indicated that an increase in apoptotic CEC count — probably from tumour vessels — predicts better survival in patients with breast cancer treated with metronomic chemotherapy.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Furstenberger, G. et al. Circulating endothelial cells and angiogenic serum factors during neoadjuvant chemotherapy of primary breast cancer. Br. J. Cancer 94, 524–531 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Norden-Zfoni, A. et al. Levels of circulating endothelial cells (CECs) and monocytes as pharmacodynamic markers of SU11248 activity in patients (pts) with metastatic imatinib-resistant GIST. Clin. Cancer Res. 2006 (in the press).

  29. Peichev, M. et al. Expression of VEGFR-2 and AC133 by circulating human CD34+ cells identifies a population of functional endothelial precursors. Blood 95, 952–958 (2000). The first functional definition of a CEP phenotype being CD133+.

    CAS  PubMed  Google Scholar 

  30. Rafii, S., Lyden, D., Benezra, R., Hattori, K. & Heissig, B. Vascular and haematopoietic stem cells: novel targets for anti-angiogenesis therapy? Nature Rev. Cancer 2, 826–835 (2002).

    Article  CAS  Google Scholar 

  31. Pelosi, E. et al. Identification of the hemangioblast in postnatal life. Blood 100, 3203–3208 (2002).

    Article  CAS  PubMed  Google Scholar 

  32. Bailey, A. S. et al. Transplanted adult hematopoietic stems cells differentiate into functional endothelial cells. Blood 103, 13–19 (2004).

    Article  CAS  PubMed  Google Scholar 

  33. Capillo, M. et al. Continuous infusion of endostatin inhibits differentiation, mobilization, and clonogenic potential of endothelial cell progenitors. Clin. Cancer Res. 9, 377–382 (2003).

    CAS  PubMed  Google Scholar 

  34. 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). The first proof-of-principle of the contribution of CEPs to cancer growth. Transplanted, marrow-derived CEPs were able to restore defective tumour angiogenesis and the growth of some types of cancer cell lines.

    Article  CAS  PubMed  Google Scholar 

  35. 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  CAS  PubMed  Google Scholar 

  36. Garcia-Barros, M. et al. Tumor response to radiotherapy regulated by endothelial cell apoptosis. Science 300, 1155–1159 (2003).

    Article  CAS  PubMed  Google Scholar 

  37. De Palma, M., Venneri, M. A., Roca, C. & Naldini, L. Targeting exogenous genes to tumor angiogenesis by transplantation of genetically modified hematopoietic stem cells. Nature Med. 9, 789–795 (2003).

    Article  CAS  PubMed  Google Scholar 

  38. Gothert, J. R. et al. Genetically tagging endothelial cells in vivo: bone marrow-derived cells do not contribute to tumor endothelium. Blood 104, 1769–1777 (2004).

    Article  CAS  PubMed  Google Scholar 

  39. Ruzinova, M. B. et al. Effect of angiogenesis inhibition by Id loss and the contribution of bone-marrow-derived endothelial cells in spontaneous murine tumors. Cancer Cell. 4, 277–289 (2003).

    Article  CAS  PubMed  Google Scholar 

  40. Duda, D. G. et al. Evidence for incorporation of bone marrow-derived endothelial cells into perfused blood vessels in tumors. Blood 107, 2774–2776 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Peters, B. A. et al. Contribution of bone marrow-derived endothelial cells to human tumor vasculature. Nature Med. 11, 261–262 (2005).

    Article  CAS  PubMed  Google Scholar 

  42. Spring, H. et al. Chemokines direct endothelial progenitors into tumor neovessels. Proc. Natl Acad. Sci. USA 102, 18111–18116 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Stoll, B. R., Migliorini, C., Kadambi, A., Munn, L. L. & Jain, R. K. A mathematical model of the contribution of endothelial progenitor cells to angiogenesis in tumors: implications for antiangiogenic therapy. Blood 102, 2555–2561 (2003).

    Article  CAS  PubMed  Google Scholar 

  44. Shaked, Y. et al. Therapy-induced acute recruitment of circulating endothelial progenitor cells to tumors. Science 313, 1785–1787 (2006).

    Article  CAS  PubMed  Google Scholar 

  45. Tozer G. M., Kanthou, C. & Baguley, B. C. Disrupting tumour blood vessels. Nature Rev. Cancer 5, 423–435 (2005).

    Article  CAS  Google Scholar 

  46. Bertolini, F. et al. Maximum tolerable dose and low-dose metronomic chemotherapy have opposite effects on the mobilization and viability of circulating endothelial progenitor cells. Cancer Res. 63, 4342–4346 (2003).

    CAS  PubMed  Google Scholar 

  47. Kerbel, R. S. Antiangiogenic therapy: A universal chemosensitization strategy for cancer? Science 312, 1171–1175 (2006).

    Article  CAS  PubMed  Google Scholar 

  48. Ingram, D. A. et al. Vessel wall-derived endothelial cells rapidly proliferate because they contain a complete hierarchy of endothelial progenitor cells. Blood 105, 2783–2786 (2005).

    Article  CAS  PubMed  Google Scholar 

  49. Zengin, E. et al. Vascular wall resident progenitor cells: a source for postnatal vasculogenesis. Development 133, 1543–1551 (2006).

    Article  CAS  PubMed  Google Scholar 

  50. Rajantie, I. et al. Adult bone marrow-derived cells recruited during angiogenesis comprise precursors for periendothelial vascular mural cells. Blood 104, 2084–2086 (2004).

    Article  CAS  PubMed  Google Scholar 

  51. Hristov, M., Erl, W., Linder, S. & Weber, P. C. Apoptotic bodies from endothelial cells enhance the number and initiate the differentiation of human endothelial progenitor cells in vitro. Blood 104, 2761–2766 (2004).

    Article  CAS  PubMed  Google Scholar 

  52. Massberg, S. et al. Platelets secrete stromal cell-derived factor 1α and recruit bone marrow-derived progenitor cell to arterial trombi in vivo. J. Exp. Med. 203, 1221–1233 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Jin, D. K. et al. Cytokine-mediated deployment of SDF-1 induces revascularization through recruitment of CXCR4+ hemangiocytes. Nature Med. 12, 557–567 (2006).

    Article  CAS  PubMed  Google Scholar 

  54. Jin, H. et al. A homing mechanism for bone marrow-derived progenitor cell recruitment to the neovasculature. J. Clin. Invest. 116, 652–662 (2006). Described a specific adhesion event (mediated by integrin α4β1 (VLA-4) and its receptors) that facilitates the homing of progenitor cells to cancer neovasculature.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Reiher, F. K. et al. Inhibition of tumor growth by systemic treatment with thrombospondin-1 peptide mimetics. Int. J. Cancer 98, 682–689 (2002).

    Article  CAS  PubMed  Google Scholar 

  56. Prewett, M. et al. Antivascular endothelial growth factor receptor (fetal liver kinase 1) monoclonal antibody inhibits tumor angiogenesis and growth of several mouse and human tumors. Cancer Res. 59, 5209–5218 (1999).

    CAS  PubMed  Google Scholar 

  57. Monestiroli S. et al. Kinetics and viability of circulating endothelial cells as surrogate angiogenesis marker in an animal model of human lymphoma. Cancer Res. 61, 4341–4344 (2001).

    CAS  PubMed  Google Scholar 

  58. Schuch, G. et al. Endostatin inhibits the vascular endothelial growth factor-induced mobilization of endothelial progenitor cells. Cancer Res. 63, 8345–8350 (2003).

    CAS  PubMed  Google Scholar 

  59. Zhang, H. et al. Circulating endothelial progenitor cells in multiple myeloma: implications and significance. Blood 105, 3286–3294 (2005).

    Article  CAS  PubMed  Google Scholar 

  60. Shaked, Y. et al. Optimal biologic dose of metronomic chemotherapy regimens is associated with maximum antiangiogenic activity. Blood. 106, 3058–3061 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Celik, I. et al. Therapeutic efficacy of endostatin exhibits a biphasic dose–response curve. Cancer Res. 65, 11044–11050 (2005).

    Article  CAS  PubMed  Google Scholar 

  62. Yee, K. W. et al. Phase 1 study of ABT-751, a novel microtubule inhibitor, in patients with refractory hematologic malignancies. Clin. Cancer Res. 11, 6615–6624 (2005).

    Article  CAS  PubMed  Google Scholar 

  63. Butzal, M. et al. Rapamycin inhibits proliferation and differentiation of human endothelial progenitor cells in vitro. Exp. Cell Res. 300, 65–71 (2004).

    Article  CAS  PubMed  Google Scholar 

  64. Kerbel, R. S. & Kamen, B. A. The anti-angiogenic basis of metronomic chemotherapy. Nature Rev. Cancer. 4, 423–436 (2004).

    Article  CAS  Google Scholar 

  65. Beaudry, P. et al. Differential effects of vascular endothelial growth factor receptor-2 inhibitor ZD6474 on circulating endothelial progenitors and mature circulating endothelial cells: implications for use as a surrogate marker of antiangiogenic activity. Clin. Cancer Res. 11, 3514–3522 (2005).

    Article  CAS  PubMed  Google Scholar 

  66. Colleoni, M. et al. Low-dose oral methotrexate and cyclophosphamide in metastatic breast cancer: antitumor activity and correlation with vascular endothelial growth factor levels. Ann. Oncol. 13, 73–80 (2002).

    Article  CAS  PubMed  Google Scholar 

  67. Colleoni, M. et al. Metronomic low-dose oral cyclophosphamide and methotrexate plus or minus thalidomide in metastatic breast cancer: antitumor activity and biological effects. Ann. Oncol. 17, 232–238 (2006).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  69. Kerbel, R. S. Inhibition of tumor angiogenesis as a strategy to circumvent acquired resistance to anti-cancer therapeutic agents. Bioessays 13, 31–36 (1991).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  71. Rigolin, G. M. et al. Neoplastic circulating endothelial cells in multiple myeloma with 13q14 deletion. Blood 107, 2531–2535 (2006).

    Article  CAS  PubMed  Google Scholar 

  72. Streubel, B. et al. Lymphoma-specific genetic aberrations in microvascular endothelial cells in B-cell lymphomas. N. Engl. J. Med. 351, 250–259 (2004).

    Article  CAS  PubMed  Google Scholar 

  73. Gunsilius, E. et al. Evidence from a leukaemia model for maintenance of vascular endothelium by bone-marrow-derived endothelial cells. Lancet 355, 1688–1691 (2000).

    Article  CAS  PubMed  Google Scholar 

  74. van Heeckeren, W. J. et al. Promise of new vascular-disrupting agents balanced with cardiac toxicity: is it time for oncologists to get to know their cardiologists? J. Clin. Oncol. 24, 1485–1488 (2006).

    Article  CAS  PubMed  Google Scholar 

  75. Tuma, R. S. Accrual delayed in adjuvant bevacizumab trial. J. Natl. Cancer Inst. 98, 439–440 (2006).

    Article  PubMed  Google Scholar 

  76. Beerepoot, L. V. et al. Phase I clinical evaluation of weekly administration of the novel vascular-targeting agent, ZD6126, in patients with solid tumors. J. Clin. Oncol. 24, 1491–1498 (2006).

    Article  CAS  PubMed  Google Scholar 

  77. Ferrari, N., Glod, J., Lee, J., Kobiler, D & Fine, H. A. Bone marrow-derived, endothelial progenitor-like cells as angiogenesis-selective gene-targeting vectors. Gene Ther. 10, 647–656 (2003).

    Article  CAS  PubMed  Google Scholar 

  78. Arbab, A. S. et al. Magnetic resonance imaging and confocal microscopy studies of magnetically labeled endothelial progenitor cells trafficking to sites of tumor angiogenesis. Stem Cells 24, 671–678 (2006).

    Article  CAS  PubMed  Google Scholar 

  79. Dignat-George, F. & Sampol, J. Circulating endothelial cells in vascular disorders: new insights into an old concept. Eur. J. Haematol. 65, 215–220 (2000).

    Article  CAS  PubMed  Google Scholar 

  80. Woywodt, A. et al. Isolation and enumeration of circulating endothelial cells by immunomagnetic isolation: proposal of a definition and a consensus protocol. J. Thromb. Haemost. 4, 671–677 (2006).

    Article  CAS  PubMed  Google Scholar 

  81. Werner, N. et al. Circulating endothelial progenitor cells and cardiovascular outcomes. N. Engl. J. Med. 353, 999–1007 (2005).

    Article  CAS  PubMed  Google Scholar 

  82. Rosenzweig, A. Circulating endothelial progenitors — cells as biomarkers. N. Engl. J. Med. 353, 1055–1057 (2005).

    Article  CAS  PubMed  Google Scholar 

  83. Aicher, A. et al. Essential role of endothelial nitric oxide synthase for mobilization of stem and progenitor cells. Nature Med. 9, 1370–1376 (2003)

    Article  CAS  PubMed  Google Scholar 

  84. Tateishi-Yumana, E. et al. Therapeutic angiogenesis for patients with limb ischaemia by autologous transplantation of bone-marrow cells: a pilot study and a randomised controlled trial. Lancet 360, 427–435 (2002).

    Article  Google Scholar 

  85. Meyer, G. P. et al. Intracoronary bone marrow cell transfer after myocardial infarction: eighteen months' follow-up data from the randomized, controlled BOOST (BOne marrOw transfer to enhance ST-elevation infarct regeneration) trial. Circulation 113, 1287–1294 (2006).

    Article  PubMed  Google Scholar 

  86. Schachinger, V. et al. Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction: final one-year results of the TOPCARE-AMI Trial. J. Am. Coll. Cardiol. 44, 1690–1699 (2004).

    Article  PubMed  Google Scholar 

  87. Conejo-Garcia, J. R. et al. Tumor-infiltrating dendritic cell precursors recruited by a β-defensin contribute to vasculogenesis under the influence of Vegf-A. Nature Med. 10, 950–958 (2004).

    Article  CAS  PubMed  Google Scholar 

  88. Grunewald, M. et al. VEGF-induced adult neovascularization: recruitment, retention, and role of accessory cells. Cell 124, 175–189 (2006).

    Article  CAS  PubMed  Google Scholar 

  89. 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  CAS  PubMed  Google Scholar 

  90. Udagawa, T., Puder, M., Wood, M., Schaefe, B. C. & D'Amato, R. J. Analysis of tumor-associated stromal cells using SCID GFP transgenic mice: contribution of local and bone marrow-derived host cells. FASEB J. 20, 95–102 (2006).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Supported in part by AIRC (Associazione Italiana per la Ricerca sul Cancro), ISS (Istituto Superiore di Sanità) and the the sixth EU Framework Programme (Integrated Project 'Angiotargeting') in the area of 'Life sciences, genomics and biotechnology for health'. F.B. is a scholar of the US National Blood Foundation. R.S.K. is a recipient of a Tier I Canada Research Chair and is supported by grants from the US National Institutes of Health, the Canadian Institutes of Health Research (CIHR), and the National Cancer Institute of Canada (NCIC), Canadian Cancer Society. We apologize to the many investigators whose papers could not be cited because of space limitations.This Review is in memory of our beloved friends and colleagues Scott Murphy and Davide Soligo.

Author information

Authors and Affiliations

  1. Division of Hematology-Oncology, Department of Medicine, European Institute of Oncology, Milan, 20141, Italy

    Francesco Bertolini & Patrizia Mancuso

  2. Department of Medical Biophysics, The Sunnybrook Health Sciences Centre, Molecular and Cellular Biology Research, University of Toronto, Toronto, M4N 3M5, Ontario, Canada

    Yuval Shaked & Robert S. Kerbel

Authors
  1. Francesco Bertolini
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yuval Shaked
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Patrizia Mancuso
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Robert S. Kerbel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Francesco Bertolini.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Francesco Bertolini's homepage

Robert S. Kerbel's homepage

Glossary

Molecularly targeted drugs

Drugs that are specifically designed to target a given molecule. In clinical oncology, these drugs usually target oncogene-derived proteins, growth factors or their receptors.

Microvessel density assay

A preclinical and clinical angiogenesis assay. The frequency of blood vessels in tumour samples is detected with antibodies against endothelial markers (such as CD34, CD31 and vWf) and counted by microscopy.

VEGF

Vascular endothelial growth factor or VEGF is an important signal protein involved in angiogenesis. It has six different isoforms (VEGFA, B, C, D and E), which range in weight from 35–44 kDa. Each bind to a specific combination of endothelial-cell-surface ligands (known as VEGFR1, 2 and 3 and neuropilin).

Dynamic contrast-enhanced magnetic resonance imaging

An imaging approach that is able to offer insights into blood flow, microvessel permeability and size, tissue oxygenation and metabolism.

FISH

A laboratory technique (fluorescence in situ hybridization) that is used to determine if (and in how many copies) a specific segment of DNA is present in a cell. It is also used to identify structurally-abnormal chromosomes. In the laboratory, a segment of DNA is chemically modified and labelled so that it will look fluorescent under a special microscope. This DNA is called a 'probe'. Probes can find matching segments of DNA.

von Willebrand factor

A large multimeric glycoprotein that is present in blood plasma and produced constitutively in endothelium (in the Weibel–Palade bodies), megakaryocytes (α-granules of platelets) and subendothelial connective tissue.

Endothelial microparticles

Under normal physiological conditions, low levels of microparticles are continually being shed into the blood from the endothelial cells that line the blood vessels. The frequency of endothelium-derived microparticles circulating in the blood might increase in some vascular and infectious diseases.

Mesenchymal cells

Mesenchymal stem cells or marrow stromal cells are stem cells that can differentiate into osteoblasts, chondrocytes, myocytes, adipocytes, neuronal cells and pancreatic islets β cells. Their endothelial potential is still under investigation.

Flow cytometry

A technique for counting, examining and sorting cells or other microscopic particles suspended in a stream of fluid. It enables simultaneous multiparametric analysis of the physical and/or chemical characteristics of single cells flowing through an optical/electronic detection apparatus.

Clonogenic potential

The capability of a given cell to generate a clone or daughter cells.

Haemangioblast

A pluripotent cell that is a common precursor to the haematopoietic and endothelial lineages. Haemangioblasts were first found in embryonic cultures, and were manipulated to differentiate along either an haematopoietic or endothelial route. Their presence in adults is currently being investigated.

Nitric oxide

An important signalling molecule in mammals, including humans, and one of the few gaseous signalling molecules known.

TIE2

A tyrosine kinase that is principally expressed on vascular endothelial cells and progenitors, and which functions as the receptor for angiopoietin 1.

Id genes

Id genes encode proteins that belong to a class of nuclear transcription factors known as helix-loop-helix proteins. It has been reported that Id genes function as negative regulators of differentiation, and Id gene expression is downregulated during cell differentiation.

Chemokines

An abbreviated term for chemoattractant cytokines. They represent a superfamily of about 30 chemotactic cytokines that function as initiators and promulgators of inflammatory reactions. They range from 8–11 kDa in molecular weight, and are produced by various cell types. The production of chemokines is induced by exogenous irritants and endogenous mediators (for example, IL1, TNFα, PDGF and IFNγ).

Mural cells

A general term to describe the cells that surround vascular endothelial cells (such as vascular smooth muscle cells and pericytes).

Pericytes

Relatively undifferentiated cells associated with the walls of small blood vessels. Pericytes support vessels, but according to some studies they can also differentiate into fibroblasts, smooth muscle cells or macrophages if required.

Corneal neovascular micropocket assay

A preclinical angiogenesis assay. Pellets that contain angiogenic factors are surgically inserted into the mouse corneal stroma next to the temporal limbus. Capillaries sprout from pre-existing vessels, grow towards the pellet, invade the corneal avascular tissue and can be counted by microscopy.

Matrigel (subcutaneous) perfusion assay

A preclinical angiogenesis assay. A semi-solid gel plug (with or without angiogenic growth factors) is surgically inserted into the flank of a mouse. After some days, capillaries sprouting from pre-existing vessels and vascular perfusion can be investigated by microscopy or by surrogate markers such as the amount of haemoglobin from circulating red blood cells.

TSP1

Thrombospondins (TSPs) form a small family of five modular glycoproteins with diverse (and partially unknown) functions. TSP1 has been found to have some endogenous anti-angiogenic activity.

Dendritic cells

Immune cells that are present in small quantities in tissues that are in contact with the external environment (for example the skin, lungs, stomach and gut). They can also be found in an immature state in the blood. Once activated, they migrate to the lymphoid tissues where they interact with T cells and B cells to initiate and shape the immune response. At certain developmental stages they grow branched projections called dendrites.

CXCR4

CXCR4 is the only known receptor of the CXCL12 chemokine, which is known to be involved in stem or progenitor, endothelial, lymphoid and nervous-cell homing and trafficking. CXCR4 is also a co-receptor for the entry of HIV into T cells.

Metronomic chemotherapy

The close, regular administration of low, non-toxic doses of chemotherapeutic drugs with no breaks over long periods of time. This strategy is known to have anti-angiogenic activity.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bertolini, F., Shaked, Y., Mancuso, P. et al. The multifaceted circulating endothelial cell in cancer: towards marker and target identification. Nat Rev Cancer 6, 835–845 (2006). https://doi.org/10.1038/nrc1971

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc1971

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