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.
Similar content being viewed by others
References
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
Asahara T et al (1997) Isolation of putative progenitor endothelial cells for angiogenesis. Science 275:964–967. doi:10.1126/science.275.5302.964
Schlaeger TM, Qin Y, Fujiwara Y, Magram J, Sato TN (1995) Vascular endothelial cell lineage-specific promoter in transgenic mice. Development 121:1089–1098
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
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
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
Asahara T et al (1999) Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. Circ Res 85:221–228
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
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
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
Garcia-Barros M et al (2003) Tumor response to radiotherapy regulated by endothelial cell apoptosis. Science 300:1155–1159. doi:10.1126/science.1082504
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
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
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
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
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 13:582–597
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Rohde E et al (2006) Blood monocytes mimic endothelial progenitor cells. Stem Cells 24:357–367. doi:10.1634/stemcells.2005-0072
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
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
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
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 8:831–840
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
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
Bergers G et al (2000) Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat Cell Biol 2:737–744. doi:10.1038/35036374
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
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
Giraudo E, Inoue M, Hanahan D (2004) An amino-bisphosphonate targets MMP-9-expressing macrophages and angiogenesis to impair cervical carcinogenesis. J Clin Invest 114:623–633
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
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
Shojaei F et al (2007) Bv8 regulates myeloid-cell-dependent tumour angiogenesis. Nature 450:825–831. doi:10.1038/nature06348
Kujawski M et al (2008) Stat3 mediates myeloid cell-dependent tumor angiogenesis in mice. J Clin Invest 118:3367–3377. doi:10.1172/JCI35213
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
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
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
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
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
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
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
Wartiovaara U et al (1998) Peripheral blood platelets express VEGF-C and VEGF which are released during platelet activation. Thromb Haemost 80:171–175
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
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
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
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
Kaplan RN et al (2005) VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438:820–827. doi:10.1038/nature04186
Pollard JW (2004) Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer 4:71–78. doi:10.1038/nrc1256
Koebel CM et al (2007) Adaptive immunity maintains occult cancer in an equilibrium state. Nature 450:903–908. doi:10.1038/nature06309
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
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
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
Ganss R, Hanahan D (1998) Tumor microenvironment can restrict the effectiveness of activated antitumor lymphocytes. Cancer Res 58:4673–4681
Haniffa MA, Collin MP, Buckley CD, Dazzi F (2009) Mesenchymal stem cells: the fibroblasts’ new clothes? Haematologica 94(2):258–263
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
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
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
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
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
Studeny M et al (2004) Mesenchymal stem cells: potential precursors for tumor stromal and targeted-delivery vehicles for anticancer agents. J Natl Cancer Inst 96:1593–1603
Capillo M et al (2003) Continuous infusion of endostatin inhibits differentiation, mobilization, and clonogenic potential of endothelial cell progenitors. Clin Cancer Res 9:377–382
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
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.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Ahn, GO., Brown, J.M. Role of endothelial progenitors and other bone marrow-derived cells in the development of the tumor vasculature. Angiogenesis 12, 159–164 (2009). https://doi.org/10.1007/s10456-009-9135-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10456-009-9135-7