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.

  • Opinion
  • Published:

Instructive role of the vascular niche in promoting tumour growth and tissue repair by angiocrine factors

Abstract

The precise mechanisms whereby anti-angiogenesis therapy blocks tumour growth or causes vascular toxicity are unknown. We propose that endothelial cells establish a vascular niche that promotes tumour growth and tissue repair not only by delivering nutrients and O2 but also through an 'angiocrine' mechanism by producing stem and progenitor cell-active trophogens. Identification of endothelial-derived instructive angiocrine factors will allow direct tumour targeting, while diminishing the unwanted side effects associated with the use of anti-angiogenic agents.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The vascular niche supports the expansion of stem and progenitor cells as well as their malignant counterparts.
Figure 2: The vascular niche supports the progression of leukaemic cells.
Figure 3: Activation of VEGFR2 tyrosine kinase signalling pathways is essential for the regeneration and remodelling of the sinusoidal endothelial cells in the bone marrow.

Similar content being viewed by others

References

  1. Folkman, J. Angiogenesis: an organizing principle for drug discovery? Nature Rev. Drug Discov. 6, 273–286 (2007).

    CAS  Google Scholar 

  2. Ferrara, N., Hillan, K. J., Gerber, H. P. & Novotny, W. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nature Rev. Drug Discov. 3, 391–400 (2004).

    CAS  Google Scholar 

  3. Kerbel, R. S. Tumor angiogenesis. N. Engl. J. Med. 358, 2039–2049 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  5. Duda, D. G., Jain, R. K. & Willett, C. G. Antiangiogenics: the potential role of integrating this novel treatment modality with chemoradiation for solid cancers. J. Clin. Oncol. 25, 4033–4042 (2007).

    CAS  PubMed  Google Scholar 

  6. Thurston, G., Noguera-Troise, I. & Yancopoulos, G. D. The Delta paradox: DLL4 blockade leads to more tumour vessels but less tumour growth. Nature Rev. Cancer 7, 327–331 (2007).

    CAS  Google Scholar 

  7. Ebos, J. M. et al. Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell 15, 232–239 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Paez-Ribes, M. et al. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 15, 220–231 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Jain, R. K. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307, 58–62 (2005).

    CAS  PubMed  Google Scholar 

  10. Lammert, E., Cleaver, O. & Melton, D. Induction of pancreatic differentiation by signals from blood vessels. Science 294, 564–567 (2001).

    CAS  PubMed  Google Scholar 

  11. Lammert, E., Cleaver, O. & Melton, D. Role of endothelial cells in early pancreas and liver development. Mech. Dev. 120, 59–64 (2003).

    CAS  PubMed  Google Scholar 

  12. Matsumoto, K., Yoshitomi, H., Rossant, J. & Zaret, K. S. Liver organogenesis promoted by endothelial cells prior to vascular function. Science 294, 559–563 (2001).

    CAS  PubMed  Google Scholar 

  13. Seandel, M. et al. Generation of a functional and durable vascular niche by the adenoviral E4ORF1 gene. Proc. Natl Acad. Sci. USA 105, 19288–19293 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Naumov, G. N., Folkman, J., Straume, O. & Akslen, L. A. Tumor-vascular interactions and tumor dormancy. APMIS 116, 569–585 (2008).

    CAS  PubMed  Google Scholar 

  15. Calabrese, C. et al. A perivascular niche for brain tumor stem cells. Cancer Cell 11, 69–82 (2007).

    CAS  PubMed  Google Scholar 

  16. Hooper, A. T. et al. Engraftment and reconstitution of hematopoiesis is dependent on VEGFR2-mediated regeneration of sinusoidal endothelial cells. Cell Stem Cell 4, 263–274 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Rosen, J. M. & Jordan, C. T. The increasing complexity of the cancer stem cell paradigm. Science 324, 1670–1673 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Quintana, E. et al. Efficient tumour formation by single human melanoma cells. Nature 456, 593–598 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Greenberg, J. I. et al. A role for VEGF as a negative regulator of pericyte function and vessel maturation. Nature 456, 809–813 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Tammela, T. et al. Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation. Nature 454, 656–660 (2008).

    CAS  PubMed  Google Scholar 

  21. Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000).

    CAS  PubMed  Google Scholar 

  22. Gimbrone, M. A. Jr, Cotran, R. S. & Folkman, J. Human vascular endothelial cells in culture. Growth and DNA synthesis. J. Cell Biol. 60, 673–684 (1974).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Jaffe, E. A., Nachman, R. L., Becker, C. G. & Minick, C. R. Culture of human endothelial cells derived from umbilical veins. Identification by morphologic and immunologic criteria. J. Clin. Invest. 52, 2745–2756 (1973).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Folkman, J. & Klagsburn, M. Angiogenic factors. Science 235, 442–447 (1987).

    CAS  PubMed  Google Scholar 

  25. Ferrara, N., Gerber, H. P. & LeCouter, J. The biology of VEGF and its receptors. Nature Med. 9, 669–676 (2003).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  27. Carmeliet, P. Mechanisms of angiogenesis and arteriogenesis. Nature Med. 6, 389–395 (2000).

    CAS  PubMed  Google Scholar 

  28. Nachman, R. L. & Jaffe, E. A. Endothelial cell culture: beginnings of modern vascular biology. J. Clin. Invest. 114, 1037–1040 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Aird, W. C. Molecular heterogeneity of tumor endothelium. Cell Tissue Res. 335, 271–281 (2009).

    CAS  PubMed  Google Scholar 

  30. Aird, W. C. Phenotypic heterogeneity of the endothelium: I. Structure, function, and mechanisms. Circ. Res. 100, 158–173 (2007).

    CAS  PubMed  Google Scholar 

  31. Yano, K. et al. Phenotypic heterogeneity is an evolutionarily conserved feature of the endothelium. Blood 109, 613–615 (2007).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  33. Coussens, L. M. & Werb, Z. Inflammation and cancer. Nature 420, 860–867 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Seandel, M., Butler, J., Lyden, D. & Rafii, S. A catalytic role for proangiogenic marrow-derived cells in tumor neovascularization. Cancer Cell 13, 181–183 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. McAllister, S. S. et al. Systemic endocrine instigation of indolent tumor growth requires osteopontin. Cell 133, 994–1005 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Shojaei, F., Zhong, C., Wu, X., Yu, L. & Ferrara, N. Role of myeloid cells in tumor angiogenesis and growth. Trends Cell Biol. 18, 372–378 (2008).

    CAS  PubMed  Google Scholar 

  37. Shojaei, F. et al. Bv8 regulates myeloid-cell-dependent tumour angiogenesis. Nature 450, 825–831 (2007).

    CAS  PubMed  Google Scholar 

  38. Yang, L. et al. Expansion of myeloid immune suppressor Gr+CD11b+ cells in tumor-bearing host directly promotes tumor angiogenesis. Cancer Cell 6, 409–421 (2004).

    CAS  PubMed  Google Scholar 

  39. Condeelis, J. & Pollard, J. W. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell 124, 263–266 (2006).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  42. De Palma, M. et al. Tumor-targeted interferon-α delivery by Tie2-expressing monocytes inhibits tumor growth and metastasis. Cancer Cell 14, 299–311 (2008).

    CAS  PubMed  Google Scholar 

  43. 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).

    CAS  PubMed  Google Scholar 

  44. 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).

    CAS  PubMed  Google Scholar 

  45. DeNardo, D. G. et al. CD4+ T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages. Cancer Cell 16, 91–102 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Shojaei, F. et al. Tumor refractoriness to anti-VEGF treatment is mediated by CD11b+Gr1+ myeloid cells. Nature Biotechnol. 25, 911–920 (2007).

    CAS  Google Scholar 

  47. Petit, I., Jin, D. & Rafii, S. The SDF-1-CXCR4 signaling pathway: a molecular hub modulating neo-angiogenesis. Trends Immunol. 28, 299–307 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Minami, E., Laflamme, M. A., Saffitz, J. E. & Murry, C. E. Extracardiac progenitor cells repopulate most major cell types in the transplanted human heart. Circulation 112, 2951–2958 (2005).

    PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  50. Madlambayan, G. J. et al. Bone marrow stem and progenitor cell contribution to neovasculogenesis is dependent on model system with SDF-1 as a permissive trigger. Blood 114, 4310–4319 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 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).

    CAS  PubMed  Google Scholar 

  52. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  54. Shaked, Y. et al. Rapid chemotherapy-induced acute endothelial progenitor cell mobilization: implications for antiangiogenic drugs as chemosensitizing agents. Cancer Cell 14, 263–273 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Urbich, C. et al. Soluble factors released by endothelial progenitor cells promote migration of endothelial cells and cardiac resident progenitor cells. J. Mol. Cell Cardiol. 39, 733–742 (2005).

    CAS  PubMed  Google Scholar 

  56. Assmus, B. et al. Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI). Circulation 106, 3009–3017 (2002).

    PubMed  Google Scholar 

  57. Orimo, A. et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 121, 335–348 (2005).

    CAS  PubMed  Google Scholar 

  58. Gao, D. et al. Endothelial progenitor cells control the angiogenic switch in mouse lung metastasis. Science 319, 195–198 (2008).

    CAS  PubMed  Google Scholar 

  59. Rafii, S. & Lyden, D. Cancer. A few to flip the angiogenic switch. Science 319, 163–164 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Pirtskhalaishvili, G. & Nelson, J. B. Endothelium-derived factors as paracrine mediators of prostate cancer progression. Prostate 44, 77–87 (2000).

    CAS  PubMed  Google Scholar 

  61. Nikolova, G. et al. The vascular basement membrane: a niche for insulin gene expression and β cell proliferation. Dev. Cell 10, 397–405 (2006).

    CAS  PubMed  Google Scholar 

  62. Nikolova, G., Strilic, B. & Lammert, E. The vascular niche and its basement membrane. Trends Cell Biol. 17, 19–25 (2007).

    CAS  PubMed  Google Scholar 

  63. Rafii, S. et al. Isolation and characterization of human bone marrow microvascular endothelial cells: hematopoietic progenitor cell adhesion. Blood 84, 10–19 (1994).

    CAS  PubMed  Google Scholar 

  64. Rafii, S. et al. Human bone marrow microvascular endothelial cells support long-term proliferation and differentiation of myeloid and megakaryocytic progenitors. Blood 86, 3353–3363 (1995).

    CAS  PubMed  Google Scholar 

  65. Shen, Q. et al. Endothelial cells stimulate self-renewal and expand neurogenesis of neural stem cells. Science 304, 1338–1340 (2004).

    CAS  PubMed  Google Scholar 

  66. Mathieu, C. et al. Endothelial cell-derived bone morphogenetic proteins control proliferation of neural stem/progenitor cells. Mol. Cell Neurosci. 38, 569–577 (2008).

    CAS  PubMed  Google Scholar 

  67. Ramirez-Castillejo, C. et al. Pigment epithelium-derived factor is a niche signal for neural stem cell renewal. Nature Neurosci. 9, 331–339 (2006).

    CAS  PubMed  Google Scholar 

  68. Leventhal, C., Rafii, S., Shahar, A. & Goldman, S. A. Endothelial trophic support of neuronal production and recruitment from adult mammalian subependyma. Mol. Cell. Neurosci. 13, 450–464 (1999).

    CAS  PubMed  Google Scholar 

  69. Louissaint, A. Jr, Rao, S., Leventhal, C. & Goldman, S. A. Coordinated interaction of neurogenesis and angiogenesis in the adult songbird brain. Neuron 34, 945–960 (2002).

    CAS  PubMed  Google Scholar 

  70. Matsunaga, T. et al. Interaction between leukemic-cell VLA-4 and stromal fibronectin is a decisive factor for minimal residual disease of acute myelogenous leukemia. Nature Med. 9, 1158–1165 (2003).

    CAS  PubMed  Google Scholar 

  71. Jin, L., Hope, K. J., Zhai, Q., Smadja-Joffe, F. & Dick, J. E. Targeting of CD44 eradicates human acute myeloid leukemic stem cells. Nature Med. 12, 1167–1174 (2006).

    PubMed  Google Scholar 

  72. 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 

  73. 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  PubMed Central  Google Scholar 

  74. Petit, I. et al. The microtubule-targeting agent CA4P regresses leukemic xenografts by disrupting interaction with vascular cells and mitochondrial-dependent cell death. Blood 111, 1951–1961 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Dias, S., Shmelkov, S. V., Lam, G. & Rafii, S. VEGF165 promotes survival of leukemic cells by Hsp90-mediated induction of Bcl-2 expression and apoptosis inhibition. Blood 99, 2532–2540 (2002).

    CAS  PubMed  Google Scholar 

  76. Koistinen, P. et al. Regulation of the acute myeloid leukemia cell line OCI/AML-2 by endothelial nitric oxide synthase under the control of a vascular endothelial growth factor signaling system. Leukemia 15, 1433–1441 (2001).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  78. Pumiglia, K. & Temple, S. PEDF: bridging neurovascular interactions in the stem cell niche. Nature Neurosci. 9, 299–300 (2006).

    CAS  PubMed  Google Scholar 

  79. Hambardzumyan, D. et al. PI3K pathway regulates survival of cancer stem cells residing in the perivascular niche following radiation in medulloblastoma in vivo. Genes Dev. 22, 436–48 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Folkins, C. et al. Anticancer therapies combining antiangiogenic and tumor cell cytotoxic effects reduce the tumor stem-like cell fraction in glioma xenograft tumors. Cancer Res. 67, 3560–3564 (2007).

    CAS  PubMed  Google Scholar 

  81. Nicosia, R. F., Tchao, R. & Leighton, J. Angiogenesis-dependent tumor spread in reinforced fibrin clot culture. Cancer Res. 43, 2159–2166 (1983).

    CAS  PubMed  Google Scholar 

  82. Rak, J. W., Hegmann, E. J., Lu, C. & Kerbel, R. S. Progressive loss of sensitivity to endothelium-derived growth inhibitors expressed by human melanoma cells during disease progression. J. Cell Physiol. 159, 245–255 (1994).

    CAS  PubMed  Google Scholar 

  83. Zeng, Q. et al. Crosstalk between tumor and endothelial cells promotes tumor angiogenesis by MAPK activation of Notch signaling. Cancer Cell 8, 13–23 (2005).

    CAS  PubMed  Google Scholar 

  84. Shen, Q. et al. Adult SVZ stem cells lie in a vascular niche: a quantitative analysis of niche cell-cell interactions. Cell Stem Cell 3, 289–300 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Tavazoie, M. et al. A specialized vascular niche for adult neural stem cells. Cell Stem Cell 3, 279–288 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Palmer, T. D., Willhoite, A. R. & Gage, F. H. Vascular niche for adult hippocampal neurogenesis. J. Comp. Neurol. 425, 479–494 (2000).

    CAS  PubMed  Google Scholar 

  87. Christov, C. et al. Muscle satellite cells and endothelial cells: close neighbors and privileged partners. Mol. Biol. Cell 18, 1397–1409 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Tang, W. et al. White fat progenitor cells reside in the adipose vasculature. Science 322, 583–586 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Yoshida, S., Sukeno, M. & Nabeshima, Y. A vasculature-associated niche for undifferentiated spermatogonia in the mouse testis. Science 317, 1722–1726 (2007).

    CAS  PubMed  Google Scholar 

  90. Barabe, F., Kennedy, J. A., Hope, K. J. & Dick, J. E. Modeling the initiation and progression of human acute leukemia in mice. Science 316, 600–604 (2007).

    CAS  PubMed  Google Scholar 

  91. Jin, L. et al. Monoclonal antibody-mediated targeting of CD123, IL-3 receptor alpha chain, eliminates human acute myeloid leukemic stem cells. Cell Stem Cell 5, 31–42 (2009).

    CAS  PubMed  Google Scholar 

  92. Kiel, M. J., Yilmaz, O. H., Iwashita, T., Terhorst, C. & Morrison, S. J. SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell 121, 1109–1121 (2005).

    CAS  PubMed  Google Scholar 

  93. Avecilla, S. T. et al. Chemokine-mediated interaction of hematopoietic progenitors with the bone marrow vascular niche is required for thrombopoiesis. Nature Med. 10, 64–71 (2004).

    CAS  PubMed  Google Scholar 

  94. Kopp, H. G. et al. Tie-2 activation contributes to hemangiogenic regeneration after myelosuppression. Blood 106, 505–513 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Kopp, H. G., Avecilla, S. T., Hooper, A. T. & Rafii, S. The bone marrow vascular niche: home of HSC differentiation and mobilization. Physiology (Bethesda) 20, 349–356 (2005).

    CAS  Google Scholar 

  96. Kopp, H. G. et al. Thrombospondins deployed by thrombopoietic cells determine angiogenic switch and extent of revascularization. J. Clin. Invest. 116, 3277–3291 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Yoshitomi, H. & Zaret, K. S. Endothelial cell interactions initiate dorsal pancreas development by selectively inducing the transcription factor Ptf1a. Development 131, 807–817 (2004).

    CAS  PubMed  Google Scholar 

  98. Swendeman, S. et al. VEGF-A stimulates ADAM17-dependent shedding of VEGFR2 and crosstalk between VEGFR2 and ERK signaling. Circ. Res. 103, 916–918 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Urbich, C. et al. FOXO-dependent expression of the proapoptotic protein Bim: pivotal role for apoptosis signaling in endothelial progenitor cells. FASEB J. 19, 974–976 (2005).

    CAS  PubMed  Google Scholar 

  100. Rak, J., Milsom, C. & Yu, J. Tissue factor in cancer. Curr. Opin. Hematol. 15, 522–528 (2008).

    CAS  PubMed  Google Scholar 

  101. Rak, J., Milsom, C., Magnus, N. & Yu, J. Tissue factor in tumour progression. Best Pract Res. Clin. Haematol. 22, 71–83 (2009).

    CAS  PubMed  Google Scholar 

  102. Milsom, C. et al. The role of tumor-and host-related tissue factor pools in oncogene-driven tumor progression. Thromb. Res. 120, S82–S91 (2007).

    PubMed  Google Scholar 

  103. Milsom, C., Yu, J., May, L., Magnus, N. & Rak, J. Diverse roles of tissue factor-expressing cell subsets in tumor progression. Semin. Thromb. Hemost. 34, 170–181 (2008).

    CAS  PubMed  Google Scholar 

  104. Palumbo, J. S. & Degen, J. L. Mechanisms linking tumor cell-associated procoagulant function to tumor metastasis. Thromb. Res. 120, S22–S28 (2007).

    PubMed  Google Scholar 

  105. Benedito, R. et al. The notch ligands Dll4 and Jagged1 have opposing effects on angiogenesis. Cell 137, 1124–1135 (2009).

    CAS  PubMed  Google Scholar 

  106. Potente, M. et al. Involvement of Foxo transcription factors in angiogenesis and postnatal neovascularization. J. Clin. Invest. 115, 2382–2392 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Phung, T. L. et al. Pathological angiogenesis is induced by sustained Akt signaling and inhibited by rapamycin. Cancer Cell 10, 159–170 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Gerritsen, M. E. et al. Branching out: a molecular fingerprint of endothelial differentiation into tube-like structures generated by Affymetrix oligonucleotide arrays. Microcirculation 10, 63–81 (2003).

    CAS  PubMed  Google Scholar 

  109. Kahn, J. et al. Gene expression profiling in an in vitro model of angiogenesis. Am. J. Pathol. 156, 1887–1900 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Fernandez, L. et al. Tumor necrosis factor-alpha and endothelial cells modulate Notch signaling in the bone marrow microenvironment during inflammation. Exp. Hematol. 36, 545–558 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Zhang, C. C. & Lodish, H. F. Cytokines regulating hematopoietic stem cell function. Curr. Opin. Hematol. 15, 307–311 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Candal, F. J. et al. BMEC-1: a human bone marrow microvascular endothelial cell line with primary cell characteristics. Microvasc. Res. 52, 221–234 (1996).

    CAS  PubMed  Google Scholar 

  113. Oostingh, G. J., Schlickum, S., Friedl, P. & Schon, M. P. Impaired induction of adhesion molecule expression in immortalized endothelial cells leads to functional defects in dynamic interactions with lymphocytes. J. Invest. Dermatol. 127, 2253–2258 (2007).

    CAS  PubMed  Google Scholar 

  114. Buser, R., Montesano, R., Garcia, I., Dupraz, P. & Pepper, M. S. Bovine microvascular endothelial cells immortalized with human telomerase. J. Cell Biochem. 98, 267–286 (2006).

    CAS  PubMed  Google Scholar 

  115. Nisato, R. E. et al. Generation and characterization of telomerase-transfected human lymphatic endothelial cells with an extended life span. Am. J. Pathol. 165, 11–24 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Yamaguchi, T. et al. Development of a new method for isolation and long-term culture of organ-specific blood vascular and lymphatic endothelial cells of the mouse. FEBS J. 275, 1988–1998 (2008).

    CAS  PubMed  Google Scholar 

  117. Fischer, C., Mazzone, M., Jonckx, B. & Carmeliet, P. FLT1 and its ligands VEGFB and PlGF: drug targets for anti-angiogenic therapy? Nature Rev. Cancer 8, 942–956 (2008).

    CAS  Google Scholar 

  118. Betsholtz, C. Insight into the physiological functions of PDGF through genetic studies in mice. Cytokine Growth Factor Rev. 15, 215–228 (2004).

    CAS  PubMed  Google Scholar 

  119. Lee, S. et al. Autocrine VEGF signaling is required for vascular homeostasis. Cell 130, 691–703 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

J.M.B. is supported by Starr Stem Cell Scholars Fellowship and Ruth L. Kirschstein National Research Service Award Institutional Research Training Grant. S.R. is supported by Howard Hughes Medical Institute, Ansary Stem Cell Institute, Anbinder and Newmans Own Foundation, National Heart Lung and Blood Institute grants HL075234 and HL097797, Qatar National Priorities Research Program, Empire State Stem Cell Board and the New York State Department of Health grant NYS C024180.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Shahin Rafii.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplemental Figure 1

Inductive and instructive angiocrine signals regulate tumorigenesis, organogenesis and tissue repair. (PDF 155 kb)

Related links

Related links

DATABASES

National Cancer Institute Drug Dictionary

Rapamycin

Rights and permissions

Reprints and permissions

About this article

Cite this article

Butler, J., Kobayashi, H. & Rafii, S. Instructive role of the vascular niche in promoting tumour growth and tissue repair by angiocrine factors. Nat Rev Cancer 10, 138–146 (2010). https://doi.org/10.1038/nrc2791

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc2791

This article is cited by

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer