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Development of lentiviral vectors for antiangiogenic gene delivery

Cancer Gene Therapy volume 8, pages 879–889 (2001)Cite this article

Abstract

Growth and metastasis of malignant tumors requires angiogenesis. Inhibition of tumor-induced angiogenesis may represent an effective cytostatic strategy. We have constructed recombinant self-inactivating lentiviral vectors expressing angiostatin and endostatin, and have tested their antiangiogenic activities. As VSV-G–pseudotyped lentiviral vectors showed low relative transduction titers on bovine aortic and human umbilical vein endothelial cells, it was difficult to achieve significant inhibition of endothelial cell growth by lentivirus-mediated antiangiogenic gene transfer directly to endothelial cells without concomitant vector-associated cytotoxicity. However, lentivirus vectors could efficiently and stably transduce T24 human bladder cancer cells that are relatively resistant to adenovirus infection due to loss of coxsackievirus-adenovirus receptor expression. Long-term expression and secretion of angiostatin and endostatin from lentivirus-transduced T24 cells resulted in significant inhibition of cellular proliferation on coculture with endothelial cells. This report represents the first use of lentivirus-based vectors to deliver the antiangiogenic factors, angiostatin and endostatin, and suggests the potential utility of antiangiogenic gene therapy with lentiviral vectors for the treatment of cancer. Cancer Gene Therapy (2001) 8, 879–889

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References

  1. Folkman J . What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst 1990 82: 4–6

    Article  CAS  PubMed  Google Scholar 

  2. Kandel J, Bossy-Wetzel E, Radvanyi F, et al . Neovascularization is associated with a switch to the export of bFGF in the multistep development of fibrosarcoma Cell 1991 66: 1095–1104

    Article  CAS  PubMed  Google Scholar 

  3. Shweiki D, Itin A, Soffer D, et al . Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis Nature 1992 359: 843–845

    Article  CAS  PubMed  Google Scholar 

  4. Lawler J . The functions of thrombospondin-1 and -2 Curr Opin Cell Biol 2000 12: 634–640

    Article  CAS  PubMed  Google Scholar 

  5. O'Reilly MS, Holmgren L, Shing Y, et al . Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma Cell 1994 79: 315–328

    Article  CAS  PubMed  Google Scholar 

  6. O'Reilly MS, Boehm T, Shing Y, et al . Endostatin: an endogenous inhibitor of angiogenesis and tumor growth Cell 1997 88: 277–285

    Article  CAS  PubMed  Google Scholar 

  7. Boehm T, Folkman J, Browder T, et al . Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance Nature 1997 390: 404–407

    Article  CAS  PubMed  Google Scholar 

  8. Dhanabal M, Ramchandran R, Volk R, et al . Endostatin: yeast production, mutants, and antitumor effect in renal cell carcinoma Cancer Res 1999 59: 189–197

    CAS  PubMed  Google Scholar 

  9. Bergers G, Javaherian K, Lo KM, et al . Effects of angiogenesis inhibitors on multistage carcinogenesis in mice Science 1999 284: 808–812

    Article  CAS  PubMed  Google Scholar 

  10. Cao Y . Therapeutic potentials of angiostatin in the treatment of cancer Haematologica 1999 84: 643–650

    CAS  PubMed  Google Scholar 

  11. Pirie-Shepherd SR . Role of carbohydrate on angiostatin in the treatment of cancer J Lab Clin Med 1999 134: 553–560

    Article  CAS  PubMed  Google Scholar 

  12. Tanaka T, Cao Y, Folkman J, et al . Viral vector–targeted antiangiogenic gene therapy utilizing an angiostatin complementary DNA Cancer Res 1998 58: 3362–3369

    CAS  PubMed  Google Scholar 

  13. Griscelli F, Li H, Bennaceur-Griscelli A, et al . Angiostatin gene transfer: inhibition of tumor growth in vivo by blockage of endothelial cell proliferation associated with a mitosis arrest Proc Natl Acad Sci USA 1998 95: 6367–6372

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Nguyen JT, Wu P, Clouse ME, et al . Adeno-associated virus-mediated delivery of antiangiogenic factors as an antitumor strategy Cancer Res 1998 58: 5673–5677

    CAS  PubMed  Google Scholar 

  15. Feldman AL, Restifo NP, Alexander HR, et al . Antiangiogenic gene therapy of cancer utilizing a recombinant adenovirus to elevate systemic endostatin levels in mice Cancer Res 2000 60: 1503–1506

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Sauter BV, Martinet O, Zhang WJ, et al . Adenovirus-mediated gene transfer of endostatin in vivo results in high level of transgene expression and inhibition of tumor growth and metastases Proc Natl Acad Sci USA 2000 97: 4802–4807

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Chen CT, Lin J, Li Q, et al . Antiangiogenic gene therapy for cancer via systemic administration of adenoviral vectors expressing secretable endostatin Hum Gene Ther 2000 11: 1983–1996

    Article  CAS  PubMed  Google Scholar 

  18. Naldini L, Blomer U, Gallay P, et al . In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector Science 1996 272: 263–267

    Article  CAS  PubMed  Google Scholar 

  19. Naldini L, Blomer U, Gage FH, et al . Efficient transfer, integration, and sustained long-term expression of the transgene in adult rat brains injected with a lentiviral vector Proc Natl Acad Sci USA 1996 93: 11382–11388

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Reiser J, Harmison G, Kluepfel-Stahl S, et al . Transduction of nondividing cells using pseudotyped defective high-titer HIV type 1 particles Proc Natl Acad Sci USA 1996 93: 15266–15271

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Zufferey R, Nagy D, Mandel RJ, et al . Multiply attenuated lentiviral vector achieves efficient gene delivery in vivo Nat Biotechnol 1997 15: 871–875

    Article  CAS  PubMed  Google Scholar 

  22. Zufferey R, Dull T, Mandel RJ, et al . Self-inactivating lentivirus vector for safe and efficient in vivo gene delivery J Virol 1998 72: 9873–9880

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Pfeifer A, Kessler T, Silletti S, et al . Suppression of angiogenesis by lentiviral delivery of PEX, a noncatalytic fragment of matrix metalloproteinase 2 Proc Natl Acad Sci USA 2000 97: 12227–12232

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Halene S, Wang L, Cooper RM, et al . Improved expression in hematopoietic and lymphoid cells in mice after transplantation of bone marrow transduced with a modified retroviral vector Blood 1999 94: 3349–3357

    CAS  PubMed  Google Scholar 

  25. He TC, Zhou S, DaCosta LT, et al . A simplified system for generating recombinant adenoviruses Proc Natl Acad Sci USA 1998 95: 2509–2514

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Li Y, Pong RC, Bergelson JM, et al . Loss of adenoviral receptor expression in human bladder cancer cells: a potential impact on the efficacy of gene therapy Cancer Res 1999 59: 325–330

    CAS  PubMed  Google Scholar 

  27. Schlegel R, Tralka TS, Willingham MC, et al . Inhibition of VSV binding and infectivity by phosphatidylserine: is phosphatidylserine a VSV-binding site? Cell 1983 32: 639–646

    Article  CAS  PubMed  Google Scholar 

  28. Mastromarino P, Conti C, Goldoni P, et al . Characterization of membrane components of the erythrocyte involved in vesicular stomatitis virus attachment and fusion at acidic pH J Gen Virol 1987 68: 2359–2369

    Article  CAS  PubMed  Google Scholar 

  29. Scappaticci FA, Smith R, Pathak A, et al . Combination angiostatin and endostatin gene transfer induces synergistic antiangiogenic activity in vitro and antitumor efficacy in leukemia and solid tumors in mice Mol Ther 2001 3: 186–196

    Article  CAS  PubMed  Google Scholar 

  30. Bergelson JM, Cunningham JA, Droguett G, et al . Isolation of a common receptor for Coxsackie B viruses and adenoviruses 2 and 5 Science 1997 275: 1320–1323

    Article  CAS  PubMed  Google Scholar 

  31. Wickham TJ, Mathias P, Cheresh DA, et al . Integrins alpha v beta 3 and alpha v beta 5 promote adenovirus internalization but not virus attachment Cell 1993 73: 309–319

    Article  CAS  PubMed  Google Scholar 

  32. Friedlander M, Brooks PC, Shaffer RW, et al . Definition of two angiogenic pathways by distinct alpha v integrins Science 1995 270: 1500–1502

    Article  CAS  PubMed  Google Scholar 

  33. Gasparini G, Brooks PC, Biganzoli E, et al . Vascular integrin alpha(v)beta3: a new prognostic indicator in breast cancer Clin Cancer Res 1998 4: 2625–2634

    CAS  PubMed  Google Scholar 

  34. Kafri T, Blomer U, Peterson DA, et al . Sustained expression of genes delivered directly into liver and muscle by lentiviral vectors Nat Genet 1997 17: 314–317

    Article  CAS  PubMed  Google Scholar 

  35. Sinclair AM, Agrawal YP, Elbar E, et al . Interaction of vesicular stomatitis virus-G pseudotyped retrovirus with CD34+ and CD34+ CD38− hematopoietic progenitor cells Gene Ther 1997 4: 918–927

    Article  CAS  PubMed  Google Scholar 

  36. Sakoda T, Kasahara N, Hamamori Y, et al . A high-titer lentiviral production system mediates efficient transduction of differentiated cells including beating cardiac myocytes J Mol Cell Cardiol 1999 31: 2037–2047

    Article  CAS  PubMed  Google Scholar 

  37. Kumar A, Gupta CM . Transbilayer distributions of red cell membrane phospholipids in unilamellar vesicles Biochim Biophys Acta 1984 769: 419–428

    Article  CAS  PubMed  Google Scholar 

  38. Emoto K, Toyama-Sorimachi N, Karasuyama H, et al . Exposure of phosphatidylethanolamine on the surface of apoptotic cells Exp Cell Res 1997 232: 430–434

    Article  CAS  PubMed  Google Scholar 

  39. Bevers EM, Comfurius P, Dekkers DW, et al . Regulatory mechanisms of transmembrane phospholipid distributions and pathophysiological implications of transbilayer lipid scrambling Lupus 1998 7: S126–S131

    Article  CAS  PubMed  Google Scholar 

  40. Gabellec MM, Steffan AM, Dodeur M, et al . Membrane lipids of hepatocytes, Kupffer cells and endothelial cells Biochem Biophys Res Commun 1983 113: 845–853

    Article  CAS  PubMed  Google Scholar 

  41. Murphy EJ, Joseph L, Stephens R, et al . Phospholipid composition of cultured human endothelial cells Lipids 1992 27: 150–153

    Article  CAS  PubMed  Google Scholar 

  42. Cansell M, Gouygou JP, Jozefonvicz J, et al . Lipid composition of cultured endothelial cells in relation to their growth Lipids 1997 32: 39–44

    Article  CAS  PubMed  Google Scholar 

  43. Pozzi D, Lisi A, De Ros I, et al . Use of octadecylrhodamine fluorescence dequenching to study vesicular stomatitis virus fusion with human aged red blood cells Photochem Photobiol 1993 57: 426–430

    Article  CAS  PubMed  Google Scholar 

  44. Chen QR, Kumar D, Stass SA, et al . Liposomes complexed to plasmids encoding angiostatin and endostatin inhibit breast cancer in nude mice Cancer Res 1999 59: 3308–3312

    CAS  PubMed  Google Scholar 

  45. Yang Y, Li Q, Ertl HC, et al . Cellular and humoral immune responses to viral antigens create barriers to lung-directed gene therapy with recombinant adenoviruses J Virol 1995 69: 2004–2015

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by American Cancer Society Grant RPG-99-355-01-MGO (B.B. and N.K.), Susan G. Komen Breast Cancer Foundation Grant 99-003100 (N.K. and T.S.), and NIAMS Grant AR46366 (N.K. and T.S.).

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Authors and Affiliations

  1. Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, Los Angeles, 90033, California, USA

    Toshiaki Shichinohe, Kazuo Mizutani, Miyako Nishida, Susan Hegerich-Gilliam & Noriyuki Kasahara

  2. Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, 90033, California, USA

    Toshiaki Shichinohe & Noriyuki Kasahara

  3. Department of Urology, Keck School of Medicine, University of Southern California, Los Angeles, 90033, California, USA

    Bernard H Bochner, Kazuo Mizutani & Susan Hegerich-Gilliam

  4. Institute for Cancer Research and Treatment, University of Torino Medical School, Candiolo, Torino, Italy

    Luigi Naldini

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  1. Toshiaki Shichinohe
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  2. Bernard H Bochner
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Correspondence to Noriyuki Kasahara.

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Shichinohe, T., Bochner, B., Mizutani, K. et al. Development of lentiviral vectors for antiangiogenic gene delivery. Cancer Gene Ther 8, 879–889 (2001). https://doi.org/10.1038/sj.cgt.7700388

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