Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Gene therapy targeting to tumor endothelium

Cancer Gene Therapy volume 14, pages 117–127 (2007)Cite this article

Abstract

Tumor-associated vasculature is a relatively accessible component of solid cancers that is essential for tumor survival and growth, providing a vulnerable target for cancer gene therapy administered by intravenous injection. Several features of tumor-associated vasculature are different from normal vasculature, including overexpression of receptors for angiogenic growth factors, markers of vasculogenesis, upregulation of coagulation cascades, aberrant expression of adhesion molecules and molecular consequences of hypoxia. Many of these differences provide candidate targets for tumor-selective ‘transductional targeting’ of genetically- or chemically modified vectors and upregulated gene expression can also enable ‘transcriptional targeting’, regulating tumor endothelia-selective expression of transgenes following nonspecific gene delivery. Tumor vasculature also represents an important site of therapeutic action by the secreted products of antiangiogenic gene therapies that are expressed in non-endothelial cells. In this review we assess the challenges faced and the vectors that may be suitable for gene delivery to exploit these targets. We also overview some of the strategies that have been developed to date and highlight the most promising areas of research.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1

Similar content being viewed by others

References

  1. Carmeliet P, Jain RK . Angiogenesis in cancer and other diseases. Nature 2000; 407: 249–257.

    Article  CAS  PubMed  Google Scholar 

  2. Hanahan D, Weinberg RA . The hallmarks of cancer. Cell 2000; 100: 57–70.

    Article  CAS  PubMed  Google Scholar 

  3. Dvorak HF . Angiogenesis: update 2005. J Thromb Haemost 2005; 3: 1835–1842.

    CAS  PubMed  Google Scholar 

  4. Bicknell R, Harris AL . Novel angiogenic signaling pathways and vascular targets. Annu Rev Pharmacol Toxicol 2004; 44: 219–238.

    CAS  PubMed  Google Scholar 

  5. Burri PH, Hlushchuk R, Djonov V . Intussusceptive angiogenesis: its emergence, its characteristics, and its significance. Dev Dyn 2004; 231: 474–488.

    PubMed  Google Scholar 

  6. Folberg R, Maniotis AJ . Vasculogenic mimicry. Apmis 2004; 112: 508–525.

    PubMed  Google Scholar 

  7. Asahara T, Takahashi T, Masuda H, Kalka C, Chen D, Iwaguro H et al. VEGF contributes to postnatal neovascularization by mobilizing bone marrow-derived endothelial progenitor cells. EMBO J 1999; 18: 3964–3972.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Lin Y, Weisdorf DJ, Solovey A, Hebbel RP . Origins of circulating endothelial cells and endothelial outgrowth from blood. J Clin Invest 2000; 105: 71–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Peters BA, Diaz LA, Polyak K, Meszler L, Romans K, Guinan EC et al. Contribution of bone marrow-derived endothelial cells to human tumor vasculature. Nat Med 2005; 11: 261–262.

    CAS  PubMed  Google Scholar 

  10. Hilbe W, Dirnhofer S, Oberwasserlechner F, Schmid T, Gunsilius E, Hilbe G et al. CD133 positive endothelial progenitor cells contribute to the tumour vasculature in non-small cell lung cancer. J Clin Pathol 2004; 57: 965–969.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Ceradini DJ, Kulkarni AR, Callaghan MJ, Tepper OM, Bastidas N, Kleinman ME et al. Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med 2004; 10: 858–864.

    CAS  PubMed  Google Scholar 

  12. Harris AL . Hypoxia – a key regulatory factor in tumour growth. Nat Rev Cancer 2002; 2: 38–47.

    CAS  PubMed  Google Scholar 

  13. Ribatti D, Nico B, Spinazzi R, Vacca A, Nussdorfer GG . The role of adrenomedullin in angiogenesis. Peptides 2005; 26: 1670–1675.

    CAS  PubMed  Google Scholar 

  14. Ruoslahti E . Vascular zip codes in angiogenesis and metastasis. Biochem Soc Trans 2004; 32: 397–402.

    CAS  PubMed  Google Scholar 

  15. Borsi L, Balza E, Carnemolla B, Sassi F, Castellani P, Berndt A et al. Selective targeted delivery of TNFalpha to tumor blood vessels. Blood 2003; 102: 4384–4392.

    CAS  PubMed  Google Scholar 

  16. Belting M, Ahamed J, Ruf W . Signaling of the tissue factor coagulation pathway in angiogenesis and cancer. Arterioscler Thromb Vasc Biol 2005; 25: 1545–1550.

    CAS  PubMed  Google Scholar 

  17. Duffy MJ . The urokinase plasminogen activator system: role in malignancy. Curr Pharm Des 2004; 10: 39–49.

    CAS  PubMed  Google Scholar 

  18. Mosesson MW . Fibrinogen and fibrin structure and functions. J Thromb Haemost 2005; 3: 1894–1904.

    CAS  PubMed  Google Scholar 

  19. Folkman J . Endogenous angiogenesis inhibitors. Apmis 2004; 112: 496–507.

    CAS  PubMed  Google Scholar 

  20. Palmer DH, Mautner V, Mirza D, Oliff S, Gerritsen W, van der Sijp JR et al. Virus-directed enzyme prodrug therapy: intratumoral administration of a replication-deficient adenovirus encoding nitroreductase to patients with resectable liver cancer. J Clin Oncol 2004; 22: 1546–1552.

    CAS  PubMed  Google Scholar 

  21. Maxwell IH, Kaletta C, Naujoks K, Maxwell F . Targeting diphtheria toxin A-chain transcription to activated endothelial cells using an E-selectin promoter. Angiogenesis 2003; 6: 31–38.

    CAS  PubMed  Google Scholar 

  22. Thorpe PE . Vascular targeting agents as cancer therapeutics. Clin Cancer Res 2004; 10: 415–427.

    PubMed  Google Scholar 

  23. Lyons M, Onion D, Green NK, Aslan K, Rajaratnam R, Bazan-Peregrino M et al. Adenovirus type 5 interactions with human blood cells may compromise systemic delivery. Mol Ther 2006; 14: 118–128.

    CAS  PubMed  Google Scholar 

  24. Green NK, Herbert CW, Hale SJ, Hale AB, Mautner V, Harkins R et al. Extended plasma circulation time and decreased toxicity of polymer-coated adenovirus. Gene Therapy 2004; 11: 1256–1263.

    CAS  PubMed  Google Scholar 

  25. Schiedner G, Hertel S, Johnston M, Dries V, van Rooijen N, Kochanek S . Selective depletion or blockade of Kupffer cells leads to enhanced and prolonged hepatic transgene expression using high-capacity adenoviral vectors. Mol Ther 2003; 7: 35–43.

    CAS  PubMed  Google Scholar 

  26. Tao N, Gao GP, Parr M, Johnston J, Baradet T, Wilson JM et al. Sequestration of adenoviral vector by Kupffer cells leads to a nonlinear dose response of transduction in liver. Mol Ther 2001; 3: 28–35.

    CAS  PubMed  Google Scholar 

  27. Mahasreshti PJ, Kataram M, Wang MH, Stockard CR, Grizzle WE, Carey D et al. Intravenous delivery of adenovirus-mediated soluble FLT-1 results in liver toxicity. Clin Cancer Res 2003; 9: 2701–2710.

    CAS  PubMed  Google Scholar 

  28. Akiyama M, Thorne S, Kirn D, Roelvink PW, Einfeld DA, King CR et al. Ablating CAR and integrin binding in adenovirus vectors reduces nontarget organ transduction and permits sustained bloodstream persistence following intraperitoneal administration. Mol Ther 2004; 9: 218–230.

    CAS  PubMed  Google Scholar 

  29. Smith T, Idamakanti N, Kylefjord H, Rollence M, King L, Kaloss M et al. In vivo hepatic adenoviral gene delivery occurs independently of the coxsackievirus-adenovirus receptor. Mol Ther 2002; 5: 770–779.

    CAS  PubMed  Google Scholar 

  30. Nagel H, Maag S, Tassis A, Nestle FO, Greber UF, Hemmi S . The alphavbeta5 integrin of hematopoietic and nonhematopoietic cells is a transduction receptor of RGD-4C fiber-modified adenoviruses. Gene Therapy 2003; 10: 1643–1653.

    CAS  PubMed  Google Scholar 

  31. Work LM, Reynolds PN, Baker AH . Improved gene delivery to human saphenous vein cells and tissue using a peptide-modified adenoviral vector. Genet Vaccines Ther 2004; 2: 14.

    PubMed  PubMed Central  Google Scholar 

  32. Biermann V, Volpers C, Hussmann S, Stock A, Kewes H, Schiedner G et al. Targeting of high-capacity adenoviral vectors. Hum Gene Ther 2001; 12: 1757–1769.

    CAS  PubMed  Google Scholar 

  33. Shi W, Bartlett JS . RGD inclusion in VP3 provides adeno-associated virus type 2 (AAV2)-based vectors with a heparan sulfate-independent cell entry mechanism. Mol Ther 2003; 7: 515–525.

    CAS  PubMed  Google Scholar 

  34. Hajitou A, Trepel M, Lilley CE, Soghomonyan S, Alauddin MM, Marini III FC et al. A hybrid vector for ligand-directed tumor targeting and molecular imaging. Cell 2006; 125: 385–398.

    CAS  PubMed  Google Scholar 

  35. White SJ, Nicklin SA, Buning H, Brosnan MJ, Leike K, Papadakis ED et al. Targeted gene delivery to vascular tissue in vivo by tropism-modified adeno-associated virus vectors. Circulation 2004; 109: 513–519.

    CAS  PubMed  Google Scholar 

  36. Nicklin SA, Von Seggern DJ, Work LM, Pek DC, Dominiczak AF, Nemerow GR et al. Ablating adenovirus type 5 fiber-CAR binding and HI loop insertion of the SIGYPLP peptide generate an endothelial cell-selective adenovirus. Mol Ther 2001; 4: 534–542.

    CAS  PubMed  Google Scholar 

  37. O'Riordan CR, Lachapelle A, Delgado C, Parkes V, Wadsworth SC, Smith AE et al. PEGylation of adenovirus with retention of infectivity and protection from neutralizing antibody in vitro and in vivo. Hum Gene Ther 1999; 10: 1349–1358.

    Article  CAS  PubMed  Google Scholar 

  38. Romanczuk H, Galer CE, Zabner J, Barsomian G, Wadsworth SC, O'Riordan CR . Modification of an adenoviral vector with biologically selected peptides: a novel strategy for gene delivery to cells of choice. Hum Gene Ther 1999; 10: 2615–2626.

    CAS  PubMed  Google Scholar 

  39. Fisher KD, Stallwood Y, Green NK, Ulbrich K, Mautner V, Seymour LW . Polymer-coated adenovirus permits efficient retargeting and evades neutralising antibodies. Gene Therapy 2001; 8: 341–348.

    CAS  PubMed  Google Scholar 

  40. Parker AL, Fisher KD, Oupicky D, Read ML, Nicklin SA, Baker AH et al. Enhanced gene transfer activity of peptide-targeted gene-delivery vectors. J Drug Target 2005; 13: 39–51.

    CAS  PubMed  Google Scholar 

  41. Schiffelers RM, Ansari A, Xu J, Zhou Q, Tang Q, Storm G et al. Cancer siRNA therapy by tumor selective delivery with ligand-targeted sterically stabilized nanoparticle. Nucleic Acids Res 2004; 32: e149.

    PubMed  PubMed Central  Google Scholar 

  42. Dasgupta P, Sun J, Wang S, Fusaro G, Betts V, Padmanabhan J et al. Disruption of the Rb–Raf-1 interaction inhibits tumor growth and angiogenesis. Mol Cell Biol 2004; 24: 9527–9541.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Hood JD, Bednarski M, Frausto R, Guccione S, Reisfeld RA, Xiang R et al. Tumor regression by targeted gene delivery to the neovasculature. Science 2002; 296: 2404–2407.

    CAS  PubMed  Google Scholar 

  44. Ogawara K, Rots MG, Kok RJ, Moorlag HE, Van Loenen AM, Meijer DK et al. A novel strategy to modify adenovirus tropism and enhance transgene delivery to activated vascular endothelial cells in vitro and in vivo. Hum Gene Ther 2004; 15: 433–443.

    CAS  PubMed  Google Scholar 

  45. Rabinowitz JE, Rolling F, Li C, Conrath H, Xiao W, Xiao X et al. Cross-packaging of a single adeno-associated virus (AAV) type 2 vector genome into multiple AAV serotypes enables transduction with broad specificity. J Virol 2002; 76: 791–801.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Dishart KL, Denby L, George SJ, Nicklin SA, Yendluri S, Tuerk MJ et al. Third-generation lentivirus vectors efficiently transduce and phenotypically modify vascular cells: implications for gene therapy. J Mol Cell Cardiol 2003; 35: 739–748.

    CAS  PubMed  Google Scholar 

  47. Gaggar A, Shayakhmetov DM, Lieber A . CD46 is a cellular receptor for group B adenoviruses. Nat Med 2003; 9: 1408–1412.

    CAS  PubMed  Google Scholar 

  48. Havenga MJ, Lemckert AA, Grimbergen JM, Vogels R, Huisman LG, Valerio D et al. Improved adenovirus vectors for infection of cardiovascular tissues. J Virol 2001; 75: 3335–3342.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Stone D, Ni S, Li ZY, Gaggar A, DiPaolo N, Feng Q et al. Development and assessment of human adenovirus type 11 as a gene transfer vector. J Virol 2005; 79: 5090–5104.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Verhoeyen E, Cosset FL . Surface-engineering of lentiviral vectors. J Gene Med 2004; 6 (Suppl 1): S83–S94.

    CAS  PubMed  Google Scholar 

  51. Shichinohe T, Bochner BH, Mizutani K, Nishida M, Hegerich-Gilliam S, Naldini L et al. Development of lentiviral vectors for antiangiogenic gene delivery. Cancer Gene Ther 2001; 8: 879–889.

    CAS  PubMed  Google Scholar 

  52. Nettelbeck DM, Miller DW, Jerome V, Zuzarte M, Watkins SJ, Hawkins RE et al. Targeting of adenovirus to endothelial cells by a bispecific single-chain diabody directed against the adenovirus fiber knob domain and human endoglin (CD105). Mol Ther 2001; 3: 882–891.

    CAS  PubMed  Google Scholar 

  53. Masood R, Gordon EM, Whitley MD, Wu BW, Cannon P, Evans L et al. Retroviral vectors bearing IgG-binding motifs for antibody-mediated targeting of vascular endothelial growth factor receptors. Int J Mol Med 2001; 8: 335–343.

    CAS  PubMed  Google Scholar 

  54. Richardson TB, Kaspers J, Porter CD . Retroviral hybrid LTR vector strategy: functional analysis of LTR elements and generation of endothelial cell specificity. Gene Therapy 2004; 11: 775–783.

    CAS  PubMed  Google Scholar 

  55. De Palma M, Venneri MA, Naldini L . In vivo targeting of tumor endothelial cells by systemic delivery of lentiviral vectors. Hum Gene Ther 2003; 14: 1193–1206.

    CAS  PubMed  Google Scholar 

  56. Shibata T, Akiyama N, Noda M, Sasai K, Hiraoka M . Enhancement of gene expression under hypoxic conditions using fragments of the human vascular endothelial growth factor and the erythropoietin genes. Int J Radiat Oncol Biol Phys 1998; 42: 913–916.

    CAS  PubMed  Google Scholar 

  57. Mavria G, Harrington KJ, Marshall CJ, Porter CD . In vivo efficacy of HSV-TK transcriptionally targeted to the tumour vasculature is augmented by combination with cytotoxic chemotherapy. J Gene Med 2005; 7: 263–275.

    CAS  PubMed  Google Scholar 

  58. Koshikawa N, Takenaga K, Tagawa M, Sakiyama S . Therapeutic efficacy of the suicide gene driven by the promoter of vascular endothelial growth factor gene against hypoxic tumor cells. Cancer Res 2000; 60: 2936–2941.

    CAS  PubMed  Google Scholar 

  59. Dancer A, Julien S, Bouillot S, Pointu H, Vernet M, Huber P . Expression of thymidine kinase driven by an endothelial-specific promoter inhibits tumor growth of Lewis lung carcinoma cells in transgenic mice. Gene Therapy 2003; 10: 1170–1178.

    CAS  PubMed  Google Scholar 

  60. Binley K, Askham Z, Martin L, Spearman H, Day D, Kingsman S et al. Hypoxia-mediated tumour targeting. Gene Therapy 2003; 10: 540–549.

    CAS  PubMed  Google Scholar 

  61. Huang ZH, Yang WY, Cheng Q, Yu JL, Li Z, Tong ZY et al. Kinase domain insert containing receptor promotor controlled suicide gene system kills human umbilical vein endothelial cells. World J Gastroenterol 2005; 11: 3686–3690.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Ozaki K, Yoshida T, Ide H, Saito I, Ikeda Y, Sugimura T et al. Use of von Willebrand factor promoter to transduce suicidal gene to human endothelial cells, HUVEC. Hum Gene Ther 1996; 7: 1483–1490.

    CAS  PubMed  Google Scholar 

  63. Shibata T, Giaccia AJ, Brown JM . Hypoxia-inducible regulation of a prodrug-activating enzyme for tumor-specific gene therapy. Neoplasia 2002; 4: 40–48.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Greenberger S, Shaish A, Varda-Bloom N, Levanon K, Breitbart E, Goldberg I et al. Transcription-controlled gene therapy against tumor angiogenesis. J Clin Invest 2004; 113: 1017–1024.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Jaggar RT, Chan HY, Harris AL, Bicknell R . Endothelial cell-specific expression of tumor necrosis factor-alpha from the KDR or E-selectin promoters following retroviral delivery. Hum Gene Ther 1997; 8: 2239–2247.

    CAS  PubMed  Google Scholar 

  66. Song W, Sun Q, Dong Z, Spencer DM, Nunez G, Nor JE . Antiangiogenic gene therapy: disruption of neovascular networks mediated by inducible caspase-9 delivered with a transcriptionally targeted adenoviral vector. Gene Therapy 2005; 12: 320–329.

    CAS  PubMed  Google Scholar 

  67. Pin RH, Reinblatt M, Bowers WJ, Federoff HJ, Fong Y . Herpes simplex virus amplicon delivery of a hypoxia-inducible angiogenic inhibitor blocks capillary formation in hepatocellular carcinoma. J Gastrointest Surg 2004; 8: 812–822; discussion 822–813.

    PubMed  Google Scholar 

  68. Savontaus MJ, Sauter BV, Huang TG, Woo SL . Transcriptional targeting of conditionally replicating adenovirus to dividing endothelial cells. Gene Therapy 2002; 9: 972–979.

    CAS  PubMed  Google Scholar 

  69. Cuevas Y, Hernandez-Alcoceba R, Aragones J, Naranjo-Suarez S, Castellanos MC, Esteban MA et al. Specific oncolytic effect of a new hypoxia-inducible factor-dependent replicative adenovirus on von Hippel-Lindau-defective renal cell carcinomas. Cancer Res 2003; 63: 6877–6884.

    CAS  PubMed  Google Scholar 

  70. Post DE, Van Meir EG . A novel hypoxia-inducible factor (HIF) activated oncolytic adenovirus for cancer therapy. Oncogene 2003; 22: 2065–2072.

    CAS  PubMed  Google Scholar 

  71. Work LM, Ritchie N, Nicklin SA, Reynolds PN, Baker AH . Dual targeting of gene delivery by genetic modification of adenovirus serotype 5 fibers and cell-selective transcriptional control. Gene Therapy 2004; 11: 1296–1300.

    CAS  PubMed  Google Scholar 

  72. Kaliberov SA, Kaliberova LN, Petersen AS, Krendelchtchikova V, Krasnykh V, Buchsbaum DJ . Oncolytic Virotherapy Employing flt-1 Driven mda-7/IL-24 Gene Delivery. In: Am Soc Gene Ther. St. Louis, Missouri, 2005.

    Google Scholar 

  73. Ponnazhagan S, Mahendra G, Kumar S, Shaw DR, Stockard CR, Grizzle WE et al. Adeno-associated virus 2-mediated antiangiogenic cancer gene therapy: long-term efficacy of a vector encoding angiostatin and endostatin over vectors encoding a single factor. Cancer Res 2004; 64: 1781–1787.

    CAS  PubMed  Google Scholar 

  74. Davidoff AM, Nathwani AC, Spurbeck WW, Ng CY, Zhou J, Vanin EF . rAAV-mediated long-term liver-generated expression of an angiogenesis inhibitor can restrict renal tumor growth in mice. Cancer Res 2002; 62: 3077–3083.

    CAS  PubMed  Google Scholar 

  75. Zacchigna S, Zentilin L, Morini M, Dell'Eva R, Noonan DM, Albini A et al. AAV-mediated gene transfer of tissue inhibitor of metalloproteinases-1 inhibits vascular tumor growth and angiogenesis in vivo. Cancer Gene Ther 2004; 11: 73–80.

    CAS  PubMed  Google Scholar 

  76. Kikuchi E, Menendez S, Ohori M, Cordon-Cardo C, Kasahara N, Bochner BH . Inhibition of orthotopic human bladder tumor growth by lentiviral gene transfer of endostatin. Clin Cancer Res 2004; 10: 1835–1842.

    CAS  PubMed  Google Scholar 

  77. Pfeifer A, Kessler T, Silletti S, Cheresh DA, Verma IM . Suppression of angiogenesis by lentiviral delivery of PEX, a noncatalytic fragment of matrix metalloproteinase 2. Proc Natl Acad Sci USA 2000; 97: 12227–12232.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Ahonen M, Ala-Aho R, Baker AH, George SJ, Grenman R, Saarialho-Kere U et al. Antitumor activity and bystander effect of adenovirally delivered tissue inhibitor of metalloproteinases-3. Mol Ther 2002; 5: 705–715.

    CAS  PubMed  Google Scholar 

  79. Kuo CJ, Farnebo F, Yu EY, Christofferson R, Swearingen RA, Carter R et al. Comparative evaluation of the antitumor activity of antiangiogenic proteins delivered by gene transfer. Proc Natl Acad Sci USA 2001; 98: 4605–4610.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Hampl M, Tanaka T, Albert PS, Lee J, Ferrari N, Fine HA . Therapeutic effects of viral vector-mediated antiangiogenic gene transfer in malignant ascites. Hum Gene Ther 2001; 12: 1713–1729.

    CAS  PubMed  Google Scholar 

  81. Liu P, Wang Y, Li YH, Yang C, Zhou YL, Li B et al. Adenovirus-mediated gene therapy with an antiangiogenic fragment of thrombospondin-1 inhibits human leukemia xenograft growth in nude mice. Leuk Res 2003; 27: 701–708.

    CAS  PubMed  Google Scholar 

  82. Kong HL, Hecht D, Song W, Kovesdi I, Hackett NR, Yayon A et al. Regional suppression of tumor growth by in vivo transfer of a cDNA encoding a secreted form of the extracellular domain of the flt-1 vascular endothelial growth factor receptor. Hum Gene Ther 1998; 9: 823–833.

    CAS  PubMed  Google Scholar 

  83. Compagni A, Wilgenbus P, Impagnatiello MA, Cotten M, Christofori G . Fibroblast growth factors are required for efficient tumor angiogenesis. Cancer Res 2000; 60: 7163–7169.

    CAS  PubMed  Google Scholar 

  84. Schuch G, Machluf M, Bartsch Jr G, Nomi M, Richard H, Atala A et al. In vivo administration of vascular endothelial growth factor (VEGF) and its antagonist, soluble neuropilin-1, predicts a role of VEGF in the progression of acute myeloid leukemia in vivo. Blood 2002; 100: 4622–4628.

    CAS  PubMed  Google Scholar 

  85. Popkov M, Jendreyko N, McGavern DB, Rader C, Barbas III CF . Targeting tumor angiogenesis with adenovirus-delivered anti-Tie-2 intrabody. Cancer Res 2005; 65: 972–981.

    CAS  PubMed  Google Scholar 

  86. Sacco MG, Cato EM, Ceruti R, Soldati S, Indraccolo S, Caniatti M et al. Systemic gene therapy with anti-angiogenic factors inhibits spontaneous breast tumor growth and metastasis in MMTVneu transgenic mice. Gene Therapy 2001; 8: 67–70.

    CAS  PubMed  Google Scholar 

  87. Jin RJ, Kwak C, Lee SG, Lee CH, Soo CG, Park MS et al. The application of an anti-angiogenic gene (thrombospondin-1) in the treatment of human prostate cancer xenografts. Cancer Gene Ther 2000; 7: 1537–1542.

    CAS  PubMed  Google Scholar 

  88. Kim SI, Kim KS, Kim HS, Kim DS, Jang Y, Chung KH et al. Inhibitory effect of the salmosin gene transferred by cationic liposomes on the progression of B16BL6 tumors. Cancer Res 2003; 63: 6458–6462.

    CAS  PubMed  Google Scholar 

  89. Albig AR, Neil JR, Schiemann WP . Fibulins 3 and 5 antagonize tumor angiogenesis in vivo. Cancer Res 2006; 66: 2621–2629.

    CAS  PubMed  Google Scholar 

  90. Metheny-Barlow LJ, Li LY . Vascular endothelial growth inhibitor (VEGI), an endogenous negative regulator of angiogenesis. Semin Ophthalmol 2006; 21: 49–58.

    PubMed  Google Scholar 

  91. Fears CY, Gladson CL, Woods A . Syndecan-2 is expressed in the microvasculature of gliomas and regulates angiogenic processes in microvascular endothelial cells. J Biol Chem 2006; 281: 14533–14536.

    CAS  PubMed  Google Scholar 

  92. De Palma M, Venneri MA, Roca C, Naldini L . Targeting exogenous genes to tumor angiogenesis by transplantation of genetically modified hematopoietic stem cells. Nat Med 2003; 9: 789–795.

    CAS  PubMed  Google Scholar 

  93. Davidoff AM, Ng CY, Brown P, Leary MA, Spurbeck WW, Zhou J et al. Bone marrow-derived cells contribute to tumor neovasculature and, when modified to express an angiogenesis inhibitor, can restrict tumor growth in mice. Clin Cancer Res 2001; 7: 2870–2879.

    CAS  PubMed  Google Scholar 

  94. Kim SK, Cargioli TG, Machluf M, Yang W, Sun Y, Al-Hashem R et al. PEX-producing human neural stem cells inhibit tumor growth in a mouse glioma model. Clin Cancer Res 2005; 11: 5965–5970.

    CAS  PubMed  Google Scholar 

  95. Durr E, Yu J, Krasinska KM, Carver LA, Yates JR, Testa JE et al. Direct proteomic mapping of the lung microvascular endothelial cell surface in vivo and in cell culture. Nat Biotechnol 2004; 22: 985–992.

    CAS  PubMed  Google Scholar 

  96. St Croix B, Rago C, Velculescu V, Traverso G, Romans KE, Montgomery E et al. Genes expressed in human tumor endothelium. Science 2000; 289: 1197–1202.

    CAS  PubMed  Google Scholar 

  97. Carson-Walter EB, Watkins DN, Nanda A, Vogelstein B, Kinzler KW, St Croix B . Cell surface tumor endothelial markers are conserved in mice and humans. Cancer Res 2001; 61: 6649–6655.

    CAS  PubMed  Google Scholar 

  98. Huminiecki L, Gorn M, Suchting S, Poulsom R, Bicknell R . Magic roundabout is a new member of the roundabout receptor family that is endothelial specific and expressed at sites of active angiogenesis. Genomics 2002; 79: 547–552.

    CAS  PubMed  Google Scholar 

  99. Carmeliet P . Angiogenesis in life, disease and medicine. Nature 2005; 438: 932–936.

    CAS  PubMed  Google Scholar 

  100. Orimo A, Gupta PB, Sgroi DC, Arenzana-Seisdedos F, Delaunay T, Naeem R et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 2005; 121: 335–348.

    CAS  PubMed  Google Scholar 

  101. Koukourakis MI, Giatromanolaki A, Harris AL, Sivridis E . Comparison of metabolic pathways between cancer cells and stromal cells in colorectal carcinomas: a metabolic survival role for tumor-associated stroma. Cancer Res 2006; 66: 632–637.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We acknowledge the support of the Clarendon Fund and Balliol College, University of Oxford and the Consejo Nacional de Ciencia y Tecnologia (CONACYT) (MBP), Cancer Research UK (ALH) and the National Translational Cancer Research Network (LWS).

Author information

Authors and Affiliations

  1. Department of Clinical Pharmacology, University of Oxford, Radcliffe Infirmary, Oxford,, UK

    M Bazan-Peregrino & L W Seymour

  2. Cancer Research UK Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford,, UK

    A L Harris

Authors
  1. M Bazan-Peregrino
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. L W Seymour
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A L Harris
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to L W Seymour.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bazan-Peregrino, M., Seymour, L. & Harris, A. Gene therapy targeting to tumor endothelium. Cancer Gene Ther 14, 117–127 (2007). https://doi.org/10.1038/sj.cgt.7701001

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.cgt.7701001

Keywords

This article is cited by

Search

Advanced search

Quick links