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Vascular and haematopoietic stem cells: novel targets for anti-angiogenesis therapy?

Key Points


  • The growth and metastasis of the majority of tumours depends on the formation of new blood vessels. Angiogenic factors that are released by tumour cells promote activation, proliferation and migration of endothelial cells to the tumour tissue, allowing for rapid formation of functional neo-vessels.

  • Endothelial cells contribute to tumour angiogenesis, and can originate from sprouting or co-option of neighbouring pre-existing vessels. Emerging evidence indicates that bone-marrow-derived circulating endothelial progenitor cells (CEPs) can contribute to the angiogenesis and growth of certain tumours.

  • The introduction of wild-type bone marrow CEPs, which express the VEGF receptor (VEGFR)-2, restores tumour angiogenesis and growth in tumour-resistant mice, indicating that bone-marrow-derived cells are essential for the angiogenesis and growth of certain tumours. Co-mobilization of VEGFR1+ haematopoietic stem and progenitor cells facilitate the incorporation of CEPs into functional tumour neo-vessels.

  • Mobilization of CEPs and pro-angiogenic haematopoietic cells from bone marrow is a dynamic process that requires angiogenic-factor-mediated activation of metalloproteinases (MMPs), specifically MMP-9, which lead to the release of soluble KIT ligand (sKitL). sKitL promotes the proliferation and motility of CEPs and haematopoietic cells within the bone-marrow microenvironment, thereby laying the framework for their mobilization to the peripheral circulation.

  • Inhibition of either VEGFR1 or VEGFR2 signalling can only partially block tumour angiogenesis and growth. Conversely, simultaneous inhibition of VEGFR1 and VEGFR2 signalling results in impaired mobilization and recruitment of VEGFR1+ haematopoietic cells and VEGFR2+ CEPs to the tumour vasculature, and is highly effective in retarding the growth of certain tumours.

  • Characterization and quantification of VEGFR2+CEPs and VEGFR1+ haematopoietic cells in the peripheral blood, and plasma levels of VEGF, sKitL, MMP-9 and placental growth factor might lead to their use as surrogate markers for assessing the response to therapy or progression of certain malignancies. Moreover, factors that are involved in the mobilization and incorporation of CEPs and pro-angiogenic haematopoietic cells provide new targets to block tumour angiogenesis and growth.


Tumours recruit neighbouring blood vessels and vascular endothelial cells to support their own blood supply. Recent evidence has indicated, however, that tumours are also capable of mobilizing bone-marrow-derived endothelial precursor cells, inducing them to migrate to the tumour and become incorporated into the developing vasculature. Tumour-derived angiogenic factors promote the recruitment of these cells, which include circulating endothelial progenitor cells and haematopoietic stem and progenitor cells. As clinical trials with anti-angiogenic agents have been confronted with therapeutic hurdles, inhibiting the recruitment of these vascular precursors might provide a novel approach to blocking tumour angiogenesis.

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Figure 1: Contribution of bone-marrow-derived cells to tumour angiogenesis.
Figure 2: Phenotypic and differentiation characteristics of CEPs.
Figure 3: Human-derived circulating endothelial progenitor cells contribute to tumour angiogenesis.
Figure 4: Haematopoietic stem, progenitors and precursor cells co-mobilize with CEPs.
Figure 5: MMP-9-mediated release of sKitL is necessary for the mobilization of CEPs and haematopoietic stem cells and progenitors.


  1. 1

    Hanahan, D. & Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86, 353–364 (1996).

    CAS  Google Scholar 

  2. 2

    Folkman, J., Watson, K., Ingber, D. & Hanahan, D. Induction of angiogenesis during the transition from hyperplasia to neoplasia. Nature 339, 58–61 (1989).

    CAS  PubMed  Google Scholar 

  3. 3

    Tlsty, T. D. Stromal cells can contribute oncogenic signals. Semin. Cancer Biol. 11, 97–104 (2001).

    CAS  PubMed  Google Scholar 

  4. 4

    Carmeliet, P. & Jain, R. K. Angiogenesis in cancer and other diseases. Nature 407, 249–257 (2000).

    CAS  Google Scholar 

  5. 5

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

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6

    Folkman, J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nature Med. 1, 27–31 (1995).

    CAS  PubMed  Google Scholar 

  7. 7

    Lyden, D. et al. Impaired recruitment of bone-marrow-derived endothelial and haematopoietic precursor cells blocks tumor angiogenesis and growth. Nature Med. 7, 1194–1201 (2001).Demonstrates the significance of mobilization and incorporation of circulating endothelial precursor and haematopoietic cells in supporting tumour angiogenesis. Transplantation and engraftment of wild-type bone marrow into tumour-resistant Id -mutant mice results in the restoration of tumour angiogenesis and growth.

    CAS  Google Scholar 

  8. 8

    Reyes, M. et al. Origin of endothelial progenitors in human postnatal bone marrow. J. Clin. Invest. 109, 337–346 (2002).Demonstration that human endothelial cells derived from CD133+ multipotential adult progenitor (MAPC) cells injected into immunocompromised mice have the potential to contribute to tumour angiogenesis of xenotransplanted, as well as spontaneous, tumours.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9

    Moore, M. A. Putting the neo into neoangiogenesis. J. Clin. Invest. 109, 313–315 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    Asahara, T. et al. Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. Circ. Res. 85, 221–228 (1999).

    CAS  PubMed  Google Scholar 

  11. 11

    Gehling, U. M. et al. In vitro differentiation of endothelial cells from AC133-positive progenitor cells. Blood 95, 3106–3112 (2000).

    CAS  PubMed  Google Scholar 

  12. 12

    Marchetti, S. et al. Endothelial cells genetically selected from differentiating mouse embryonic stem cells incorporate at sites of neovascularization in vivo. J. Cell Sci. 115, 2075–2085 (2002).

    CAS  PubMed  Google Scholar 

  13. 13

    Davidoff, A. M. Bone marrow-derived cells contribute to tumor neovasculature and, when modified to express an angiogenesis inhibitor, can restrict tumor growth in mice. Clin. Cancer Res. 7, 2870–2879 (2001).

    CAS  PubMed  Google Scholar 

  14. 14

    Ito, H. et al. Endothelial progenitor cells as putative targets for angiostatin. Cancer Res. 59, 5875–5877 (1999).

    CAS  PubMed  Google Scholar 

  15. 15

    Arafat, W. O. et al. Genetically modified CD34+ cells exert a cytotoxic bystander effect on human endothelial and cancer cells. Clin. Cancer Res. 6, 4442–4448 (2000).

    CAS  PubMed  Google Scholar 

  16. 16

    Carmeliet, P. & Luttun, A. The emerging role of the bone marrow-derived stem cells in (therapeutic) angiogenesis. Thromb. Haemost. 86, 289–297 (2001).

    CAS  PubMed  Google Scholar 

  17. 17

    Dvorak, H. F., Nagy, J. A., Dvorak, J. T. & Dvorak, A. M. Identification and characterization of the blood vessels of solid tumors that are leaky to circulating macromolecules. Am. J. Pathol. 133, 95–109 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    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 

  19. 19

    Bergers, G., Javaherian, K., Lo, K. M., Folkman, J. & Hanahan, D. Effects of angiogenesis inhibitors on multistage carcinogenesis in mice. Science 284, 808–812 (1999).

    CAS  Google Scholar 

  20. 20

    Holash, J. et al. Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science 284, 1994–1998 (1999).Shows the role of vessel co-option in supporting tumour angiogenesis. The TIE2/angiopoietin signalling pathway is involved in the remodelling during co-option process.

    CAS  Google Scholar 

  21. 21

    Leung, D. W., Cachianes, G., Kuang, W. J., Goeddel, D. V. & Ferrara, N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246, 1306–1309 (1989).

    CAS  Google Scholar 

  22. 22

    Kim, K. J. et al. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 362, 841–844 (1993).

    CAS  PubMed  Google Scholar 

  23. 23

    Shalaby, F. et al. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature 376, 62–66 (1995).

    CAS  PubMed  Google Scholar 

  24. 24

    Terman, B. I. et al. Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growth factor. Biochem. Biophys. Res. Commun. 187, 1579–1586 (1992).

    CAS  PubMed  Google Scholar 

  25. 25

    Neufeld, G., Cohen, T., Gengrinovitch, S. & Poltorak, Z. Vascular endothelial growth factor (VEGF) and its receptors. FASEB J. 13, 9–22 (1999).

    CAS  PubMed  Google Scholar 

  26. 26

    Millauer, B., Shawver, L. K., Plate, K. H., Risau, W. & Ullrich, A. Glioblastoma growth inhibited in vivo by a dominant-negative Flk-1 mutant. Nature 367, 576–579 (1994).

    CAS  PubMed  Google Scholar 

  27. 27

    Pepper, M. S. & Mandriota, S. J. Regulation of vascular endothelial growth factor receptor-2 (Flk-1) expression in vascular endothelial cells. Exp. Cell Res. 241, 414–425 (1998).

    CAS  PubMed  Google Scholar 

  28. 28

    Fong, G. H., Rossant, J., Gertsenstein, M. & Breitman, M. L. Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature 376, 66–70 (1995).

    CAS  PubMed  Google Scholar 

  29. 29

    Hiratsuka, S. et al. Involvement of Flt-1 tyrosine kinase (vascular endothelial growth factor receptor-1) in pathological angiogenesis. Cancer Res. 61, 1207–1213 (2001).

    CAS  PubMed  Google Scholar 

  30. 30

    Benjamin, L. E. & Keshet, E. 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  Google Scholar 

  31. 31

    Benjamin, L. E., Golijanin, D., Itin, A., Pode, D. & Keshet, E. 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 

  32. 32

    Mandriota, S. J. et al. Vascular endothelial growth factor-C-mediated lymphangiogenesis promotes tumour metastasis. EMBO J. 20, 672–682 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    Skobe, M. et al. Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. Nature Med. 7, 192–198 (2001).

    CAS  Google Scholar 

  34. 34

    Makinen, T. et al. Inhibition of lymphangiogenesis with resulting lymphedema in transgenic mice expressing soluble VEGF receptor-3. Nature Med. 7, 199–205 (2001).

    CAS  PubMed  Google Scholar 

  35. 35

    Folberg, R., Hendrix, M. J. & Maniotis, A. J. Vasculogenic mimicry and tumor angiogenesis. Am. J. Pathol. 156, 361–381 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    Hendrix, M. J. et al. Expression and functional significance of VE-cadherin in aggressive human melanoma cells: role in vasculogenic mimicry. Proc. Natl Acad. Sci. USA 98, 8018–8023 (2001).

    CAS  Google Scholar 

  37. 37

    Chang, Y. S. et al. Mosaic blood vessels in tumors: frequency of cancer cells in contact with flowing blood. Proc. Natl Acad. Sci. USA 97, 14608–14613 (2000).

    CAS  Google Scholar 

  38. 38

    Folkman, J. Can mosaic tumor vessels facilitate molecular diagnosis of cancer? Proc. Natl Acad. Sci. USA 98, 398–400 (2001).

    CAS  PubMed  Google Scholar 

  39. 39

    Lyden, D. et al. Id1 and Id3 are required for neurogenesis, angiogenesis and vascularization of tumour xenografts. Nature 401, 670–677 (1999).Reports that Id -mutant mice fail to support the growth of xenotransplanted tumours. The mechanism for tumour resistance in Id -mutant mice is mainly due to defects in tumour angiogenesis.

    CAS  PubMed  Google Scholar 

  40. 40

    Segal, M. S., Bihorac, A. & Koc, M. Circulating endothelial cells: tea leaves for renal disease. Am. J. Physiol. Renal Physiol. 283, F11–F19 (2002).

    CAS  PubMed  Google Scholar 

  41. 41

    Mutunga, M. et al. Circulating endothelial cells in patients with septic shock. Am. J. Respir. Crit. Care Med. 163, 195–200 (2001).

    CAS  PubMed  Google Scholar 

  42. 42

    George, F. et al. Demonstration of Rickettsia conorii-induced endothelial injury in vivo by measuring circulating endothelial cells, thrombomodulin, and von Willebrand factor in patients with Mediterranean spotted fever. Blood 82, 2109–2116 (1993).

    CAS  PubMed  Google Scholar 

  43. 43

    Lefevre, P., George, F., Durand, J. M. & Sampol, J. Detection of circulating endothelial cells in thrombotic thrombocytopenic purpura. Thromb. Haemost. 69, 522 (1993).

    CAS  PubMed  Google Scholar 

  44. 44

    Shi, Q. et al. Proof of fallout endothelialization of impervious Dacron grafts in the aorta and inferior vena cava of the dog. J. Vasc. Surg. 20, 546–556 (1994).

    CAS  PubMed  Google Scholar 

  45. 45

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

    CAS  PubMed  Google Scholar 

  46. 46

    Asahara, T. et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science 275, 964–967 (1997).Shows that bone-marrow-derived endothelial progenitors can contribute to post-natal angiogenic processes, including hind-limb ischaemia.

    CAS  Google Scholar 

  47. 47

    Shi, Q. et al. Evidence for circulating bone marrow-derived endothelial cells. Blood 92, 362–367 (1998).Shows that bone-marrow-derived cells can contribute to the endothelialization of the Dacron grafts. Most of the endothelial cells on the surface of the implanted Dacron grafts originated from the transplanted donor bone-marow-derived endothelial cells.

    CAS  PubMed  Google Scholar 

  48. 48

    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).Shows the potential of bone-marrow-derived circulating endothelial precursor cells to generate late outgrowth highly proliferative endothelial monolayers. By contrast, circulating endothelial cells and vascular-wall-derived endothelial cells gave rise to early outgrowth endothelial cells with limited proliferative potential.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    Rafii, S. Circulating endothelial precursors: mystery, reality, and promise. J. Clin. Invest. 105, 17–19 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    Takahashi, T. et al. Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization. Nature Med. 5, 434–438 (1999).

    CAS  PubMed  Google Scholar 

  51. 51

    Rafii, S. et al. Characterization of haematopoietic cells arising on the textured surface of left ventricular assist devices. Ann. Thorac. Surg. 60, 1627–1632 (1995).

    CAS  PubMed  Google Scholar 

  52. 52

    Gill, M. et al. Vascular trauma induces rapid but transient mobilization of VEGFR2(+)AC133(+) endothelial precursor cells. Circ. Res. 88, 167–174 (2001).

    CAS  PubMed  Google Scholar 

  53. 53

    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).This report, in conjunction with references 11 and 54 , shows that CD133 is expressed on the circulating endothelial precursor cells, and its expression diminishes after differentiation to adherent mature endothelial cells.

    CAS  PubMed  Google Scholar 

  54. 54

    Quirici, N. et al. Differentiation and expansion of endothelial cells from human bone marrow CD133(+) cells. Br. J. Haematol. 115, 186–194 (2001).

    CAS  PubMed  Google Scholar 

  55. 55

    Miraglia, S. et al. A novel five-transmembrane haematopoietic stem cell antigen: isolation, characterization, and molecular cloning. Blood 90, 5013–5021 (1997).

    CAS  PubMed  Google Scholar 

  56. 56

    Yin, A. H. et al. AC133, a novel marker for human haematopoietic stem and progenitor cells. Blood 90, 5002–5012 (1997).

    CAS  PubMed  Google Scholar 

  57. 57

    Miraglia, S., Godfrey, W. & Buck, D. A response to AC133 haematopoietic stem cell antigen: human homologue of mouse kidney prominin or distinct member of a novel protein family? Blood 91, 4390–4391 (1998).

    CAS  PubMed  Google Scholar 

  58. 58

    Coffin, J. D., Harrison, J., Schwartz, S. & Heimark, R. Angioblast differentiation and morphogenesis of the vascular endothelium in the mouse embryo. Dev. Biol. 148, 51–62 (1991).

    CAS  PubMed  Google Scholar 

  59. 59

    Robert, B., St John, P. L., Hyink, D. P. & Abrahamson, D. R. Evidence that embryonic kidney cells expressing flk-1 are intrinsic, vasculogenic angioblasts. Am. J. Physiol. 271, F744–F753 (1996).

    CAS  PubMed  Google Scholar 

  60. 60

    Caprioli, A., Jaffredo, T., Gautier, R., Dubourg, C. & Dieterlen-Lievre, F. Blood-borne seeding by haematopoietic and endothelial precursors from the allantois. Proc. Natl Acad. Sci. USA 95, 1641–1646 (1998).

    CAS  PubMed  Google Scholar 

  61. 61

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

    CAS  PubMed  Google Scholar 

  62. 62

    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 

  63. 63

    Cameliet, 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).

    Google Scholar 

  64. 64

    Luttun, A. et al. Revascularization of ischemic tissues by PlGF treatment, and inhibition of tumor angiogenesis, arthritis and atherosclerosis by anti-Flt1. Nature Med. 1, 1 (2002).

    Google Scholar 

  65. 65

    Polverini, P. J. & Leibovich, S. J. Induction of neovascularization in vivo and endothelial proliferation in vitro by tumor-associated macrophages. Lab. Invest. 51, 635–642 (1984).

    CAS  PubMed  Google Scholar 

  66. 66

    Polverini, P. J., Cotran, P. S., Gimbrone, M. A. Jr & Unanue, E. R. Activated macrophages induce vascular proliferation. Nature 269, 804–806 (1977).

    CAS  PubMed  Google Scholar 

  67. 67

    Dahlqvist, K., Umemoto, E. Y., Brokaw, J. J., Dupuis, M. & McDonald, D. M. Tissue macrophages associated with angiogenesis in chronic airway inflammation in rats. Am. J. Respir. Cell. Mol. Biol. 20, 237–247 (1999).

    CAS  PubMed  Google Scholar 

  68. 68

    Ezaki, T. et al. Time course of endothelial cell proliferation and microvascular remodeling in chronic inflammation. Am. J. Pathol. 158, 2043–2055 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69

    McDonald, D. M. Angiogenesis and remodeling of airway vasculature in chronic inflammation. Am. J. Respir. Crit. Care Med. 164, S39–S45 (2001).

    CAS  PubMed  Google Scholar 

  70. 70

    Leibovich, S. J. et al. Macrophage-induced angiogenesis is mediated by tumour necrosis factor-alpha. Nature 329, 630–632 (1987).

    CAS  PubMed  Google Scholar 

  71. 71

    Di Pietro, L. A. & Polverini, P. J. Angiogenic macrophages produce the angiogenic inhibitor thrombospondin 1. Am. J. Pathol. 143, 678–684 (1993).

    CAS  Google Scholar 

  72. 72

    Coussens, L. M., Tinkle, C. L., Hanahan, D. & Werb, Z. MMP-9 supplied by bone marrow-derived cells contributes to skin carcinogenesis. Cell 103, 481–490 (2000).Shows the essential role of tumour-associated macrophages in supporting tumour growth. MMP-9 that is supplied by tumour-infiltrating macrophages restores impaired tumour growth in Mmp-9-deficient mice. This indicates that MMP-9, provided by bone-marrow-derived cells, is necessary for tumour growth.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

    Takakura, N. et al. A role for haematopoietic stem cells in promoting angiogenesis. Cell 102, 199–209 (2000).

    CAS  Google Scholar 

  74. 74

    Donovan, M. J. et al. Brain derived neurotrophic factor is an endothelial cell survival factor required for intramyocardial vessel stabilization. Development 127, 4531–4540 (2000).

    CAS  PubMed  Google Scholar 

  75. 75

    Skobe, M. et al. Concurrent induction of lymphangiogenesis, angiogenesis, and macrophage recruitment by vascular endothelial growth factor-C in melanoma. Am. J. Pathol. 159, 893–903 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76

    Kadambi, A. et al. Vascular endothelial growth factor (VEGF)-C differentially affects tumor vascular function and leukocyte recruitment: role of VEGF-receptor 2 and host VEGF-A. Cancer Res. 61, 2404–2408 (2001).

    CAS  Google Scholar 

  77. 77

    Reya, T., Morrison, S. J., Clarke, M. F. & Weissman, I. L. Stem cells, cancer, and cancer stem cells. Nature 414, 105–111 (2001).

    CAS  Google Scholar 

  78. 78

    Krause, D. S. et al. Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell 105, 369–377 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79

    Blau, H. M., Brazelton, T. R. & Weimann, J. M. The evolving concept of a stem cell: entity or function? Cell 105, 829–841 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80

    Cheng, T. et al. Haematopoietic stem cell quiescence maintained by p21Cip1/Waf1. Science 287, 1804–1808 (2000).

    CAS  PubMed  Google Scholar 

  81. 81

    Vu, T. H. & Werb, Z. Matrix metalloproteinases: effectors of development and normal physiology. Genes Dev. 14, 2123–2133 (2000).

    CAS  PubMed  Google Scholar 

  82. 82

    Bergers, G. et al. Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nature Cell Biol. 2, 737–744 (2000).

    CAS  Google Scholar 

  83. 83

    Engsig, M. T. et al. Matrix metalloproteinase 9 and vascular endothelial growth factor are essential for osteoclast recruitment into developing long bones. J. Cell Biol. 151, 879–890 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84

    Heissig, B. et al. Recruitment of stem and progenitor cells from the bone marrow niche requires Mmp-9 mediated release of Kit-ligand. Cell 109, 625–637 (2002).Shows the mechanism by which bone-marrow-derived stem and progenitor cells are recruited from the bone-marrow microenvironment to the peripheral circulation. Physiological stressors, including bone-marrow suppression or elevation of angiogenic factors, induce MMP-9, resulting in the release of soluble KIT ligand, driving the proliferation and mobilization of stem and progenitor cells.

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85

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

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86

    Ziegler, B. L. et al. KDR receptor: a key marker defining haematopoietic stem cells. Science 285, 1553–1558 (1999).

    CAS  PubMed  Google Scholar 

  87. 87

    Sawano, A. et al. Flt-1, vascular endothelial growth factor receptor 1, is a novel cell surface marker for the lineage of monocyte-macrophages in humans. Blood 97, 785–791 (2001).

    CAS  PubMed  Google Scholar 

  88. 88

    Clauss, M. et al. The vascular endothelial growth factor receptor Flt-1 mediates biological activities. Implications for a functional role of placenta growth factor in monocyte activation and chemotaxis. J. Biol. Chem. 271, 17629–17634 (1996).

    CAS  PubMed  Google Scholar 

  89. 89

    Barleon, B. et al. Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1. Blood 87, 3336–3343 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90

    Cho, N. K. et al. Developmental control of blood cell migration by the Drosophila VEGF pathway. Cell 108, 865–876 (2002).

    CAS  PubMed  Google Scholar 

  91. 91

    Hattori, K. et al. Placental growth factor reconstitutes hematopoiesis by recruiting VEGFR1(+) stem cells from bone-marrow microenvironment. Nature Med. 1, 1 (2002).Defines the mechanism by which angiogenic factors, including placental-derived growth factor (PlGF) and vascular endothelial growth factor (VEGF), recruit haematopoietic cells from bone marrow to the tumour vasculature. VEGFR1 is expressed on haematopoietic stem and progenitor cells and conveys signals that promote motility and MMP-9-mediated release of sKitL, thereby directing mobilization of these cells to the peripheral circulation.

    Google Scholar 

  92. 92

    Gerber, H. P. et al. VEGF regulates haematopoietic stem cell survival by an internal autocrine loop mechanism. Nature 417, 954–958 (2002).Shows the expression of VEGF receptors, including VEGFR1, on the haematopoietic stem cells, conveying signals that support proliferation and survival of these cells through a novel intrakine signalling mechanism.

    CAS  PubMed  Google Scholar 

  93. 93

    Eriksson, U. & Alitalo, K. VEGF receptor 1 stimulates stem-cell recruitment and new hope for angiogenesis therapies. Nature Med. 8, 775–777 (2002).

    CAS  PubMed  Google Scholar 

  94. 94

    Dias, S. et al. Inhibition of both paracrine and autocrine VEGF/VEGFR-2 signaling pathways is essential to induce long-term remission of xenotransplanted human leukemias. Proc. Natl Acad. Sci. USA 98, 10857–10862 (2001).

    CAS  PubMed  Google Scholar 

  95. 95

    Dias, S. et al. Autocrine stimulation of VEGFR-2 activates human leukemic cell growth and migration. J. Clin. Invest. 106, 511–521 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96

    Gomez-Navarro, J. et al. Genetically modified CD34+ cells as cellular vehicles for gene delivery into areas of angiogenesis in a rhesus model. Gene Ther. 7, 43–52 (2000).

    CAS  PubMed  Google Scholar 

  97. 97

    Levenberg, S., Golub, J. S., Amit, M., Itskovitz-Eldor, J. & Langer, R. Endothelial cells derived from human embryonic stem cells. Proc. Natl Acad. Sci. USA 99, 4391–4396 (2002).

    CAS  PubMed  Google Scholar 

  98. 98

    Vittet, D. et al. Embryonic stem cells differentiate in vitro to endothelial cells through successive maturation steps. Blood 88, 3424–3431 (1996).

    CAS  PubMed  Google Scholar 

  99. 99

    Kabrun, N. et al. Flk-1 expression defines a population of early embryonic haematopoietic precursors. Development 124, 2039–2048 (1997).

    CAS  PubMed  Google Scholar 

  100. 100

    Choi, K., Kennedy, M., Kazarov, A., Papadimitriou, J. C. & Keller, G. A common precursor for haematopoietic and endothelial cells. Development 125, 725–732 (1998).

    CAS  Google Scholar 

  101. 101

    Hirashima, M., Kataoka, H., Nishikawa, S., Matsuyoshi, N. & Nishikawa, S. Maturation of embryonic stem cells into endothelial cells in an in vitro model of vasculogenesis. Blood 93, 1253–1263 (1999).

    CAS  Google Scholar 

  102. 102

    Yamashita, J. et al. Flk1-positive cells derived from embryonic stem cells serve as vascular progenitors. Nature 408, 92–96 (2000).

    CAS  PubMed  Google Scholar 

  103. 103

    Wijelath, E. S. et al. Novel vascular endothelial growth factor binding domains of fibronectin enhance vascular endothelial growth factor biological activity. Circ. Res. 91, 25–31 (2002).Demonstrates the capacity of fibronectin to bind to VEGF. Co-engagment of VEGFA/fibronectin with the VEGFR2/integrin complex that is expressed on endothelial cells can potentiate VEGF signalling.

    CAS  PubMed  Google Scholar 

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This work was supported by grants from the National Heart, Lung and Blood Institute, the American Cancer Society, the Leukemia and Lymphoma Society, the Doris Duke Charitable Foundation, the Children's Brain Tumor Foundation, the National Cancer Institute and Angiogenex.

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Correspondence to Shahin Rafii.

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Are either mature, differentiated precursor cells (like monocytes or macrophages), progenitor cells or immature haematopoietic stem cells.


Pluripotent cells that have the capacity to undergo self-renewal and stochastically differentiate into specific lineages, including the full compliment of erythroid, megakaryocytic, lymphoid and myelo-monocytic progenitors. Progenitors have limited proliferative capacity and have lost the potential to reconstitute haematopoiesis. Precursor cells, such as monocytes and macrophages, are terminally differentiated cells.


The peri-endothelial cell layer, which stabilizes the vessel-wall integrity.


(LVADs). Pulsatile, left ventricular assist devices for extended circulatory support that are implanted in patients that are awaiting cardiac transplantation. The blood-contacting surfaces of LVADs immediately colonize with haematopoietic and endothelial cells, generating a non-thrombogenic neo-intimal surface.


Clusters of totipotent cells that are formed as a result of in vitro culture of embryonic stem cells, in the absence of supportive stroma or growth factors. Exposure of embryoid bodies to specific growth factors induces differentiation of these cells.


Incubation of bone-marrow-derived endothelial progenitors with growth factors such as VEGF, FGF2, IGF, collagen and fibronectin leads to the development of mature adherent endothelial colonies after 2 weeks. These are referred to as colony-forming units of endothelial cells (CFU-ECs). This is an unique characteristic of bone-marrow-derived endothelial progenitors, as mature vessel-wall-derived endothelial cells readily attach and proliferate, and are known as early outgrowth CFU-ECs.

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Rafii, S., Lyden, D., Benezra, R. et al. Vascular and haematopoietic stem cells: novel targets for anti-angiogenesis therapy?. Nat Rev Cancer 2, 826–835 (2002).

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