Tumor angiogenesis: molecular pathways and therapeutic targets

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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.

References

  1. 1

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

  2. 2

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

  3. 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).

  4. 4

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

  5. 5

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

  6. 6

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

  7. 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).

  8. 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).

  9. 9

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

  10. 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).

  11. 11

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

  12. 12

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

  13. 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).

  14. 14

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

  15. 15

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

  16. 16

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

  17. 17

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

  18. 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).

  19. 19

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

  20. 20

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

  21. 21

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

  22. 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).

  23. 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).

  24. 24

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

  25. 25

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

  26. 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).

  27. 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).

  28. 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).

  29. 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).

  30. 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).

  31. 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).

  32. 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).

  33. 33

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

  34. 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).

  35. 35

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

  36. 36

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

  37. 37

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

  38. 38

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

  39. 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).

  40. 40

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

  41. 41

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

  42. 42

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

  43. 43

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

  44. 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).

  45. 45

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

  46. 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).

  47. 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).

  48. 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).

  49. 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).

  50. 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).

  51. 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).

  52. 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).

  53. 53

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

  54. 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).

  55. 55

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

  56. 56

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

  57. 57

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

  58. 58

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

  59. 59

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

  60. 60

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

  61. 61

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

  62. 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).

  63. 63

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

  64. 64

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

  65. 65

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

  66. 66

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

  67. 67

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

  68. 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).

  69. 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).

  70. 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).

  71. 71

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

  72. 72

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

  73. 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).

  74. 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).

  75. 75

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

  76. 76

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

  77. 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).

  78. 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).

  79. 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).

  80. 80

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

  81. 81

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

  82. 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).

  83. 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).

  84. 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).

  85. 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).

  86. 86

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

  87. 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).

  88. 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).

  89. 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).

  90. 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).

  91. 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).

  92. 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).

  93. 93

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

  94. 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).

  95. 95

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

  96. 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).

  97. 97

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

  98. 98

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

  99. 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).

  100. 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).

  101. 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).

  102. 102

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

  103. 103

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

  104. 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).

  105. 105

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

  106. 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).

  107. 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).

  108. 108

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

  109. 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).

  110. 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).

  111. 111

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

  112. 112

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

  113. 113

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

  114. 114

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

  115. 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).

  116. 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).

  117. 117

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

  118. 118

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

  119. 119

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

  120. 120

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

  121. 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).

  122. 122

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

  123. 123

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

  124. 124

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

  125. 125

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

  126. 126

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

  127. 127

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

  128. 128

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

  129. 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).

  130. 130

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

  131. 131

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

  132. 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).

  133. 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).

  134. 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).

  135. 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).

  136. 136

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

  137. 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).

  138. 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).

  139. 139

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

  140. 140

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

  141. 141

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

  142. 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. 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).

  144. 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).

  145. 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).

  146. 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).

  147. 147

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

  148. 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).

  149. 149

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

  150. 150

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

  151. 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).

  152. 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).

  153. 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).

  154. 154

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

  155. 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).

  156. 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).

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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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Correspondence to David A Cheresh.

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