Skip to main content

Thank you for visiting 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.

Viral vector-mediated transduction of a modified thrombospondin-2 cDNA inhibits tumor growth and angiogenesis


Gene therapy represents a possible alternative to the chronic delivery of recombinant antiangiogenic proteins to cancer patients. We have constructed retroviral and adenoviral vectors that express murine N-terminal fragments of thrombospondin-2 (NfTSP2), a potent endogenous inhibitor of tumor growth and angiogenesis. To test the possibility of anticancer gene therapy using NfTSP2, we tested whether an ex vivo retrovirus-mediated procedure could be used for the treatment of tumors. The treatment of tumor-bearing mice with syngenic immortalized cell lines expressing NfTSP2 led to a tumor volume reduction up to 70% as compared with the controls (P<0.005). In addition, the established tumors were eradicated in 40% of the mice treated with NfTSP2-expressing cells. Furthermore, the intratumoral injection of the NfTSP2-expressing adenoviral vector to the human squamous cell carcinoma in nude mice resulted in a significant reduction of the growth rates and the volumes of the carcinoma (P<0.05). Immunohistochemical staining of the tumors indicated that the total area and the average size of tumor vessels were significantly reduced in the treatment group versus the controls (P<0.05). In conclusion, the present study clearly demonstrates that the viral vector-mediated transfer of the NfTSP2 gene could inhibit the growth of tumors by perturbing tumor-associated angiogenesis.

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

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7


  1. Hanahan D, Folkman J . Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 1996; 86: 353–364.

    CAS  Article  Google Scholar 

  2. Folkman J, D'Amore PA . Blood vessel formation: what is its molecular basis? Cell 1996; 87: 1153–1155.

    CAS  Article  Google Scholar 

  3. Folkman J . Seminars in medicine of the Beth Israel Hospital, Boston. Clinical applications of research on angiogenesis. N Engl J Med 1995; 333: 1757–1763.

    CAS  Article  Google Scholar 

  4. Volpert OV et al. Inhibition of angiogenesis by thrombospondin-2. Biochem Biophys Res Commun 1995; 217: 326–332.

    CAS  Article  Google Scholar 

  5. Hawighorst T et al. Thrombospondin-2 plays a protective role in multistep carcinogenesis: a novel host anti-tumor defense mechanism. EMBO J 2001; 20: 2631–2640.

    CAS  Article  Google Scholar 

  6. Streit M et al. Thrombospondin-2: a potent endogenous inhibitor of tumor growth and angiogenesis. Proc Natl Acad Sci USA 1999; 96: 14888–14893.

    CAS  Article  Google Scholar 

  7. Streit M et al. Systemic inhibition of tumor growth and angiogenesis by thrombospondin-2 using cell-based antiangiogenic gene therapy. Cancer Res 2002; 62: 2004–2012.

    CAS  Google Scholar 

  8. Bornstein P et al. Thrombospondin 2, a matricellular protein with diverse functions. Matrix Biol 2000; 19: 557–568.

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  10. Miyake S et al. Efficient generation of recombinant adenoviruses using adenovirus DNA–terminal protein complex and a cosmid bearing the full-length virus genome. Proc Natl Acad Sci USA 1996; 93: 1320–1324.

    CAS  Article  Google Scholar 

  11. Adams JC, Tucker RP . The thrombospondin type 1 repeat (TSR) superfamily: diverse proteins with related roles in neuronal development. Dev Dyn 2000; 218: 280–299.

    CAS  Article  Google Scholar 

  12. Good DJ et al. A tumor suppressor-dependent inhibitor of angiogenesis is immunologically and functionally indistinguishable from a fragment of thrombospondin. Proc Natl Acad Sci USA 1990; 87: 6624–6628.

    CAS  Article  Google Scholar 

  13. Qabar AN, Bullock J, Matej L, Polverini P . Expression and characterization of novel thrombospondin 1 type I repeat fusion proteins. Biochem J 2000; 346 Pt 1: 147–153.

    CAS  Article  Google Scholar 

  14. Hagedorn M, Bikfalvi A . Target molecules for anti-angiogenic therapy: from basic research to clinical trials. Crit Rev Oncol Hematol 2000; 34: 89–110.

    CAS  Article  Google Scholar 

  15. O'Reilly MS, Holmgren L, Chen C, Folkman J . Angiostatin induces and sustains dormancy of human primary tumors in mice. Nat Med 1996; 2: 689–692.

    CAS  Article  Google Scholar 

  16. Feldman AL, Libutti SK . Progress in antiangiogenic gene therapy of cancer. Cancer Res 2000; 89: 1181–1194.

    CAS  Google Scholar 

  17. Griscelli F 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.

    CAS  Article  Google Scholar 

  18. Sauter BV 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.

    CAS  Article  Google Scholar 

  19. Tanaka T et al. Viral vector-mediated transduction of a modified platelet factor 4 cDNA inhibits angiogenesis and tumor growth. Nat Med 1997; 3: 437–442.

    CAS  Article  Google Scholar 

  20. Yu SS, Kim JM, Kim S . High efficiency retroviral vectors that contain no viral coding sequences. Gene Therapy 2000; 7: 797–804.

    CAS  Article  Google Scholar 

  21. Nanni P et al. TS/A: a new metastasizing cell line from a BALB/c spontaneous mammary adenocarcinoma. Clin Exp Metast 1983; 1: 373–380.

    CAS  Article  Google Scholar 

  22. Yu SS, Kim JM, Kim S . The 17 nucleotides downstream from the env gene stop codon are important for murine leukemia virus packaging. J Virol 2000; 74: 8775–8780.

    CAS  Article  Google Scholar 

  23. Kim JM et al. Angiostatin gene transfer as an effective treatment strategy in murine collagen-induced arthritis. Arthritis Rheum 2002; 46: 793–801.

    CAS  Article  Google Scholar 

  24. Martell M et al. High-throughput real-time reverse transcription-PCR quantitation of hepatitis C virus RNA. J Clin Microbiol 1999; 37: 327–332.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Streit M et al. Overexpression of thrombospondin-1 decreases angiogenesis and inhibits the growth of human cutaneous squamous cell carcinomas. Am J Pathol 1999; 155: 441–452.

    CAS  Article  Google Scholar 

  26. Regulier E et al. Adenovirus-mediated delivery of antiangiogenic genes as an antitumor approach. Cancer Gene Ther 2001; 8: 45–54.

    CAS  Article  Google Scholar 

Download references


This work was supported by grants from the Korean Ministry of Health and Welfare (Grant No. 02-PJ1-PG11-VN01-SV01-0031).

Author information

Authors and Affiliations


Rights and permissions

Reprints and Permissions

About this article

Cite this article

Hahn, W., Ho, SH., Jeong, JG. et al. Viral vector-mediated transduction of a modified thrombospondin-2 cDNA inhibits tumor growth and angiogenesis. Gene Ther 11, 739–745 (2004).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:


  • thrombospondin-2
  • angiogenesis
  • tumor
  • retrovirus vector
  • adenovirus vector

Further reading


Quick links