Vascular Integrins: Therapeutic and Imaging Targets of Tumor Angiogenesis

  • Curzio RüeggEmail author
  • Gian Carlo Alghisi
Part of the Recent Results in Cancer Research book series (RECENTCANCER, volume 180)


Cells, including endothelial cells, continuously sense their surrounding environment and rapidly adapt to changes in order to assure tissues and organs homeostasis. The extracellular matrix (ECM) provides a physical scaffold for cell positioning and represents an instructive interface allowing cells to communicate over short distances. Cell surface receptors of the integrin family emerged through evolution as essential mediators and integrators of ECM-dependent communication. In preclinical studies, pharmacological inhibition of vascular integrins suppressed angiogenesis and inhibited tumor progression. αVβ3 and αVβ5 were the first integrins targeted to suppress tumor angiogenesis. Subsequently, additional integrins, in particular α1β1, α2β1, α5β1, and α6β4, emerged as potential therapeutic targets. Integrin inhibitors are currently tested in clinical trials for their safety and antiangiogenic/antitumor activity. In this chapter, we review the role of integrins in angiogenesis and present recent advances in the use of integrin antagonists as potential therapeutics in cancer and discuss future perspectives.


Tumor Angiogenesis Isolation Limb Perfusion Antiangiogenic Activity Angiogenic Vessel Integrin Antagonist 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Work in our laboratory was supported by funds from the Molecular Oncology Program of the National Center for Competence in Research (NCCR), a research instrument of the Swiss National Science Foundation, the Swiss Cancer League/Oncosuisse, the Swiss National Science Foundation, and the Medic Foundation. We apologize to those colleagues whose work could not be cited due to space limitations.


  1. Abdollahi A, Griggs DW, Zieher H, Roth A, Lipson KE, Saffrich R, Grone H-J, Hallahan DE, Reisfeld RA, Debus J, Niethammer AG, Huber PE (2005) Inhibition of alpha(v)beta3 integrin survival signaling enhances antiangiogenic and antitumor effects of radiotherapy. Clin Cancer Res 11: 6270–6279PubMedCrossRefGoogle Scholar
  2. Alghisi GC, Ruegg C (2006) Vascular integrins in tumor angiogenesis: mediators and therapeutic targets. Endothelium 13:113–135PubMedCrossRefGoogle Scholar
  3. Bader B, Rayburn H, Crowley D, Hynes R (1998) Extensive vasculogenesis, angiogenesis, and organogenesis precede lethality in mice lacking all alpha v integrins. Cell 95:507–519PubMedCrossRefGoogle Scholar
  4. Barrett T, Brechbiel M, Bernardo M, Choyke PL (2007) MRI of tumor angiogenesis. J Magn Reson Imaging 26:235–249PubMedCrossRefGoogle Scholar
  5. Beer AJ, Haubner R, Sarbia M, Goebel M, Luderschmidt S, Grosu AL, Schnell O, Niemeyer M, Kessler H, Wester HJ, Weber WA, Schwaiger M (2006) Positron emission tomography using [18F]Galacto-RGD identifies the level of integrin alpha(v)beta3 expression in man. Clin Cancer Res 12:3942–3949PubMedCrossRefGoogle Scholar
  6. Bello L, Lucini V, Carrabba G, Giussani C, Machluf M, Pluderi M, Nikas D, Zhang J, Tomei G, Villani RM, Carroll RS, Bikfalvi A, Black PM (2001) Simultaneous inhibition of glioma angiogenesis, cell proliferation, and invasion by a naturally occurring fragment of human metalloproteinase-2. Cancer Res 61: 8730–8736PubMedGoogle Scholar
  7. Belvisi L, Riccioni T, Marcellini M, Vesci L, Chiarucci I, Efrati D, Potenza D, Scolastico C, Manzoni L, Lombardo K, Stasi MA, Orlandi A, Ciucci A, Nico B, Ribatti D, Giannini G, Presta M, Carminati P, Pisano C (2005) Biological and molecular properties of a new alpha(v)beta3/alpha(v)beta5 integrin antagonist. Mol Cancer Ther 4:1670–1680PubMedCrossRefGoogle Scholar
  8. Bhaskar V, Fox M, Breinberg D, Wong MH, Wales PE, Rhodes S, Dubridge RB, Ramakrishnan V (2007a) Volociximab, a chimeric integrin alpha5beta1 antibody, inhibits the growth of VX2 tumors in rabbits. Invest New Drugs 26(1):7–12PubMedCrossRefGoogle Scholar
  9. Bhaskar V, Zhang D, Fox M, Seto P, Wong MH, Wales PE, Powers D, Chao DT, Dubridge RB, Ramakrishnan V (2007b) A function blocking anti-mouse integrin alpha5beta1 antibody inhibits angiogenesis and impedes tumor growth in vivo. J Transl Med 5:61PubMedCrossRefGoogle Scholar
  10. Bieler G, Hasmim M, Monnier Y, Imaizumi N, Ameyar M, Bamat J, Ponsonnet L, Chouaib S, Grell M, Goodman SL, Lejeune F, Ruegg C (2007) Distinctive role of integrin-mediated adhesion in TNF-induced PKB/Akt and NF-kappaB activation and endothelial cell survival. Oncogene 26: 5722–5732PubMedCrossRefGoogle Scholar
  11. Brooks PC, Clark RA, Cheresh DA (1994) Requirement of vascular integrin alpha v beta 3 for angiogenesis. Science 264:569–571PubMedCrossRefGoogle Scholar
  12. Burke PA, DeNardo SJ, Miers LA, Lamborn KR, Matzku S, DeNardo GL (2002) Cilengitide targeting of alpha(v)beta3 integrin receptor synergizes with radioimmunotherapy to increase efficacy and apoptosis in breast cancer xenografts. Cancer Res 62:4263–4272PubMedGoogle Scholar
  13. Cacciari B, Spalluto G (2005) Non peptidic alphavbeta3 antagonists: recent developments. Curr Med Chem 12:51–70PubMedGoogle Scholar
  14. Cai W, Wu Y, Chen K, Cao Q, Tice DA, Chen X (2006) In vitro and in vivo characterization of 64Cu-labeled Abegrin, a humanized monoclonal antibody against integrin alpha v beta 3. Cancer Res 66:9673–9681PubMedCrossRefGoogle Scholar
  15. Camenisch G, Pisabarro MT, Sherman D, Kowalski J, Nagel M, Hass P, Xie MH, Gurney A, Bodary S, Liang XH, Clark K, Beresini M, Ferrara N, Gerber HP (2002) ANGPTL3 stimulates endothelial cell adhesion and migration via integrin alpha vbeta 3 and induces blood vessel formation in vivo. J Biol Chem 277: 17281–17290PubMedCrossRefGoogle Scholar
  16. Chen X, Plasencia C, Hou Y, Neamati N (2005) Synthesis and biological evaluation of dimeric RGD peptide-paclitaxel conjugate as a model for integrin-targeted drug delivery. J Med Chem 48:1098–1106PubMedCrossRefGoogle Scholar
  17. Choe YS, Lee KH (2007) Targeted in vivo imaging of angiogenesis: present status and perspectives. Curr Pharm Des 13:17–31PubMedCrossRefGoogle Scholar
  18. Cianfrocca ME, Kimmel KA, Gallo J, Cardoso T, Brown MM, Hudes G, Lewis N, Weiner L, Lam GN, Brown SC, Shaw DE, Mazar AP, Cohen RB (2006) Phase 1 trial of the antiangiogenic peptide ATN-161 (Ac-PHSCN-NH(2)), a beta integrin antagonist, in patients with solid tumours. Br J Cancer 94:1621–1626PubMedGoogle Scholar
  19. Cohen S, Trikha M, Mascelli M (2000) Potential future clinical applications for the GPIIb/IIIa antagonist, abciximab in thrombosis, vascular and oncological indications. Pathol Oncol Res 6: 163–174PubMedCrossRefGoogle Scholar
  20. Collo G, Pepper MS (1999) Endothelial cell integrin alpha5beta1 expression is modulated by cytokines and during migration in vitro. J Cell Sci 112: 569–578PubMedGoogle Scholar
  21. Condeelis J, Pollard JW (2006) Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell 124:263–266PubMedCrossRefGoogle Scholar
  22. Coutifaris C, Omigbodun A, Coukos G (2005) The fibronectin receptor alpha5 integrin subunit is upregulated by cell-cell adhesion via a cyclic AMP-dependent mechanism: implications for human trophoblast migration. Am J Obstet Gynecol 192:1240–1253; discussion 1253–1255Google Scholar
  23. De Palma M, Naldini L (2006) Role of haematopoietic cells and endothelial progenitors in tumour angiogenesis. Biochim Biophys Acta 1766: 159–166PubMedGoogle Scholar
  24. Decristoforo C, Faintuch-Linkowski B, Rey A, von Guggenberg E, Rupprich M, Hernandez-Gonzales I, Rodrigo T, Haubner R (2006) [99mTc]HYNIC-RGD for imaging integrin alphavbeta3 expression. Nucl Med Biol 33:945–952PubMedCrossRefGoogle Scholar
  25. Dietrich T, Onderka J, Bock F, Kruse FE, Vossmeyer D, Stragies R, Zahn G, Cursiefen C (2007) Inhibition of inflammatory lymphangiogenesis by integrin alpha5 blockade. Am J Pathol 171: 361–372PubMedCrossRefGoogle Scholar
  26. Dormond O, Ruegg C (2003) Regulation of endothelial cell integrin function and angiogenesis by COX-2, cAMP and protein kinase A. Thromb Haemost 90:577–585PubMedGoogle Scholar
  27. Eskens FALM, Dumez H, Hoekstra R, Perschl A, Brindley C, Bottcher S, Wynendaele W, Drevs J, Verweij J, van Oosterom AT (2003) Phase I and pharmacokinetic study of continuous twice weekly intravenous administration of Cilengitide (EMD 121974), a novel inhibitor of the integrins [alpha]v[beta]3 and [alpha]v[beta]5 in patients with advanced solid tumours. Eur J Cancer 39: 917–926PubMedCrossRefGoogle Scholar
  28. Francis SE, Goh KL, Hodivala-Dilke K, Bader BL, Stark M, Davidson D, Hynes RO (2002) Central roles of alpha5beta1 integrin and fibronectin in vascular development in mouse embryos and embryoid bodies. Arterioscler Thromb Vasc Biol 22:927–933PubMedCrossRefGoogle Scholar
  29. Giancotti FG (2007) Targeting integrin beta4 for cancer and anti-angiogenic therapy. Trends Pharmacol Sci 28:506–511PubMedCrossRefGoogle Scholar
  30. Ginsberg MH, Partridge A, Shattil SJ (2005) Integrin regulation. Curr Opin Cell Biol 17:509–516PubMedCrossRefGoogle Scholar
  31. Gutheil JC, Campbell TN, Pierce PR, Watkins JD, Huse WD, Bodkin DJ, Cheresh DA (2000) Targeted antiangiogenic therapy for cancer using vitaxin: a humanized monoclonal antibody to the integrin aVb3. Clin Cancer Res 6:3056–3061PubMedGoogle Scholar
  32. Hamano Y, Kalluri R (2005) Tumstatin, the NC1 domain of alpha3 chain of type IV collagen, is an endogenous inhibitor of pathological angiogenesis and suppresses tumor growth. Biochem Biophys Res Commun 333:292–298PubMedCrossRefGoogle Scholar
  33. Hammes H, Brownlee M, Jonczyk A, Sutter A, Preissner K (1996) Subcutaneous injection of a cyclic peptide antagonist of vitronectin receptor-type integrins inhibits retinal neovascularization. Nat Med 2:529–533PubMedCrossRefGoogle Scholar
  34. Hansma AHG, Broxterman HJ, van der Horst I, Yuana Y, Boven E, Giaccone G, Pinedo HM, Hoekman K (2005) Recombinant human endostatin administered as a 28-day continuous intravenous infusion, followed by daily subcutaneous injections: a phase I and pharmacokinetic study in patients with advanced cancer. Ann Oncol 16: 1695–1701PubMedCrossRefGoogle Scholar
  35. Hasmim M, Vassalli G, Alghisi G, Bamat J, Ponsonnet L, Bieler G, Bonnard C, Paroz C, Oguey D, Rüegg C (2005) Expressed isolated integrin b1 subunit cytodomain induces endothelial cell death secondary to detachment. Thromb Haemost 94: 1060–1070PubMedGoogle Scholar
  36. Haubner R, Gratias R, Diefenbach B, Goodman SL, Jonczyk A, Kessler H (1996) Structural and functional aspects of rgd-containing cyclic pentapeptides as highly potent and selective integrin αvβ3 antagonists. J. Am. Chem. Soc. 118:7461–7472CrossRefGoogle Scholar
  37. Herbst RS, Hess KR, Tran HT, Tseng JE, Mullani NA, Charnsangavej C, Madden T, Davis DW, McConkey DJ, O’Reilly MS, Ellis LM, Pluda J, Hong WK, Abbruzzese JL (2002) Phase I study of recombinant human endostatin in patients with advanced solid tumors. J Clin Oncol 20: 3792–3803PubMedCrossRefGoogle Scholar
  38. Hodivala-Dilke KM, McHugh KP, Tsakiris DA, Rayburn H, Crowley D, Ullman-Cullere M, Ross FP, Coller BS, Teitelbaum S, Hynes RO (1999) β3-integrin–deficient mice are a model for Glanzmann thrombasthenia showing placental defects and reduced survival. J Clin Invest 103:229–238PubMedCrossRefGoogle Scholar
  39. Hong YK, Lange-Asschenfeldt B, Velasco P, Hirakawa S, Kunstfeld R, Brown LF, Bohlen P, Senger DR, Detmar M (2004) VEGF-A promotes tissue repair-associated lymphatic vessel formation via VEGFR-2 and the alpha1beta1 and alpha2beta1 integrins. Faseb J 18: 1111–1113PubMedGoogle Scholar
  40. Hood JD, Bednarski M, Frausto R, Guccione S, Reisfeld RA, Xiang R, Cheresh DA (2002) Tumor regression by targeted gene delivery to the neovasculature. Science 296:2404–2407PubMedCrossRefGoogle Scholar
  41. Hsu AR, Hou LC, Veeravagu A, Greve JM, Vogel H, Tse V, Chen X (2006) In vivo near-infrared fluorescence imaging of integrin alphavbeta3 in an orthotopic glioblastoma model. Mol Imaging Biol 8:315–323PubMedCrossRefGoogle Scholar
  42. Hynes RO (2002) A reevaluation of integrins as regulators of angiogenesis. Nat Med 8:918–921PubMedCrossRefGoogle Scholar
  43. Hynes RO (2007) Cell-matrix adhesion in vascular development. J Thromb Haemost 5(Suppl 1): 32–40PubMedCrossRefGoogle Scholar
  44. Jin H, Su J, Garmy-Susini B, Kleeman J, Varner J (2006) Integrin alpha4beta1 promotes monocyte trafficking and angiogenesis in tumors. Cancer Res 66:2146–2152PubMedCrossRefGoogle Scholar
  45. Kawaguchi T, Yamashita Y, Kanamori M, Endersby R, Bankiewicz KS, Baker SJ, Bergers G, Pieper RO (2006) The PTEN/Akt pathway dictates the direct alphaVbeta3-dependent growth-inhibitory action of an active fragment of tumstatin in glioma cells in vitro and in vivo. Cancer Res 66:11331–11340PubMedCrossRefGoogle Scholar
  46. Kim D, Jeon C, Kim JH, Kim MS, Yoon CH, Choi IS, Kim SH, Bae YS (2006) Cytoplasmic transduction peptide (CTP): new approach for the delivery of biomolecules into cytoplasm in vitro and in vivo. Exp Cell Res 312:1277–1288PubMedCrossRefGoogle Scholar
  47. Kim S, Bell K, Mousa SA, Varner JA (2000) Regulation of angiogenesis in vivo by ligation of integrin a5b1 with the central cell-binding domain of fibronectin. Am J Pathol 156: 1345–1362PubMedGoogle Scholar
  48. Klotz O, Park JK, Pleyer U, Hartmann C, Baatz H (2000) Inhibition of corneal neovascularization by alpha(v)-integrin antagonists in the rat. Graefes Arch Clin Exp Ophthalmol 238:88–93PubMedCrossRefGoogle Scholar
  49. Koivunen E, Wang B, Ruoslahti E (1994) Isolation of a highly specific ligand for the alpha 5 beta 1 integrin from a phage display library. J Cell Biol 124:373–380PubMedCrossRefGoogle Scholar
  50. Kumar CC, Malkowski M, Yin Z, Tanghetti E, Yaremko B, Nechuta T, Varner J, Liu M, Smith EM, Neustadt B, Presta M, Armstrong L (2001) Inhibition of angiogenesis and tumor growth by SCH221153, a dual avb3 and avb5 integrin receptor antagonist. Cancer Res 61:2232–2238PubMedGoogle Scholar
  51. Kuwada SK (2007) Drug evaluation: volociximab, an angiogenesis-inhibiting chimeric monoclonal antibody. Curr Opin Mol Ther 9:92–98PubMedGoogle Scholar
  52. Lejeune FJ, Lienard D, Matter M, Ruegg C (2006) Efficiency of recombinant human TNF in human cancer therapy. Cancer Immun 6:6PubMedGoogle Scholar
  53. Liu S, Hsieh WY, Jiang Y, Kim YS, Sreerama SG, Chen X, Jia B, Wang F (2007) Evaluation of a (99m)Tc-labeled cyclic RGD tetramer for noninvasive imaging integrin alpha(v)beta3-positive breast cancer. Bioconjug Chem 18:438–446PubMedCrossRefGoogle Scholar
  54. Livant DL, Brabec RK, Pienta KJ, Allen DL, Kurachi K, Markwart S, Upadhyaya A (2000) Anti-invasive, antitumorigenic, and antimetastatic activities of the PHSCN sequence in prostate carcinoma. Cancer Res 60:309–320PubMedGoogle Scholar
  55. Loges S, Butzal M, Otten J, Schweizer M, Fischer U, Bokemeyer C, Hossfeld DK, Schuch G, Fiedler W (2007) Cilengitide inhibits proliferation and differentiation of human endothelial progenitor cells in vitro. Biochem Biophys Res Commun 357:1016–1020PubMedCrossRefGoogle Scholar
  56. Luo BH, Carman CV, Springer TA (2007) Structural basis of integrin regulation and signaling. Annu Rev Immunol 25:619–647PubMedCrossRefGoogle Scholar
  57. MacDonald T, Taga T, Shimada H, Tabrizi P, Zlokovic B, Cheresh D, Laug W (2001) Preferential susceptibility of brain tumors to the antiangiogenic effects of an alpha(v) integrin antagonist. Neurosurgery 48:151–157PubMedCrossRefGoogle Scholar
  58. Maeshima Y, Colorado PC, Torre A, Holthaus KA, Grunkemeyer JA, Ericksen MB, Hopfer H, Xiao Y, Stillman IE, Kalluri R (2000) Distinct antitumor properties of a Type IV collagen domain derived from basement membrane. J Biol Chem 275:21340–21348PubMedCrossRefGoogle Scholar
  59. Maeshima Y, Sudhakar A, Lively JC, Ueki K, Kharbanda S, Kahn CR, Sonenberg N, Hynes RO, Kalluri R (2002) Tumstatin, an endothelial cell-specific inhibitor of protein synthesis. Science 295:140–143PubMedCrossRefGoogle Scholar
  60. Mahabeleshwar GH, Feng W, Phillips DR, Byzova TV (2006) Integrin signaling is critical for pathological angiogenesis. J Exp Med 203: 2495–2507PubMedCrossRefGoogle Scholar
  61. Marinelli L, Meyer A, Heckmann D, Lavecchia A, Novellino E, Kessler H (2005) Ligand binding analysis for human alpha5beta1 integrin: strategies for designing new alpha5beta1 integrin antagonists. J Med Chem 48:4204–4207PubMedCrossRefGoogle Scholar
  62. Martin PL, Jiao Q, Cornacoff J, Hall W, Saville B, Nemeth JA, Schantz A, Mata M, Jang H, Fasanmade AA, Anderson L, Graham MA, Davis HM, Treacy G (2005) Absence of adverse effects in cynomolgus macaques treated with CNTO 95, a fully human anti-av integrin monoclonal antibody, despite widespread tissue binding. Clin Cancer Res 11:6959–6965PubMedCrossRefGoogle Scholar
  63. McNeel DG, Eickhoff J, Lee FT, King DM, Alberti D, Thomas JP, Friedl A, Kolesar J, Marnocha R, Volkman J, Zhang J, Hammershaimb L, Zwiebel JA, Wilding G (2005) Phase I trial of a monoclonal antibody specific for avb3 integrin (MEDI-522) in patients with advanced malignancies, including an assessment of effect on tumor perfusion. Clin Cancer Res 11:7851–7860PubMedCrossRefGoogle Scholar
  64. Meerovitch K, Bergeron F, Leblond L, Grouix B, Poirier C, Bubenik M, Chan L, Gourdeau H, Bowlin T, Attardo G (2003) A novel RGD antagonist that targets both alphavbeta3 and alpha5beta1 induces apoptosis of angiogenic endothelial cells on type I collagen. Vascul Pharmacol 40:77–89PubMedCrossRefGoogle Scholar
  65. Minamiguchi K, Kumagai H, Masuda T, Kawada M, Ishizuka M, Takeuchi T (2001) Thiolutin, an inhibitor of HUVEC adhesion to vitronectin, reduces paxillin in HUVECs and suppresses tumor cell-induced angiogenesis. Int J Cancer 93:307–316PubMedCrossRefGoogle Scholar
  66. Mitjans F, Sander D, Adan J, Sutter A, Martinez JM, Jaggle CS, Moyano JM, Kreysch HG, Piulats J, Goodman SL (1995) An anti-alpha v-integrin antibody that blocks integrin function inhibits the development of a human melanoma in nude mice. J Cell Sci 108:2825–2838PubMedGoogle Scholar
  67. Mitjans F, Meyer T, Fittschen C, Goodman S, Jonczyk A, Marshall J, Reyes G, Piulats J (2000) In vivo therapy of malignant melanoma by means of antagonists of alphav integrins. Int J Cancer 87: 716–723PubMedCrossRefGoogle Scholar
  68. Mitra A, Coleman T, Borgman M, Nan A, Ghandehari H, Line BR (2006) Polymeric conjugates of mono- and bi-cyclic alphaVbeta3 binding peptides for tumor targeting. J Control Release 114:175–183PubMedCrossRefGoogle Scholar
  69. Mould AP, Burrows L, Humphries MJ (1998) Identification of amino acid residues that form part of the ligand-binding pocket of integrin alpha 5beta 1. J. Biol. Chem. 273:25664–25672PubMedCrossRefGoogle Scholar
  70. Mullamitha SA, Ton NC, Parker GJ, Jackson A, Julyan PJ, Roberts C, Buonaccorsi GA, Watson Y, Davies K, Cheung S, Hope L, Valle JW, Radford JA, Lawrance J, Saunders MP, Munteanu MC, Nakada MT, Nemeth JA, Davis HM, Jiao Q, Prabhakar U, Lang Z, Corringham RE, Beckman RA, Jayson GC (2007) Phase I evaluation of a fully human anti-alphav integrin monoclonal antibody (CNTO 95) in patients with advanced solid tumors. Clin Cancer Res 13:2128–2135PubMedCrossRefGoogle Scholar
  71. Murakami M, Elfenbein A, Simons M (2008) Non-canonical fibroblast growth factor signaling in angiogenesis. Cardiovasc Res 78(2):223–231PubMedCrossRefGoogle Scholar
  72. Nabors LB, Mikkelsen T, Rosenfeld SS, Hochberg F, Akella NS, Fisher JD, Cloud GA, Zhang Y, Carson K, Wittemer SM, Colevas AD, Grossman SA (2007) Phase I and correlative biology study of cilengitide in patients with recurrent malignant glioma. J Clin Oncol 25:1651–1657PubMedCrossRefGoogle Scholar
  73. Nakada MT, Cao G, Sassoli PM, DeLisser HM (2006) c7E3 Fab inhibits human tumor angiogenesis in a SCID mouse human skin xenograft model. Angiogenesis 9:171–176PubMedCrossRefGoogle Scholar
  74. Nam JO, Jeong HW, Lee BH, Park RW, Kim IS (2005) Regulation of tumor angiogenesis by fastatin, the fourth FAS1 domain of betaig-h3, via alphavbeta3 integrin. Cancer Res 65:4153–4161PubMedCrossRefGoogle Scholar
  75. Nikolopoulos SN, Blaikie P, Yoshioka T, Guo W, Giancotti FG (2004) Integrin [beta]4 signaling promotes tumor angiogenesis. Cancer Cell 6:471–483PubMedCrossRefGoogle Scholar
  76. Ning S, Chen Z, Dirks A, Husbeck B, Hsu M, Bedogni B, O’Neill M, Powell MB, Knox SJ (2007) Targeting integrins and PI3K/Akt-mediated signal transduction pathways enhances radiation-induced anti-angiogenesis. Radiat Res 168: 125–133PubMedCrossRefGoogle Scholar
  77. Nisato RE, Tille J-C, Jonczyk A, Goodman SL, Pepper MS (2004) alphav beta3 and alphav beta5 integrin antagonists inhibit angiogenesis in vitro. Angiogenesis 6:105–119CrossRefGoogle Scholar
  78. O’Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS, Flynn E, Birkhead JR, Olsen BR, Folkman J (1997) Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 88:277–285PubMedCrossRefGoogle Scholar
  79. Oba M, Fukushima S, Kanayama N, Aoyagi K, Nishiyama N, Koyama H, Kataoka K (2007) Cyclic RGD peptide-conjugated polyplex micelles as a targetable gene delivery system directed to cells possessing alphavbeta3 and alphavbeta5 integrins. Bioconjug Chem 18:1415–1423PubMedCrossRefGoogle Scholar
  80. Oguey D, George P, Ruegg C (2000) Disruption of integrin-dependent adhesion and survival of endothelial cells by recombinant adenovirus expressing isolated beta integrin cytoplasmic domains. Gene Ther 7:1292–1303PubMedCrossRefGoogle Scholar
  81. Orecchia A, Lacal PM, Schietroma C, Morea V, Zambruno G, Failla CM (2003) Vascular endothelial growth factor receptor-1 is deposited in the extracellular matrix by endothelial cells and is a ligand for the alpha 5 beta 1 integrin. J Cell Sci 116:3479–3489PubMedCrossRefGoogle Scholar
  82. Perruzzi CA, de Fougerolles AR, Koteliansky VE, Whelan MC, Westlin WF, Senger DR (2003) Functional overlap and cooperativity among alphav and beta1 integrin subfamilies during skin angiogenesis. J Invest Dermatol 120: 1100–1109PubMedCrossRefGoogle Scholar
  83. Pfeifer A, Kessler T, Silletti S, Cheresh DA, Verma IM (2000) Suppression of angiogenesis by lentiviral delivery of PEX, a noncatalytic fragment of matrix metalloproteinase 2. PNAS 97:12227–12232PubMedCrossRefGoogle Scholar
  84. Posey J, Khazaeli M, DelGrosso A, Saleh M, Lin C, Huse W, LoBuglio A (2001) A pilot trial of Vitaxin, a humanized anti-vitronectin receptor (anti alpha v beta 3) antibody in patients with metastatic cancer. Cancer Biother Radiopharm 16:125–132PubMedCrossRefGoogle Scholar
  85. Raguse J-D, Gath HJ, Bier J, Riess H, Oettle H (2004) Cilengitide (EMD 121974) arrests the growth of a heavily pretreated highly vascularised head and neck tumour. Oral Oncol 40:228–230PubMedCrossRefGoogle Scholar
  86. Ramakrishnan V, Bhaskar V, Law DA, Wong MH, DuBridge RB, Breinberg D, O’Hara C, Powers DB, Liu G, Grove J, Hevezi P, Cass KM, Watson S, Evangelista F, Powers RA, Finck B, Wills M, Caras I, Fang Y, McDonald D, Johnson D, Murray R, Jeffry U (2006) Preclinical evaluation of an anti-alpha5beta1 integrin antibody as a novel anti-angiogenic agent. J Exp Ther Oncol 5: 273–286PubMedGoogle Scholar
  87. Reinmuth N, Liu W, Ahmad SA, Fan F, Stoeltzing O, Parikh AA, Bucana CD, Gallick GE, Nickols MA, Westlin WF, Ellis LM (2003) Alphavbeta3 integrin antagonist S247 decreases colon cancer metastasis and angiogenesis and improves survival in mice. Cancer Res 63:2079–2087PubMedGoogle Scholar
  88. Reynolds AR, Reynolds LE, Nagel TE, Lively JC, Robinson SD, Hicklin DJ, Bodary SC, Hodivala-Dilke KM (2004) Elevated Flk1 (vascular endothelial growth factor receptor 2) signaling mediates enhanced angiogenesis in b3-integrin-deficient mice. Cancer Res 64:8643–8650PubMedCrossRefGoogle Scholar
  89. Reynolds L, Wyder L, Lively J, Taverna D, Robinson S, Huang X, Sheppard D, Hynes R, Hodivala-Dilke K (2002) Enhanced pathological angiogenesis in mice lacking beta3 integrin or beta3 and beta5 integrins. Nat Med 8:27–34PubMedCrossRefGoogle Scholar
  90. Romer LH, Birukov KG, Garcia JG (2006) Focal adhesions: paradigm for a signaling nexus. Circ Res 98:606–616PubMedCrossRefGoogle Scholar
  91. Ruegg C, Yilmaz A, Bieler G, Bamat J, Chaubert P, Lejeune FJ (1998) Evidence for the involvement of endothelial cell integrin alphaVbeta3 in the disruption of the tumor vasculature induced by TNF and IFN-gamma. Nat Med 4:408–414PubMedCrossRefGoogle Scholar
  92. Ruegg C, Mutter N (2007) Anti-angiogenic therapies in cancer: achievements and open questions. Bull Cancer 94:753–762PubMedGoogle Scholar
  93. Sabherwal Y, Rothman VL, Dimitrov S, L’Heureux DZ, Marcinkiewicz C, Sharma M, Tuszynski GP (2006) Integrin alpha2beta1 mediates the anti-angiogenic and anti-tumor activities of angiocidin, a novel tumor-associated protein. Exp Cell Res 312:2443–2453PubMedCrossRefGoogle Scholar
  94. Scott KA, Arnott CH, Robinson SC, Moore RJ, Thompson RG, Marshall JF, Balkwill FR (2004) TNF-alpha regulates epithelial expression of MMP-9 and integrin alphavbeta6 during tumour promotion. A role for TNF-alpha in keratinocyte migration? Oncogene 23:6954–6966PubMedCrossRefGoogle Scholar
  95. Senger DR, Claffey KP, Benes JE, Perruzzi CA, Sergiou AP, Detmar M (1997) Angiogenesis promoted by vascular endothelial growth factor: regulation through alpha 1beta 1 and alpha 2beta 1 integrins. Proc Natl Acad Sci 94: 13612–13617PubMedCrossRefGoogle Scholar
  96. Senger DR, Perruzzi CA, Streit M, Koteliansky VE, de Fougerolles AR, Detmar M (2002) The a1b1 and a2b1 integrins provide critical support for vascular endothelial growth factor signaling, endothelial cell migration, and tumor angiogenesis. Am J Pathol 160:195–204PubMedGoogle Scholar
  97. Serini G, Valdembri D, Bussolino F (2006) Integrins and angiogenesis: a sticky business. Exp Cell Res 312(5):651–658PubMedCrossRefGoogle Scholar
  98. Shin IS, Jang BS, Danthi SN, Xie J, Yu S, Le N, Maeng JS, Hwang IS, Li KC, Carrasquillo JA, Paik CH (2007) Use of antibody as carrier of oligomers of peptidomimetic alphavbeta3 antagonist to target tumor-induced neovasculature. Bioconjug Chem 18:821–828PubMedCrossRefGoogle Scholar
  99. Smith JW (2003) Cilengitide Merck. Curr Opin Investig Drugs 4:741–745PubMedGoogle Scholar
  100. Stoeltzing O, Liu W, Reinmuth N, Fan F, Parry G, Parikh A, McCarty M, Bucana C, Mazar A, Ellis L (2003) Inhibition of integrin alpha5beta1 function with a small peptide (ATN-161) plus continuous 5-FU infusion reduces colorectal liver metastases and improves survival in mice. Int J Cancer 104:496–503PubMedCrossRefGoogle Scholar
  101. Strieth S, Eichhorn ME, Sutter A, Jonczyk A, Berghaus A, Dellian M (2006) Antiangiogenic combination tumor therapy blocking alpha(v)-integrins and VEGF-receptor-2 increases therapeutic effects in vivo. Int J Cancer 119:423–431PubMedCrossRefGoogle Scholar
  102. Stupack DG (2007) The biology of integrins. Oncology (Williston Park) 21:6–12Google Scholar
  103. Stupp R, Ruegg C (2007) Integrin inhibitors reaching the clinic. J Clin Oncol 25:1637–1638PubMedCrossRefGoogle Scholar
  104. Taga T, Suzuki A, Gonzalez-Gomez I, Gilles FH, Stins M, Shimada H, Barsky L, Weinberg KI, Laug WE (2002) Alphav-Integrin antagonist EMD 121974 induces apoptosis in brain tumor cells growing on vitronectin and tenascin. Int J Cancer 98:690–697PubMedCrossRefGoogle Scholar
  105. Takada Y, Xiaojing X, Scott S (2007) The integrins. Genome Biol 8:215PubMedCrossRefGoogle Scholar
  106. Tanjore H, Zeisberg EM, Gerami-Naini B, Kalluri R (2007) Beta1 integrin expression on endothelial cells is required for angiogenesis but not for vasculogenesis. Dev Dyn 237:75–82CrossRefGoogle Scholar
  107. Tomiyama Y (2000) Glanzmann thrombasthenia: integrin alpha IIb beta 3 deficiency. Int J Hematol 72:448–454PubMedGoogle Scholar
  108. Travis MA, Humphries JD, Humphries MJ (2003) An unraveling tale of how integrins are activated from within. Trends Pharmacol Sci 24:192–197PubMedCrossRefGoogle Scholar
  109. Trikha M, Zhou Z, Nemeth J, Chen Q, Sharp C, Emmell E, Giles-Komar J, Nakada M (2004) CNTO 95, a fully human monoclonal antibody that inhibits av integrins, has antitumor and antiangiogenic activity in vivo. Int J Cancer 110:326–335PubMedCrossRefGoogle Scholar
  110. Tsopanoglou NE, Papaconstantinou ME, Flordellis CS, Maragoudakis ME (2004) On the mode of action of thrombin-induced angiogenesis: thrombin peptide, TP508, mediates effects in endothelial cells via alphavbeta3 integrin. Thromb Haemost 92: 846–857PubMedGoogle Scholar
  111. Ulbrich H, Eriksson EE, Lindbom L (2003) Leukocyte and endothelial cell adhesion molecules as targets for therapeutic interventions in inflammatory disease. Trends Pharmacol Sci 24:640–647PubMedCrossRefGoogle Scholar
  112. Umeda N, Kachi S, Akiyama H, Zahn G, Vossmeyer D, Stragies R, Campochiaro PA (2006) Suppression and regression of choroidal neovascularization by systemic administration of an alpha5beta1 integrin antagonist. Mol Pharmacol 69:1820–1828PubMedCrossRefGoogle Scholar
  113. Varner JA, Nakada MT, Jordan RE, Coller BS (1999) Inhibition of angiogenesis and tumor growth by murine 7E3, the parent antibodyof c7E3 Fab (abciximab; ReoProTM). Angiogenesis 3:53–60PubMedCrossRefGoogle Scholar
  114. Vlahakis NE, Young BA, Atakilit A, Hawkridge AE, Issaka RB, Boudreau N, Sheppard D (2007) Integrin alpha9beta1 directly binds to vascular endothelial growth factor (VEGF)-A and contributes to VEGF-A-induced angiogenesis. J Biol Chem 282:15187–15196PubMedCrossRefGoogle Scholar
  115. Wickstrom SA, Alitalo K, KeskiOja J (2005) Endostatin signaling and regulation of endothelial cell-matrix interactions. Adv Cancer Res 94:197–229PubMedCrossRefGoogle Scholar
  116. Woodall BP, Nystrom A, Iozzo RA, Eble JA, Niland S, Krieg T, Eckes B, Pozzi A, Iozzo RV (2008) Integrin alpha 2beta 1 is the required receptor for endorepellin angiostatic activity. J Biol Chem 283(4):2335–2343PubMedCrossRefGoogle Scholar
  117. Wu H, Beuerlein G, Nie Y, Smith H, Lee BA, Hensler M, Huse WD, Watkins JD (1998) Stepwise in vitro affinity maturation of Vitaxin, an alpha vbeta 3-specific humanized mAb. Proc Natl Acad Sci 95:6037–6042PubMedCrossRefGoogle Scholar
  118. Xie J, Shen Z, Li KC, Danthi N (2007) Tumor angiogenic endothelial cell targeting by a novel integrin-targeted nanoparticle. Int J Nanomed 2:479–485Google Scholar
  119. Xiong JP, Stehle T, Zhang R, Joachimiak A, Frech M, Goodman SL, Arnaout MA (2002) Crystal structure of the extracellular segment of integrin alpha Vbeta3 in complex with an Arg-Gly-Asp ligand. Science 296:151–155PubMedCrossRefGoogle Scholar
  120. Zaric J, Ruegg C (2005) Integrin-mediated adhesion and soluble ligand binding stabilize COX-2 protein levels in endothelial cells by inducing expression and preventing degradation. J Biol Chem 280:1077–1085PubMedCrossRefGoogle Scholar
  121. Zhang D, Pier T, McNeel DG, Wilding G, Friedl A (2007) Effects of a monoclonal anti-alphavbeta3 integrin antibody on blood vessels – a pharmacodynamic study. Invest New Drugs 25:49–55PubMedCrossRefGoogle Scholar
  122. Zhou Y, Peng H, Ji Q, Qi J, Zhu Z, Yang C (2006) Discovery of small molecule inhibitors of integrin alphavbeta3 through structure-based virtual screening. Bioorg Med Chem Lett 16: 5878–5882PubMedCrossRefGoogle Scholar
  123. Zhu J, Motejlek K, Wang D, Zang K, Schmidt A, Reichardt LF (2002) β8 integrins are required for vascular morphogenesis in mouse embryos. Development 129:2891–2903PubMedGoogle Scholar
  124. Zweers MC, Davidson JM, Pozzi A, Hallinger R, Janz K, Quondamatteo F, Leutgeb B, Krieg T, Eckes B (2007) Integrin alpha2beta1 is required for regulation of murine wound angiogenesis but is dispensable for reepithelialization. J Invest Dermatol 127:467–478PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2010

Authors and Affiliations

  1. 1.Division of Experimental OncologyCentre Pluridisciplinaire d’OncologieEpalingesSwitzerland

Personalised recommendations