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Tumor angiogenesis: molecular pathways and therapeutic targets

Abstract

As angiogenesis is essential for tumor growth and metastasis, controlling tumor-associated angiogenesis is a promising tactic in limiting cancer progression. The tumor microenvironment comprises numerous signaling molecules and pathways that influence the angiogenic response. Understanding how these components functionally interact as angiogenic stimuli or as repressors and how mechanisms of resistance arise is required for the identification of new therapeutic strategies. Achieving a durable and efficient antiangiogenic response will require approaches to simultaneously or sequentially target multiple aspects of the tumor microenvironment.

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Figure 1: Multiple origins of tumor-induced neovascularization.
Figure 2: Tumor microenvironments that favor blood vessel growth.
Figure 3: Mediators of endothelial activation and the tumor angiogenic response.
Figure 4: Intracellular signaling effectors of the angiogenic response.

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References

  1. Carmeliet, P. & Jain, R.K. Molecular mechanisms and clinical applications of angiogenesis. Nature 473, 298–307 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Folkman, J. Role of angiogenesis in tumor growth and metastasis. Semin. Oncol. 29, 15–18 (2002).

    CAS  PubMed  Google Scholar 

  3. Herbert, S.P. & Stainier, D.Y.R. Molecular control of endothelial cell behaviour during blood vessel morphogenesis. Nat. Rev. Mol. Cell Biol. 12, 551–564 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Folkman, J. & Hanahan, D. Switch to the angiogenic phenotype during tumorigenesis. Princess Takamatsu Symp. 22, 339–347 (1991).

    CAS  PubMed  Google Scholar 

  5. Weis, S.M. & Cheresh, D.A. Pathophysiological consequences of VEGF-induced vascular permeability. Nature 437, 497–504 (2005).

    CAS  PubMed  Google Scholar 

  6. Hellberg, C., Ostman, A. & Heldin, C.H. PDGF and vessel maturation. Recent Results Cancer Res. 180, 103–114 (2010).

    CAS  PubMed  Google Scholar 

  7. Franco, O.E., Shaw, A.K., Strand, D.W. & Hayward, S.W. Cancer associated fibroblasts in cancer pathogenesis. Semin. Cell Dev. Biol. 21, 33–39 (2010).

    CAS  PubMed  Google Scholar 

  8. Gonda, T.A., Varro, A., Wang, T.C. & Tycko, B. Molecular biology of cancer-associated fibroblasts: can these cells be targeted in anti-cancer therapy? Semin. Cell Dev. Biol. 21, 2–10 (2010).

    CAS  PubMed  Google Scholar 

  9. Xing, F., Saidou, J. & Watabe, K. Cancer associated fibroblasts (CAFs) in tumor microenvironment. Front. Biosci. 15, 166–179 (2010).

    CAS  PubMed Central  Google Scholar 

  10. Sund, M. et al. Function of endogenous inhibitors of angiogenesis as endothelium-specific tumor suppressors. Proc. Natl. Acad. Sci. USA 102, 2934–2939 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Demaria, S. et al. Cancer and inflammation: promise for biologic therapy. J. Immunother. 33, 335–351 (2010).

    PubMed  PubMed Central  Google Scholar 

  12. Grivennikov, S.I., Greten, F.R. & Karin, M. Immunity, inflammation, and cancer. Cell 140, 883–899 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Dvorak, H.F. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N. Engl. J. Med. 315, 1650–1659 (1986).

    CAS  PubMed  Google Scholar 

  14. Jones, C.A. et al. Robo4 stabilizes the vascular network by inhibiting pathological angiogenesis and endothelial hyperpermeability. Nat. Med. 14, 448–453 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Park, K.W. et al. Robo4 is a vascular-specific receptor that inhibits endothelial migration. Dev. Biol. 261, 251–267 (2003).

    CAS  PubMed  Google Scholar 

  16. Rizzolio, S. & Tamagnone, L. Multifaceted role of neuropilins in cancer. Curr. Med. Chem. 18, 3563–3575 (2011).

    CAS  PubMed  Google Scholar 

  17. Zygmunt, T. et al. Semaphorin-plexinD1 signaling limits angiogenic potential via the VEGF decoy receptor sFlt1. Dev. Cell 21, 301–314 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Kim, J., Oh, W.J., Gaiano, N., Yoshida, Y. & Gu, C. Semaphorin 3E-Plexin-D1 signaling regulates VEGF function in developmental angiogenesis via a feedback mechanism. Genes Dev. 25, 1399–1411 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Campbell, N.E. et al. Extracellular matrix proteins and tumor angiogenesis. J. Oncol. 2010, 586905 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Desgrosellier, J.S. & Cheresh, D.A. Integrins in cancer: biological implications and therapeutic opportunities. Nat. Rev. Cancer 10, 9–22 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Humphries, J.D., Byron, A. & Humphries, M.J. Integrin ligands at a glance. J. Cell Sci. 119, 3901–3903 (2006).

    CAS  PubMed  Google Scholar 

  22. Stupack, D.G. & Cheresh, D.A. Get a ligand, get a life: integrins, signaling and cell survival. J. Cell Sci. 115, 3729–3738 (2002).

    CAS  PubMed  Google Scholar 

  23. Stupack, D.G., Puente, X.S., Boutsaboualoy, S., Storgard, C.M. & Cheresh, D.A. Apoptosis of adherent cells by recruitment of caspase-8 to unligated integrins. J. Cell Biol. 155, 459–470 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Nyberg, P., Xie, L. & Kalluri, R. Endogenous inhibitors of angiogenesis. Cancer Res. 65, 3967–3979 (2005).

    CAS  PubMed  Google Scholar 

  25. Ribatti, D. Endogenous inhibitors of angiogenesis: a historical review. Leuk. Res. 33, 638–644 (2009).

    CAS  PubMed  Google Scholar 

  26. Brooks, P.C., Clark, R.A. & Cheresh, D.A. Requirement of vascular integrin a v b 3 for angiogenesis. Science 264, 569–571 (1994).

    CAS  PubMed  Google Scholar 

  27. Brooks, P.C. et al. Integrin a v b 3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels. Cell 79, 1157–1164 (1994).

    CAS  PubMed  Google Scholar 

  28. Gladson, C.L. & Cheresh, D.A. Glioblastoma expression of vitronectin and the a v b 3 integrin. Adhesion mechanism for transformed glial cells. J. Clin. Invest. 88, 1924–1932 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Desgrosellier, J.S. et al. An integrin avb3-c-Src oncogenic unit promotes anchorage-independence and tumor progression. Nat. Med. 15, 1163–1169 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Gladson, C.L. Expression of integrin a v b 3 in small blood vessels of glioblastoma tumors. J. Neuropathol. Exp. Neurol. 55, 1143–1149 (1996).

    CAS  PubMed  Google Scholar 

  31. MacDonald, T.J. et al. Preferential susceptibility of brain tumors to the antiangiogenic effects of an a(v) integrin antagonist. Neurosurgery 48, 151–157 (2001).

    CAS  PubMed  Google Scholar 

  32. Reardon, D.A. et al. Cilengitide: an RGD pentapeptide anb3 and anb5 integrin inhibitor in development for glioblastoma and other malignancies. Future Oncol. 7, 339–354 (2011).

    CAS  PubMed  Google Scholar 

  33. Tabatabai, G. et al. Targeting integrins in malignant glioma. Target. Oncol. 5, 175–181 (2010).

    PubMed  Google Scholar 

  34. Reardon, D.A., Nabors, L.B., Stupp, R. & Mikkelsen, T. Cilengitide: an integrin-targeting arginine-glycine-aspartic acid peptide with promising activity for glioblastoma multiforme. Expert Opin. Investig. Drugs 17, 1225–1235 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Avraamides, C.J., Garmy-Susini, B. & Varner, J.A. Integrins in angiogenesis and lymphangiogenesis. Nat. Rev. Cancer 8, 604–617 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  37. Sawamiphak, S. et al. Ephrin-B2 regulates VEGFR2 function in developmental and tumour angiogenesis. Nature 465, 487–491 (2010).

    CAS  PubMed  Google Scholar 

  38. Wang, Y. et al. Ephrin-B2 controls VEGF-induced angiogenesis and lymphangiogenesis. Nature 465, 483–486 (2010).

    CAS  PubMed  Google Scholar 

  39. Meyer, R.D. et al. PEST motif serine and tyrosine phosphorylation controls vascular endothelial growth factor receptor 2 stability and downregulation. Mol. Cell. Biol. 31, 2010–2025 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Serini, G., Napione, L., Arese, M. & Bussolino, F. Besides adhesion: new perspectives of integrin functions in angiogenesis. Cardiovasc. Res. 78, 213–222 (2008).

    CAS  PubMed  Google Scholar 

  41. Eliceiri, B.P. Integrin and growth factor receptor crosstalk. Circ. Res. 89, 1104–1110 (2001).

    CAS  PubMed  Google Scholar 

  42. Alam, N. et al. The integrin-growth factor receptor duet. J. Cell. Physiol. 213, 649–653 (2007).

    CAS  PubMed  Google Scholar 

  43. Somanath, P.R., Ciocea, A. & Byzova, T.V. Integrin and growth factor receptor alliance in angiogenesis. Cell Biochem. Biophys. 53, 53–64 (2009).

    CAS  PubMed  Google Scholar 

  44. Mahabeleshwar, G.H., Feng, W., Reddy, K., Plow, E.F. & Byzova, T.V. Mechanisms of integrin vascular endothelial growth factor receptor cross-aactivation in angiogenesis. Circ. Res. 101, 570–580 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Lakshmikanthan, S. et al. Rap1 promotes VEGFR2 activation and angiogenesis by a mechanism involving integrin avb3. Blood 118, 2015–2026 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Hutchings, H., Ortega, N. & Plouet, J. Extracellular matrix-bound vascular endothelial growth factor promotes endothelial cell adhesion, migration, and survival through integrin ligation. FASEB J. 17, 1520–1522 (2003).

    CAS  PubMed  Google Scholar 

  47. Cascone, I., Napione, L., Maniero, F., Serini, G. & Bussolino, F. Stable interaction between a5b1 integrin and Tie2 tyrosine kinase receptor regulates endothelial cell response to Ang-1. J. Cell Biol. 170, 993–1004 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Carlson, T.R., Feng, Y., Maisonpierre, P.C., Mrksich, M. & Morla, A.O. Direct cell adhesion to the angiopoietins mediated by integrins. J. Biol. Chem. 276, 26516–26525 (2001).

    CAS  PubMed  Google Scholar 

  49. Deryugina, E.I. & Quigley, J.P. Pleiotropic roles of matrix metalloproteinases in tumor angiogenesis: contrasting, overlapping and compensatory functions. Biochim. Biophys. Acta 1803, 103–120 (2010).

    CAS  PubMed  Google Scholar 

  50. Sounni, N.E., Paye, A., Host, L. & Noel, A. MT-MMPS as regulators of vessel stability associated with angiogenesis. Front. Pharmacol. 2, 111 (2011).

    PubMed  PubMed Central  Google Scholar 

  51. Davis, G.E., Bayless, K.J., Davis, M.J. & Meininger, G.A. Regulation of tissue injury responses by the exposure of matricryptic sites within extracellular matrix molecules. Am. J. Pathol. 156, 1489–1498 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Xu, J. et al. Proteolytic exposure of a cryptic site within collagen type IV is required for angiogenesis and tumor growth in vivo. J. Cell Biol. 154, 1069–1079 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Pillai, R.S. MicroRNA function: multiple mechanisms for a tiny RNA? RNA 11, 1753–1761 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. van Kouwenhove, M., Kedde, M. & Agami, R. MicroRNA regulation by RNA-binding proteins and its implications for cancer. Nat. Rev. Cancer 11, 644–656 (2011).

    CAS  PubMed  Google Scholar 

  55. Hua, Z. et al. MiRNA-directed regulation of VEGF and other angiogenic factors under hypoxia. PLoS ONE 1, e116 (2006).

    PubMed  PubMed Central  Google Scholar 

  56. Fish, J.E. & Srivastava, D. MicroRNAs: opening a new vein in angiogenesis research. Sci. Signal. 2, pe1 (2009).

    PubMed  PubMed Central  Google Scholar 

  57. Wang, S. & Olson, E.N. AngiomiRs—key regulators of angiogenesis. Curr. Opin. Genet. Dev. 19, 205–211 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Anand, S. & Cheresh, D.A. MicroRNA-mediated regulation of the angiogenic switch. Curr. Opin. Hematol. 18, 171–176 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Bonauer, A., Boon, R.A. & Dimmeler, S. Vascular microRNAs. Curr. Drug Targets 11, 943–949 (2010).

    CAS  PubMed  Google Scholar 

  60. Olson, P. et al. MicroRNA dynamics in the stages of tumorigenesis correlate with hallmark capabilities of cancer. Genes Dev. 23, 2152–2165 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Anand, S. et al. MicroRNA-132-mediated loss of p120RasGAP activates the endothelium to facilitate pathological angiogenesis. Nat. Med. 16, 909–914 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Cascio, S. et al. miR-20b modulates VEGF expression by targeting HIF-1α and STAT3 in MCF-7 breast cancer cells. J. Cell. Physiol. 224, 242–249 (2010).

    CAS  PubMed  Google Scholar 

  63. Fang, L. et al. MicroRNA miR-93 promotes tumor growth and angiogenesis by targeting integrin-b8. Oncogene 30, 806–821 (2011).

    CAS  PubMed  Google Scholar 

  64. Yamakuchi, M. et al. P53-induced microRNA-107 inhibits HIF-1 and tumor angiogenesis. Proc. Natl. Acad. Sci. USA 107, 6334–6339 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Cha, S.T. et al. MicroRNA-519c suppresses hypoxia-inducible factor-1a expression and tumor angiogenesis. Cancer Res. 70, 2675–2685 (2010).

    CAS  PubMed  Google Scholar 

  66. Huynh, C. et al. Efficient in vivo microRNA targeting of liver metastasis. Oncogene 30, 1481–1488 (2011).

    CAS  PubMed  Google Scholar 

  67. Kota, J. et al. Therapeutic microRNA delivery suppresses tumorigenesis in a murine liver cancer model. Cell 137, 1005–1017 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Christensen, M., Larsen, L.A., Kauppinen, S. & Schratt, G. Recombinant adeno-associated virus-mediated microRNA delivery into the postnatal mouse brain reveals a role for miR-134 in dendritogenesis in vivo. Front Neural Circuits 3, 16 (2010).

    PubMed  PubMed Central  Google Scholar 

  69. Takeshita, F. et al. Systemic delivery of synthetic microRNA-16 inhibits the growth of metastatic prostate tumors via downregulation of multiple cell-cycle genes. Mol. Ther. 18, 181–187 (2010).

    CAS  PubMed  Google Scholar 

  70. Trang, P. et al. Systemic delivery of tumor suppressor microRNA mimics using a neutral lipid emulsion inhibits lung tumors in mice. Mol. Ther. 19, 1116–1122 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Murphy, E.A. et al. Nanoparticle-mediated drug delivery to tumor vasculature suppresses metastasis. Proc. Natl. Acad. Sci. USA 105, 9343–9348 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Hood, J.D. et al. Tumor regression by targeted gene delivery to the neovasculature. Science 296, 2404–2407 (2002).

    CAS  PubMed  Google Scholar 

  73. McCarty, M.F. et al. Overexpression of PDGF-BB decreases colorectal and pancreatic cancer growth by increasing tumor pericyte content. J. Clin. Invest. 117, 2114–2122 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 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 

  75. Stockmann, C. et al. Deletion of vascular endothelial growth factor in myeloid cells accelerates tumorigenesis. Nature 456, 814–818 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Bussolati, B., Grange, C. & Camussi, G. Tumor exploits alternative strategies to achieve vascularization. FASEB J. 25, 2874–2882 (2011).

    CAS  PubMed  Google Scholar 

  77. Xiong, Y.Q. et al. Human hepatocellular carcinoma tumor-derived endothelial cells manifest increased angiogenesis capability and drug resistance compared with normal endothelial cells. Clin. Cancer Res. 15, 4838–4846 (2009).

    CAS  PubMed  Google Scholar 

  78. Bussolati, B. et al. Neural-cell adhesion molecule (NCAM) expression by immature and tumor-derived endothelial cells favors cell organization into capillary-like structures. Exp. Cell Res. 312, 913–924 (2006).

    CAS  PubMed  Google Scholar 

  79. Hu, H. et al. Antibody library-based tumor endothelial cells surface proteomic functional screen reveals migration-stimulating factor as an anti-angiogenic target. Mol. Cell. Proteomics 8, 816–826 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Chung, A.S., Lee, J. & Ferrara, N. Targeting the tumour vasculature: insights from physiological angiogenesis. Nat. Rev. Cancer 10, 505–514 (2010).

    CAS  PubMed  Google Scholar 

  81. Jain, R.K. et al. Biomarkers of response and resistance to antiangiogenic therapy. Nat. Rev. Clin. Oncol. 6, 327–338 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Österlund, P. et al. Hypertension and overall survival in metastatic colorectal cancer patients treated with bevacizumab-containing chemotherapy. Br. J. Cancer 104, 599–604 (2011).

    PubMed  PubMed Central  Google Scholar 

  83. Dahlberg, S.E., Sandler, A.B., Brahmer, J.R., Schiller, J.H. & Johnson, D.H. Clinical course of advanced non-small-cell lung cancer patients experiencing hypertension during treatment with bevacizumab in combination with carboplatin and paclitaxel on ECOG 4599. J. Clin. Oncol. 28, 949–954 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Maitland, M.L. et al. Ambulatory monitoring detects sorafenib-induced blood pressure elevations on the first day of treatment. Clin. Cancer Res. 15, 6250–6257 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Lassoued, W. et al. Effect of VEGF and VEGF Trap on vascular endothelial cell signaling in tumors. Cancer Biol. Ther. 10, 1326–1333 (2011).

    Google Scholar 

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

    CAS  PubMed  Google Scholar 

  87. Lyden, D. et al. Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nat. Med. 7, 1194–1201 (2001).

    CAS  PubMed  Google Scholar 

  88. Butler, J.M., 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Kobayashi, H. et al. Angiocrine factors from Akt-activated endothelial cells balance self-renewal and differentiation of haematopoietic stem cells. Nat. Cell Biol. 12, 1046–1056 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Solinas, G., Germano, G., Mantovani, A. & Allavena, P. Tumor-associated macrophages (TAM) as major players of the cancer-related inflammation. J. Leukoc. Biol. 86, 1065–1073 (2009).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  92. Mazzieri, R. et al. Targeting the ANG2/TIE2 axis inhibits tumor growth and metastasis by impairing angiogenesis and disabling rebounds of proangiogenic myeloid cells. Cancer Cell 19, 512–526 (2011).

    CAS  PubMed  Google Scholar 

  93. Pander, J. et al. Activation of tumor-promoting type 2 macrophages by EGFR-targeting antibody cetuximab. Clin. Cancer Res. 17, 5668–5673 (2011).

    CAS  PubMed  Google Scholar 

  94. 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 

  95. Kerbel, R.S. Improving conventional or low dose metronomic chemotherapy with targeted antiangiogenic drugs. Cancer Res. Treat. 39, 150–159 (2007).

    PubMed  PubMed Central  Google Scholar 

  96. Shaked, Y. & Kerbel, R.S. Antiangiogenic strategies on defense: on the possibility of blocking rebounds by the tumor vasculature after chemotherapy. Cancer Res. 67, 7055–7058 (2007).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  99. Daenen, L.G. et al. Low-dose metronomic cyclophosphamide combined with vascular disrupting therapy induces potent antitumor activity in preclinical human tumor xenograft models. Mol. Cancer Ther. 8, 2872–2881 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Maniotis, A.J. et al. Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry. Am. J. Pathol. 155, 739–752 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Bissell, M.J. Tumor plasticity allows vasculogenic mimicry, a novel form of angiogenic switch. A rose by any other name? Am. J. Pathol. 155, 675–679 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Fausto, N. Vasculogenic mimicry in tumors. Fact or artifact? Am. J. Pathol. 156, 359 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 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 

  104. McDonald, D.M., Munn, L. & Jain, R.K. Vasculogenic mimicry: how convincing, how novel, and how significant? Am. J. Pathol. 156, 383–388 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Shubik, P. & Warren, B.A. Additional literature on “vasculogenic mimicry” not cited. Am. J. Pathol. 156, 736 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Frenkel, S. et al. Demonstrating circulation in vasculogenic mimicry patterns of uveal melanoma by confocal indocyanine green angiography. Eye (Lond.) 22, 948–952 (2008).

    CAS  Google Scholar 

  107. Yao, X.H., Ping, Y.F. & Bian, X.W. Contribution of cancer stem cells to tumor vasculogenic mimicry. Protein Cell 2, 266–272 (2011).

    PubMed  PubMed Central  Google Scholar 

  108. Shen, R. et al. Precancerous stem cells can serve as tumor vasculogenic progenitors. PLoS ONE 3, e1652 (2008).

    PubMed  PubMed Central  Google Scholar 

  109. Bussolati, B., Grange, C., Sapino, A. & Camussi, G. Endothelial cell differentiation of human breast tumour stem/progenitor cells. J. Cell. Mol. Med. 13, 309–319 (2009).

    CAS  PubMed  Google Scholar 

  110. Bussolati, B., Bruno, S., Grange, C., Ferrando, U. & Camussi, G. Identification of a tumor-initiating stem cell population in human renal carcinomas. FASEB J. 22, 3696–3705 (2008).

    CAS  PubMed  Google Scholar 

  111. Alvero, A.B. et al. Stem-like ovarian cancer cells can serve as tumor vascular progenitors. Stem Cells 27, 2405–2413 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Wang, R. et al. Glioblastoma stem-like cells give rise to tumour endothelium. Nature 468, 829–833 (2010).

    CAS  PubMed  Google Scholar 

  113. Ricci-Vitiani, L. et al. Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells. Nature 468, 824–828 (2010).

    CAS  PubMed  Google Scholar 

  114. Wurmser, A.E. et al. Cell fusion-independent differentiation of neural stem cells to the endothelial lineage. Nature 430, 350–356 (2004).

    CAS  PubMed  Google Scholar 

  115. Hovinga, K.E. et al. Inhibition of notch signaling in glioblastoma targets cancer stem cells via an endothelial cell intermediate. Stem Cells 28, 1019–1029 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Du, R. et al. HIF1α induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion. Cancer Cell 13, 206–220 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Biswas, S.K. & Mantovani, A. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat. Immunol. 11, 889–896 (2010).

    CAS  PubMed  Google Scholar 

  118. Lin, E.Y. et al. Macrophages regulate the angiogenic switch in a mouse model of breast cancer. Cancer Res. 66, 11238–11246 (2006).

    CAS  PubMed  Google Scholar 

  119. Pollard, J.W. Trophic macrophages in development and disease. Nat. Rev. Immunol. 9, 259–270 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  121. Schmid, M.C. et al. Receptor tyrosine kinases and TLR/IL1Rs unexpectedly activate myeloid cell PI3K3, a single convergent point promoting tumor inflammation and progression. Cancer Cell 19, 715–727 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Ruhrberg, C. & De Palma, M. A double agent in cancer: deciphering macrophage roles in human tumors. Nat. Med. 16, 861–862 (2010).

    CAS  PubMed  Google Scholar 

  123. Steidl, C. et al. Tumor-associated macrophages and survival in classic Hodgkin's lymphoma. N. Engl. J. Med. 362, 875–885 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  126. Folkman, J. Tumor angiogenesis: therapeutic implications. N. Engl. J. Med. 285, 1182–1186 (1971).

    CAS  PubMed  Google Scholar 

  127. Bergers, G. & Hanahan, D. Modes of resistance to anti-angiogenic therapy. Nat. Rev. Cancer 8, 592–603 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Ellis, L.M. & Hicklin, D.J. Pathways mediating resistance to vascular endothelial growth factor-targeted therapy. Clin. Cancer Res. 14, 6371–6375 (2008).

    CAS  PubMed  Google Scholar 

  129. Ebos, J.M., Lee, C.R. & Kerbel, R.S. Tumor and host-mediated pathways of resistance and disease progression in response to antiangiogenic therapy. Clin. Cancer Res. 15, 5020–5025 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Fischer, C. et al. Anti-PlGF inhibits frowth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels. Cell 131, 463–475 (2007).

    CAS  PubMed  Google Scholar 

  131. Loges, S., Schmidt, T. & Carmeliet, P. “Antimyeloangiogenic” therapy for cancer by inhibiting PlGF. Clin. Cancer Res. 15, 3648–3653 (2009).

    CAS  PubMed  Google Scholar 

  132. Van de Veire, S. et al. Further pharmacological and genetic evidence for the efficacy of PlGF inhibition in cancer and eye disease. Cell 141, 178–190 (2010).

    CAS  PubMed  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  134. 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 

  135. Park, Y.H. et al. Trastuzumab treatment improves brain metastasis outcomes through control and durable prolongation of systemic extracranial disease in HER2-overexpressing breast cancer patients. Br. J. Cancer 100, 894–900 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Sipkins, D.A. et al. Detection of tumor angiogenesis in vivo by aVb3-targeted magnetic resonance imaging. Nat. Med. 4, 623–626 (1998).

    CAS  PubMed  Google Scholar 

  137. Beer, A.J. et al. Positron emission tomography using [18F]Galacto-RGD identifies the level of integrin a(v)b3 expression in man. Clin. Cancer Res. 12, 3942–3949 (2006).

    CAS  PubMed  Google Scholar 

  138. Battle, M.R., Goggi, J.L., Allen, L., Barnett, J. & Morrison, M.S. Monitoring tumor response to antiangiogenic sunitinib therapy with 18F-fluciclatide, an 18F-labeled ΑVΒ3-integrin and ΑV Β5-integrin imaging agent. J. Nucl. Med. 52, 424–430 (2011).

    CAS  PubMed  Google Scholar 

  139. Pasqualini, R. & Ruoslahti, E. Organ targeting in vivo using phage display peptide libraries. Nature 380, 364–366 (1996).

    CAS  PubMed  Google Scholar 

  140. Ruoslahti, E. Vascular zip codes in angiogenesis and metastasis. Biochem. Soc. Trans. 32, 397–402 (2004).

    CAS  PubMed  Google Scholar 

  141. Ruoslahti, E., Bhatia, S.N. & Sailor, M.J. Targeting of drugs and nanoparticles to tumors. J. Cell Biol. 188, 759–768 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Cao, Q. et al. Phage display peptide probes for imaging early response to bevacizumab treatment. Amino Acids published online, doi:10.1007/s00726-010-0548-9 (16 March 2010).

  143. Bussolati, B. et al. Targeting of human renal tumor-derived endothelial cells with peptides obtained by phage display. J. Mol. Med. 85, 897–906 (2007).

    CAS  PubMed  Google Scholar 

  144. Mueller, J., Gaertner, F.C., Blechert, B., Janssen, K.P. & Essler, M. Targeting of tumor blood vessels: a phage-displayed tumor-homing peptide specifically binds to matrix metalloproteinase-2-processed collagen IV and blocks angiogenesis in vivo. Mol. Cancer Res. 7, 1078–1085 (2009).

    CAS  PubMed  Google Scholar 

  145. Samanta, S., Sistla, R. & Chaudhuri, A. The use of RGDGWK-lipopeptide to selectively deliver genes to mouse tumor vasculature and its complexation with p53 to inhibit tumor growth. Biomaterials 31, 1787–1797 (2010).

    CAS  PubMed  Google Scholar 

  146. Loi, M. et al. Combined targeting of perivascular and endothelial tumor cells enhances anti-tumor efficacy of liposomal chemotherapy in neuroblastoma. J. Control. Release 145, 66–73 (2010).

    CAS  PubMed  Google Scholar 

  147. Sugahara, K.N. et al. Coadministration of a tumor-penetrating peptide enhances the efficacy of cancer drugs. Science 328, 1031–1035 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Teesalu, T., Sugahara, K.N., Kotamraju, V.R. & Ruoslahti, E. C-end rule peptides mediate neuropilin-1-dependent cell, vascular, and tissue penetration. Proc. Natl. Acad. Sci. USA 106, 16157–16162 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Sugahara, K.N. et al. Tissue-penetrating delivery of compounds and nanoparticles into tumors. Cancer Cell 16, 510–520 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Sugahara, K.N. et al. Coadministration of a tumor-penetrating peptide enhances the efficacy of cancer drugs. Science 328, 1031–1035 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Nagengast, W.B. et al. VEGF-PET imaging is a noninvasive biomarker showing differential changes in the tumor during sunitinib treatment. Cancer Res. 71, 143–153 (2011).

    CAS  PubMed  Google Scholar 

  152. Nagengast, W.B. et al. VEGF-SPECT with (111)In-bevacizumab in stage III/IV melanoma patients. Eur. J. Cancer 47, 1595–1602 (2011).

    CAS  PubMed  Google Scholar 

  153. Nayak, T.K., Garmestani, K., Baidoo, K.E., Milenic, D.E. & Brechbiel, M.W. PET imaging of tumor angiogenesis in mice with VEGF-A-targeted (86)Y-CHX-A''-DTPA-bevacizumab. Int. J. Cancer 128, 920–926 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Niu, G. & Chen, X. PET imaging of angiogenesis. PET Clin. 4, 17–38 (2009).

    PubMed  PubMed Central  Google Scholar 

  155. Dumont, R.A. et al. Noninvasive imaging of aVb3 function as a predictor of the antimigratory and antiproliferative effects of dasatinib. Cancer Res. 69, 3173–3179 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Vakoc, B.J. et al. Three-dimensional microscopy of the tumor microenvironment in vivo using optical frequency domain imaging. Nat. Med. 15, 1219–1223 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

D.A.C. is supported by grants from the US National Institutes of Health (grants R37 CA50286, R01 CA95262, R01 CA45726, P01 HL57900 and R01 HL103956).

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Weis, S., Cheresh, D. Tumor angiogenesis: molecular pathways and therapeutic targets. Nat Med 17, 1359–1370 (2011). https://doi.org/10.1038/nm.2537

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