Advertisement

Angiogenesis

, Volume 12, Issue 2, pp 159–164 | Cite as

Role of endothelial progenitors and other bone marrow-derived cells in the development of the tumor vasculature

  • G-One Ahn
  • J. Martin Brown
Original Paper

Abstract

Increasing evidence suggests the importance of bone marrow-derived cells for blood vessel formation (neovascularization) in tumors, which can occur in two mechanisms: angiogenesis and vasculogenesis. Angiogenesis results from proliferation and sprouting of existing blood vessels close to the tumor, while vasculogenesis is believed to arise from recruitment of circulating cells, largely derived from the bone marrow, and de novo clonal formation of blood vessels from these cells. Although bone marrow-derived cells are crucial for neovascularization, current evidence suggests a promotional role of these cells on the existing blood vessels rather than de novo neovascularization in tumors. This is believed to be due to the highly proangiogenic features of these cells. The bone marrow-derived cells are heterogeneous, consisting of many different cell types including endothelial progenitor cells, myeloid cells, lymphocytes, and mesenchymal cells. These cells are highly orchestrated under the influence of the specific tumor microenvironment, which varies depending on the tumor type, thereby tightly regulating neovascularization in the tumors. In this review, we highlight some of the recent findings on each of these cell types by outlining some of the essential proangiogenic cytokines that these cells secrete to promote tumor angiogenesis and vasculogenesis.

Keywords

Angiogenesis Bone marrow-derived cells Endothelial progenitor cells Lymphocytes Monocytes Macrophages Myeloid cells SDF-1 Vasculogenesis VEGF 

Notes

Acknowledgments

This work was supported by National Institutes of Health grants CA118202 and CA128873 awarded to JMB. GOA is a recipient of Gary Slezak/American Brain Tumor Association Translational Grant.

References

  1. 1.
    Rafii S, Lyden D (2003) Therapeutic stem and progenitor cell transplantation for organ vascularization and regeneration. Nat Med 9:702–712. doi: 10.1038/nm0603-702 PubMedCrossRefGoogle Scholar
  2. 2.
    Asahara T et al (1997) Isolation of putative progenitor endothelial cells for angiogenesis. Science 275:964–967. doi: 10.1126/science.275.5302.964 PubMedCrossRefGoogle Scholar
  3. 3.
    Schlaeger TM, Qin Y, Fujiwara Y, Magram J, Sato TN (1995) Vascular endothelial cell lineage-specific promoter in transgenic mice. Development 121:1089–1098PubMedGoogle Scholar
  4. 4.
    Motoike T et al (2000) Universal GFP reporter for the study of vascular development. Genesis 28:75–81. doi: 10.1002/1526-968X(200010)28:2<75::AID-GENE50>3.0.CO;2-S PubMedCrossRefGoogle Scholar
  5. 5.
    Nolan DJ et al (2007) Bone marrow-derived endothelial progenitor cells are a major determinant of nascent tumor neovascularization. Genes Dev 21:1546–1558. doi: 10.1101/gad.436307 PubMedCrossRefGoogle Scholar
  6. 6.
    Lyden D et al (2001) Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nat Med 7:1194–1201. doi: 10.1038/nm1101-1194 PubMedCrossRefGoogle Scholar
  7. 7.
    Asahara T et al (1999) Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. Circ Res 85:221–228PubMedGoogle Scholar
  8. 8.
    Takahashi T et al (1999) Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization. Nat Med 5:434–438. doi: 10.1038/8462 PubMedCrossRefGoogle Scholar
  9. 9.
    Qin G et al (2006) Functional disruption of a4 integrin mobilizes bone marrow-derived endothelial progenitors and augments ischemic neovascularization. J Exp Med 203:153–163. doi: 10.1084/jem.20050459 PubMedCrossRefGoogle Scholar
  10. 10.
    Ceradini DJ et al (2004) Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med 10:858–864. doi: 10.1038/nm1075 PubMedCrossRefGoogle Scholar
  11. 11.
    Garcia-Barros M et al (2003) Tumor response to radiotherapy regulated by endothelial cell apoptosis. Science 300:1155–1159. doi: 10.1126/science.1082504 PubMedCrossRefGoogle Scholar
  12. 12.
    De Palma M, Venneri MA, Roca C, Naldini L (2003) Targeting exogenous genes to tumor angiogenesis by transplantation of genetically modified hematopoietic stem cells. Nat Med 9:789–795. doi: 10.1038/nm871 PubMedCrossRefGoogle Scholar
  13. 13.
    Gothert JR et al (2004) Genetically tagging endothelial cells in vivo: bone marrow-derived cells do not contribute to tumor endothelium. Blood 104:1769–1777. doi: 10.1182/blood-2003-11-3952 PubMedCrossRefGoogle Scholar
  14. 14.
    Purhonen S et al (2008) Bone marrow-derived circulating endothelial precursors do not contribute to vascular endothelium and are not needed for tumor growth. Proc Natl Acad Sci USA 105:6620–6625. doi: 10.1073/pnas.0710516105 PubMedCrossRefGoogle Scholar
  15. 15.
    Shinde Patil VR et al (2005) Bone marrow-derived lin(−)c-kit(+)Sca-1+ stem cells do not contribute to vasculogenesis in Lewis lung carcinoma. Neoplasia 7:234–240. doi: 10.1593/neo.04523 PubMedCrossRefGoogle Scholar
  16. 16.
    Machein MR, Renninger S, de Lima-Hahn E, Plate KH (2003) Minor contribution of bone marrow-derived endothelial progenitors to the vascularization of murine gliomas. Brain Pathol 13:582–597PubMedGoogle Scholar
  17. 17.
    Ahn GO, Brown JM (2008) Matrix metalloproteinase-9 is required for tumor vasculogenesis but not for angiogenesis: role of bone marrow-derived myelomonocytic cells. Cancer Cell 13:193–205. doi: 10.1016/j.ccr.2007.11.032 PubMedCrossRefGoogle Scholar
  18. 18.
    Kerbel RS et al (2008) Endothelial progenitor cells are cellular hubs essential for neoangiogenesis of certain aggressive adenocarcinomas and metastatic transition but not adenomas. Proc Natl Acad Sci USA 105:E54. doi: 10.1073/pnas.0804876105 PubMedCrossRefGoogle Scholar
  19. 19.
    Salven P et al (2008) EPCs are again claimed to be essential in yet other models despite the irreproducibility of the original experiments introducing them. Proc Natl Acad Sci USA 105:E55. doi: 10.1073/pnas.0805971105 CrossRefGoogle Scholar
  20. 20.
    Peters BA et al (2005) Contribution of bone marrow-derived endothelial cells to human tumor vasculature. Nat Med 11:261–262. doi: 10.1038/nm1200 PubMedCrossRefGoogle Scholar
  21. 21.
    Naik RP et al (2008) Circulating endothelial progenitor cells correlate to stage in patients with invasive breast cancer. Breast Cancer Res Treat 107:133–138. doi: 10.1007/s10549-007-9519-6 PubMedCrossRefGoogle Scholar
  22. 22.
    Igreja C et al (2007) Characterization and clinical relevance of circulating and biopsy-derived endothelial progenitor cells in lymphoma patients. Haematologica 92:469–477. doi: 10.3324/haematol.10723 PubMedCrossRefGoogle Scholar
  23. 23.
    Gao D et al (2008) Endothelial progenitor cells control the angiogenic switch in mouse lung metastasis. Science 319:195–198. doi: 10.1126/science.1150224 PubMedCrossRefGoogle Scholar
  24. 24.
    Shaked Y et al (2008) Rapid chemotherapy-induced acute endothelial progenitor cell mobilization: implications for antiangiogenic drugs as chemosensitizing agents. Cancer Cell 14:263–273. doi: 10.1016/j.ccr.2008.08.001 PubMedCrossRefGoogle Scholar
  25. 25.
    Shaked Y et al (2006) Therapy-induced acute recruitment of circulating endothelial progenitor cells to tumors. Science 313:1785–1787. doi: 10.1126/science.1127592 PubMedCrossRefGoogle Scholar
  26. 26.
    Vidal A et al (2005) p130Rb2 and p27kip1 cooperate to control mobilization of angiogenic progenitors from the bone marrow. Proc Natl Acad Sci USA 102:6890–6895. doi: 10.1073/pnas.0405823102 PubMedCrossRefGoogle Scholar
  27. 27.
    Yamazaki M et al (2008) Sonic hedgehog derived from human pancreatic cancer cells augments angiogenic function of endothelial progenitor cells. Cancer Sci 99:1131–1138. doi: 10.1111/j.1349-7006.2008.00795.x PubMedCrossRefGoogle Scholar
  28. 28.
    Furstenberger G et al (2006) Circulating endothelial cells and angiogenic serum factors during neoadjuvant chemotherapy of primary beast cancer. Br J Cancer 94:524–531. doi: 10.1038/sj.bjc.6602952 PubMedCrossRefGoogle Scholar
  29. 29.
    Li B et al (2006) VEGF and PlGF promote adult vasculogenesis by enhancing EPC recruitment and vessel formation at the site of tumor neovascularization. FASEB J 20:1495–1497. doi: 10.1096/fj.05-5137fje PubMedCrossRefGoogle Scholar
  30. 30.
    Yang L et al (2004) Expansion of myeloid immune suppressor Gr+CD11b+ cells in tumor-bearing host directly promotes tumor angiogenesis. Cancer Cell 6:409–421. doi: 10.1016/j.ccr.2004.08.031 PubMedCrossRefGoogle Scholar
  31. 31.
    Yang L et al (2008) Abrogation of TGF beta signaling in mammary carcinomas recruits Gr-1+CD11b+ myeloid cells that promote metastasis. Cancer Cell 13:23–35. doi: 10.1016/j.ccr.2007.12.004 PubMedCrossRefGoogle Scholar
  32. 32.
    Lin EA et al (2006) Macrophages regulate the angiogenic switch in a mouse model of breast cancer. Cancer Res 66:11238–11246. doi: 10.1158/0008-5472.CAN-06-1278 PubMedCrossRefGoogle Scholar
  33. 33.
    Rohde E et al (2006) Blood monocytes mimic endothelial progenitor cells. Stem Cells 24:357–367. doi: 10.1634/stemcells.2005-0072 PubMedCrossRefGoogle Scholar
  34. 34.
    Dineen SP et al (2008) Vascular endothelial growth factor receptor 2 mediates macrophage infiltration into orthotopic pancreatic tumors in mice. Cancer Res 68:4340–4346. doi: 10.1158/0008-5472.CAN-07-6705 PubMedCrossRefGoogle Scholar
  35. 35.
    Rafii S, Lyden D, Benezra R, Hattori K, Heissig B (2002) Vascular and haematopoietic stem cells: novel targets for anti-angiogenesis therapy? Nat Rev Cancer 2:826–835. doi: 10.1038/nrc925 PubMedCrossRefGoogle Scholar
  36. 36.
    Fujiyama S et al (2003) Bone marrow monocyte lineage cells adhere on injured endothelium in a monocyte chemoattractant protein-1-dependent manner and accelerate reendothelialization as endothelial progenitor cells. Circ Res 93:980–989. doi: 10.1161/01.RES.0000099245.08637.CE PubMedCrossRefGoogle Scholar
  37. 37.
    Luttun A et al (2002) Revascularization of ischemic tissues by PlGF treatment, and inhibition of tumor angiogenesis, arthritis, and atherosclerosis by anti-Flt1. Nat Med 8:831–840PubMedGoogle Scholar
  38. 38.
    Bailey AS et al (2006) Myeloid lineage progenitors give rise to vascular endothelium. Proc Natl Acad Sci USA 103:13156–13161. doi: 10.1073/pnas.0604203103 PubMedCrossRefGoogle Scholar
  39. 39.
    Li B et al (2009) Low levels of tumor necrosis factor a increase tumor growth by inducing an endothelial phenotype of monocytes recruited to the tumor site. Cancer Res 69:338–348. doi: 10.1158/0008-5472.CAN-08-1565 PubMedCrossRefGoogle Scholar
  40. 40.
    Bergers G et al (2000) Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat Cell Biol 2:737–744. doi: 10.1038/35036374 PubMedCrossRefGoogle Scholar
  41. 41.
    Du R et al (2008) HIF1a induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion. Cancer Cell 13:206–220. doi: 10.1016/j.ccr.2008.01.034 PubMedCrossRefGoogle Scholar
  42. 42.
    Coussens LM, Tinkle CL, Hanahan D, Werb Z (2000) MMP-9 supplied by bone marrow-derived cells contribute to skin carcinogenesis. Cell 103:481–490. doi: 10.1016/S0092-8674(00)00139-2 PubMedCrossRefGoogle Scholar
  43. 43.
    Giraudo E, Inoue M, Hanahan D (2004) An amino-bisphosphonate targets MMP-9-expressing macrophages and angiogenesis to impair cervical carcinogenesis. J Clin Invest 114:623–633PubMedGoogle Scholar
  44. 44.
    Nozawa H, Chiu C, Hanahan D (2006) Infiltrating neutrophils mediate the initial angiogenic switch in a mouse model of multistage carcinogenesis. Proc Natl Acad Sci USA 105:12493–12498. doi: 10.1073/pnas.0601807103 CrossRefGoogle Scholar
  45. 45.
    Joyce JA et al (2004) Cathepsin cysteine proteases are effectors of invasive growth and angiogenesis during multistage tumorigenesis. Cancer Cell 5:443–453. doi: 10.1016/S1535-6108(04)00111-4 PubMedCrossRefGoogle Scholar
  46. 46.
    Shojaei F et al (2007) Bv8 regulates myeloid-cell-dependent tumour angiogenesis. Nature 450:825–831. doi: 10.1038/nature06348 PubMedCrossRefGoogle Scholar
  47. 47.
    Kujawski M et al (2008) Stat3 mediates myeloid cell-dependent tumor angiogenesis in mice. J Clin Invest 118:3367–3377. doi: 10.1172/JCI35213 PubMedCrossRefGoogle Scholar
  48. 48.
    Sierra JR et al (2008) Tumor angiogenesis and progression are enhanced by Sema4D produced by tumor-associated macrophages. J Exp Med 205:1673–1685. doi: 10.1084/jem.20072602 PubMedCrossRefGoogle Scholar
  49. 49.
    Grunewald M et al (2006) VEGF-induced adult neovascularization: recruitment, retention, and role of accessory cells. Cell 124:175–189. doi: 10.1016/j.cell.2005.10.036 PubMedCrossRefGoogle Scholar
  50. 50.
    Aghi M, Cohen KS, Klein RJ, Scadden DT, Chiocca EA (2006) Tumor stromal-derived factor-1 recruits vascular progenitors to mitotic neovasculature, where microenvironment influences their differentiated phenotypes. Cancer Res 66:9054–9064. doi: 10.1158/0008-5472.CAN-05-3759 PubMedCrossRefGoogle Scholar
  51. 51.
    Coussens LM et al (1999) Inflammatory mast cells up-regulate angiogenesis during squamous epithelial carcinogenesis. Genes Dev 13:1382–1397. doi: 10.1101/gad.13.11.1382 PubMedCrossRefGoogle Scholar
  52. 52.
    Heissig B et al (2005) Low-dose irradiation promotes tissue revascularization through VEGF release from mast cells and MMP-9 mediated progenitor cell mobilization. J Exp Med 202:739–750. doi: 10.1084/jem.20050959 PubMedCrossRefGoogle Scholar
  53. 53.
    Soucek L et al (2007) Mast cells are required for angiogenesis and macroscopic expansion of Myc-induced pancreatic islet tumors. Nat Med 13:1211–1218. doi: 10.1038/nm1649 PubMedCrossRefGoogle Scholar
  54. 54.
    Salgado R et al (2001) Platelets and vascular endothelial growth factor (VEGF): a morphological and functional study. Angiogenesis 4:37–43. doi: 10.1023/A:1016611230747 PubMedCrossRefGoogle Scholar
  55. 55.
    Wartiovaara U et al (1998) Peripheral blood platelets express VEGF-C and VEGF which are released during platelet activation. Thromb Haemost 80:171–175PubMedGoogle Scholar
  56. 56.
    Rafii S, Psaila B, Butler J, Jin DK, Lyden D (2008) Regulation of vasculogenesis by platelet-mediated recruitment of bone marrow-derived cells. Arterioscler Thromb Vasc Biol 28:217–222. doi: 10.1161/ATVBAHA.107.151159 PubMedCrossRefGoogle Scholar
  57. 57.
    Janowska-Wieczorek A et al (2005) Microvesicles derived from activated platelets induce metastasis and angiogenesis in lung cancer. Int J Cancer 113:752–760. doi: 10.1002/ijc.20657 PubMedCrossRefGoogle Scholar
  58. 58.
    Shojaei F et al (2007) Tumor refractoriness to anti-VEGF treatment is mediated by CD11b+Gr1+ myeloid cells. Nat Biotechnol 25:911–920. doi: 10.1038/nbt1323 PubMedCrossRefGoogle Scholar
  59. 59.
    Hiratsuka S, Watanabe A, Aburatani H, Maru Y (2006) Tumour-mediated upregulation of chemoattractants and recruitment of myeloid cells predetermines lung metastasis. Nat Cell Biol 8:1369–1375. doi: 10.1038/ncb1507 PubMedCrossRefGoogle Scholar
  60. 60.
    Kaplan RN et al (2005) VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438:820–827. doi: 10.1038/nature04186 PubMedCrossRefGoogle Scholar
  61. 61.
    Pollard JW (2004) Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer 4:71–78. doi: 10.1038/nrc1256 PubMedCrossRefGoogle Scholar
  62. 62.
    Koebel CM et al (2007) Adaptive immunity maintains occult cancer in an equilibrium state. Nature 450:903–908. doi: 10.1038/nature06309 PubMedCrossRefGoogle Scholar
  63. 63.
    Daniel D et al (2003) Immune enhancement of skin carcinogenesis by CD4+ T cells. J Exp Med 197:1017–1028. doi: 10.1084/jem.20021047 PubMedCrossRefGoogle Scholar
  64. 64.
    Muller-Hermelink N et al (2008) TNFR1 signaling and IFN-g signaling determine whether T cells induce tumor dormancy or promote multistage carcinogenesis. Cancer Cell 13:507–518. doi: 10.1016/j.ccr.2008.04.001 PubMedCrossRefGoogle Scholar
  65. 65.
    Manning EA et al (2007) A vascular endothelial growth factor receptor-2 inhibitor enhances antitumor immunity through an immune-based mechanism. Clin Cancer Res 13:3951–3959. doi: 10.1158/1078-0432.CCR-07-0374 PubMedCrossRefGoogle Scholar
  66. 66.
    Ganss R, Hanahan D (1998) Tumor microenvironment can restrict the effectiveness of activated antitumor lymphocytes. Cancer Res 58:4673–4681PubMedGoogle Scholar
  67. 67.
    Haniffa MA, Collin MP, Buckley CD, Dazzi F (2009) Mesenchymal stem cells: the fibroblasts’ new clothes? Haematologica 94(2):258–263PubMedCrossRefGoogle Scholar
  68. 68.
    Mishira PJ et al (2008) Carcinoma-associated fibroblast-like differentiation of human mesenchymal stem cells. Cancer Res 68:4331–4339. doi: 10.1158/0008-5472.CAN-08-0943 CrossRefGoogle Scholar
  69. 69.
    Au P, Tam J, Fukumura D, Jain RK (2008) Bone marrow-derived mesenchymal stem cells facilitate engineering of long-lasting functional vasculature. Blood 111:4551–4558. doi: 10.1182/blood-2007-10-118273 PubMedCrossRefGoogle Scholar
  70. 70.
    de Palma M et al (2005) 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. doi: 10.1016/j.ccr.2005.08.002 PubMedCrossRefGoogle Scholar
  71. 71.
    Bexell D et al (2009) Bone marrow multipotent mesenchymal stromal cells act as pericyte-like migratory vesicles in experimental gliomas. Mol Ther 17:183–190. doi: 10.1038/mt.2008.229 PubMedCrossRefGoogle Scholar
  72. 72.
    Beckermann BM et al (2008) VEGF expression by mesenchymal stem cells contributes to angiogenesis in pancreatic carcinoma. Br J Cancer 99:622–631. doi: 10.1038/sj.bjc.6604508 PubMedCrossRefGoogle Scholar
  73. 73.
    Studeny M et al (2004) Mesenchymal stem cells: potential precursors for tumor stromal and targeted-delivery vehicles for anticancer agents. J Natl Cancer Inst 96:1593–1603PubMedCrossRefGoogle Scholar
  74. 74.
    Capillo M et al (2003) Continuous infusion of endostatin inhibits differentiation, mobilization, and clonogenic potential of endothelial cell progenitors. Clin Cancer Res 9:377–382PubMedGoogle Scholar
  75. 75.
    Suriano R et al (2008) 17Beta-estradiol mobilizes bone marrow-derived endothelial progenitor cells to tumors. Cancer Res 68:6038–6042. doi: 10.1158/0008-5472.CAN-08-1009 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  1. 1.Division of Cancer and Radiation Biology, Department of Radiation OncologyStanford University School of MedicineStanfordUSA

Personalised recommendations