Advertisement

Journal of Molecular Medicine

, Volume 87, Issue 5, pp 493–506 | Cite as

Antitumor and antimetastatic activities of vesicular stomatitis virus matrix protein in a murine model of breast cancer

  • Wei Shi
  • Qingqing Tang
  • Xiancheng Chen
  • Ping Cheng
  • Peidu Jiang
  • Xiaomei Jing
  • Xiang Chen
  • Ping Chen
  • Yongsheng Wang
  • Yuquan Wei
  • Yanjun WenEmail author
Original Article

Abstract

Vesicular stomatitis virus (VSV) matrix protein (MP) is capable of inducing in vitro apoptosis of tumor cells in the absence of other viral components. Here, we report the potent antitumor and antimetastatic effects of recombinant plasmid pVAX-MP complexed with cationic liposome (DOTAP:Chol) against highly metastatic 4T1 mammary tumor. Mice with 10-day established 4T1 metastatic carcinomas showed a significant reduction in spontaneous lung metastases as well as an evident inhibition in the growths of primary tumors yet without conspicuous systemic toxic effects following a 35-day course of intravenous therapy with pVAX-MP:liposome complexes once every 5 days; the therapy significantly prolonged the survival of the tumor-bearing mice consequently. The histomorphometric analysis revealed an increased percent apoptosis and decreased expression of MMP-9 in pVAX-MP:liposome complexes group. In summary, these results indicate that pVAX-MP:liposome complexes have the ability to inhibit the growths and metastases of mouse breast cancer and they may be a novel and potentially effective therapy against human advanced breast cancer.

Keywords

Vesicular stomatitis virus matrix protein 4T1 mammary tumor Metastases DOTAP:Chol Apoptosis 

Notes

Author contributions

Wei Shi, Qingqing Tang, Xiancheng Chen, Peidu Jiang, Xiaomei Jing and Yongsheng Wang devoted to the experimental work, data analysis and manuscript writing; Ping Cheng, Xiang Chen, Ping Chen contributed to the construction of expression vector and the preparation of liposome; Yanjun Wen and Yuquan Wei were engaged in devising project.

Acknowledgements

This work was supported by National 973 Project (No. 2004CB518807) and High-tech Research and Development Program (863 Program) of China (No. 2007 AA021106).

Competing interest statement

None.

Supplementary material

109_2009_444_MOESM1_ESM.pdf (51 kb)
ESM Fig. 1 The expression of VSV-MP in COS cells by Western blot analysis. Lane 1 pVAX-MP:lipo complexes. Lane 2 pVAX:lipo complexes (PDF 51.4 KB)
109_2009_444_MOESM2_ESM.pdf (146 kb)
ESM Fig. 2 Complete RT-PCR analysis of VSV-MP gene expression in primary tumor and lung (upper panel). Lane 1: primary tumor, administration of pVAX-MP:lipo complexes. Lane 2: primary tumor, administration of pVAX:lipo complexes. Lane 3: primary tumor, NS treatment. Lane 4: lung, administration of pVAX-MP:lipo complexes. Lane 5: lung, administration of pVAX:lipo complexes. Lane 6: lung, NS treatment. Amplification of primers for β-actin serves as the internal positive control (bottom panel) (PDF 146 KB)

References

  1. 1.
    World Health organization (February 2006) Fact sheet No 297: CancerGoogle Scholar
  2. 2.
    Hortobagyi GN (1998) Treatment of breast cancer. N Engl J Med 339:974–984CrossRefPubMedGoogle Scholar
  3. 3.
    Dexter DL, Kowalski HM, Blazar BA, Fligiel Z, Vogel R, Heppner GH (1978) Heterogeneity of tumor cells from a single mouse mammary tumor. Cancer Res 38:3174–3181PubMedGoogle Scholar
  4. 4.
    Aslakson CJ, Miller FR (1992) Selective events in the metastatic process defined by analysis of the sequential dissemination of subpopulations of a mouse mammary tumor. Cancer Res 52:1399–1405PubMedGoogle Scholar
  5. 5.
    Pulaski BA, Rosenberg SO (1998) Reduction of established spontaneous mammary carcinoma metastases following immunotherapy with major histocompatibility complex class II and B 7.1 cell-based tumor vaccines. Cancer Res 58:1486–1493PubMedGoogle Scholar
  6. 6.
    Pulaski BA, Terman DS, Khan S (2000) Cooperativity of staphylococcal aureus entertoxin B superantigen, Major Histocompatibility Complex Class II, and CD80 for immunotherapy of advanced spontaneous metastases in a clinically relevant postoperative mouse breast cancer model. Cancer Res 60:2710–2715PubMedGoogle Scholar
  7. 7.
    Yang J, Mani SA, Donaher JL (2004) Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 117:927–939CrossRefPubMedGoogle Scholar
  8. 8.
    Stojdl DF, Lichty B, Knowles S (2000) Exploiting tumor-specific defects in the interferon pathway with a previously unknown oncolytic virus. Nat Med 6:821–825CrossRefPubMedGoogle Scholar
  9. 9.
    Balachandran S, Barber GN (2004) Defective translational control facilitates vesicular stomatitis virus oncolysis. Cancer Cell 5:51–65CrossRefPubMedGoogle Scholar
  10. 10.
    Balachandran S, Barber GN (2000) Vesicular stomatitis virus (VSV) therapy of tumors. IUBMB Life 50:135–138PubMedGoogle Scholar
  11. 11.
    Balachandran S, Porosnicu M, Barber GN (2001) Oncolytic activity of vesicular stomatitis virus is effective against tumors exhibiting aberrant p53, Ras, or myc function and involves the induction of apoptosis. J Virol 75:3474–3479CrossRefPubMedGoogle Scholar
  12. 12.
    Stojdl DF, Lichty BD, tenOever BR (2003) VSV strains with defects in their ability to shutdown innate immunity are potent systemic anti-cancer agents. Cancer Cell 4:263–275CrossRefPubMedGoogle Scholar
  13. 13.
    Shinozaki K, Ebert O, Koumioti C (2004) Oncolysis of multifocal hepatocellular carcinoma in the rat liver by hepatic artery infusion of vesicular stomatitis virus. Mol Ther 9:368–376CrossRefPubMedGoogle Scholar
  14. 14.
    Ahmed M, Cramer SD, Lyles DS (2004) Sensitivity of prostate tumors to wild type and M protein mutant vesicular stomatitis viruses. Virol 330:34–49CrossRefGoogle Scholar
  15. 15.
    Li Q, Wei YQ (2004) Induction of apoptosis and tumor regression by vesicular stomatitis virus in the presence of gemcitabine in lung cancer. Int J Cancer 112:143–149CrossRefPubMedGoogle Scholar
  16. 16.
    Ebert O, Harbaran S, Shinozaki K, Woo SL (2005) Systemic therapy of experimental breast cancer metastases by mutant vesicular stomatitis virus in immune-competent mice. Cancer Gen Ther. 12:350–358CrossRefGoogle Scholar
  17. 17.
    Gaddy DF, Lyles DS (2007) Oncolytic vesicular stomatitis virus induces apoptosis via signaling through PKR, FAS, and Daxx. J Virol 81:2792–2804CrossRefPubMedGoogle Scholar
  18. 18.
    Letchworth GJ, Rodriguez LL, Del CBJ (1999) Vesicular stomatitis. Vet J 157:239–60CrossRefPubMedGoogle Scholar
  19. 19.
    Bi Z, Quandt P, Komatsu T, Barna M, Reiss CS (1995) IL-12 promotes enhanced recovery from vesicular stomatitis virus infection of the central nervous system. J Immunol 155:5684–5689PubMedGoogle Scholar
  20. 20.
    Forger JM, III Bronson RT, Huang AS, Reiss CS (1991) Murine infection by vesicular stomatitis virus: initial characterization of the H-2 d system. J Virol 65:4950–4958PubMedGoogle Scholar
  21. 21.
    Huneycutt BS, Bi Z, Aoki CJ, Reiss CS (1993) Central neuropathogenesis of vesicular stomatitis virus infection of immunodeficient mice. J Virol 67:6698–6706PubMedGoogle Scholar
  22. 22.
    Huneycutt BS, Plakhov IV, Shusterman Z, Bartido SM, Huang A, Reiss CS, Aoki C (1994) Distribution of vesicular stomatitis virus proteins in the brains of BALB/c mice following intranasal inoculation: an immunohistochemical analysis. Brain Res 635:81–95CrossRefPubMedGoogle Scholar
  23. 23.
    Lundh B, Kristensson K, Norrby E (1987) Selective infections of olfactory and respiratory epithelium by vesicular stomatitis and Sendai viruses. Neuropathol Appl Neurobiol 13:111–122CrossRefPubMedGoogle Scholar
  24. 24.
    Plakhov IV, Arlund EE, Aoki C, Reiss CS (1995) The earliest events in vesicular stomatitis virus infection of the murine olfactory neuroepithelium and entry of the central nervous system. Virol 209:257–262CrossRefGoogle Scholar
  25. 25.
    Sur JH, Allende R (2003) Vesicular stomatitis virus infection and neuropathogenesis in the murine model are associated with apoptosis. Vet Pathol 40:512–520CrossRefPubMedGoogle Scholar
  26. 26.
    Black BL, Lyles DS (1992) Vesicular stomatitis virus matrix protein inhibits host cell-directed transcription of target genes in vivo. J Virol 66:4058–64PubMedGoogle Scholar
  27. 27.
    Black BL, Rhodes RB, McKenzie M, Lyles DS (1993) The role of vesicular stomatitis virus matrix protein in inhibition of host-directed gene expression is genetically separable from its function in virus assembly. J Virol 67:4814–21PubMedGoogle Scholar
  28. 28.
    Paik SY, Banerjea AC, Harmison GG, Chen CJ, Schubert M (1995) Inducible and conditional inhibition of human immunodeficiency virus proviral expression by vesicular stomatitis matrix protein. J Virol 69:3529–3537PubMedGoogle Scholar
  29. 29.
    Ferran MC, Lucas-Lenard JM (1997) The vesicular stomatitis virus matrix protein inhibits transcription from the human beta interferon promoter. J Virol 71:371–377PubMedGoogle Scholar
  30. 30.
    Ahmed M, Lyles DS (1998) Effect of vesicular stomatitis virus matrix protein on transcription directed by host RNA polymerases I, II, and III. J Virol 72:8413–9PubMedGoogle Scholar
  31. 31.
    Yuan H, Yoza BK, Lyles DS (1998) Inhibition of host RNA polymerase II-dependent transcription by vesicular stomatitis virus results from inactivation of TFIID. Virol 251:83–92Google Scholar
  32. 32.
    Yuan H, Puckett S, Lyles DS (2001) Inhibition of host transcription by vesicular stomatitis virus involves a novel mechanism that is independent of phosphorylation of TATA-binding protein (TBP) or association of TBP with TBP-associated factor subunits. J Virol 75:4453–4458CrossRefPubMedGoogle Scholar
  33. 33.
    Ahmed M, McKenzie MO, Puckett S (2003) Ability of the matrix protein of vesicular stomatitis virus to suppress beta interferon gene expression is genetically correlated with the inhibition of host RNA and protein synthesis. J Virol 77:4646–4657CrossRefPubMedGoogle Scholar
  34. 34.
    Her LS, Lund E, Dahlberg JE (1997) Inhibition of Ran guanosine triphosphatase dependent nuclear transport by the matrix protein of vesicular stomatitis virus. Science 276:1845–1848CrossRefPubMedGoogle Scholar
  35. 35.
    Petersen JM, Her LS, Varvel V (2000) The matrix protein of vesicular stomatitis virus inhibits nucleocytoplasmic transport when it is in the nucleus and associated with nuclear pore complexes. Mol Cell Biol 20:8590–8601CrossRefPubMedGoogle Scholar
  36. 36.
    Kobbe CV, Deursen JMV, Rodrigues JP, Sitterlin D, Bachi A, Wu X, Wilm M, Carmo-Fonseca M, Izaurralde E (2000) Vesicular stomatitis virus matrix protein inhibits host cell gene expression by targeting the nucleoporin Nup98. Mol Cell 6:1243–252CrossRefGoogle Scholar
  37. 37.
    Templeton NS, Lasic DD, Frederik PM (1997) Improved DNA:liposome complexes for increased systemic delivery and gene expression. Nat Biotech 15:647–652CrossRefGoogle Scholar
  38. 38.
    Ito I, Began G, Mohiuddin I (2003) Increased uptake of liposome–DNA complexes by lung metastases following intravenous administration. Mol Ther 7:409–418CrossRefPubMedGoogle Scholar
  39. 39.
    Bell JC, Lichty B, Stojdl D (2003) Getting oncolytic virus therapies off the ground. Cancer Cell 4:7–11CrossRefPubMedGoogle Scholar
  40. 40.
    Thurston G (1998) Cationic liposomes target angiogenic endothelial cells in tumors and chronic inflammation in mice. J Clin Invest 101:1401–1413CrossRefPubMedGoogle Scholar
  41. 41.
    Zhong Q, Wen YJ, Zhao X (2008) Efficient inhibition of cisplatin-resistant human ovarian cancer growth and prolonged survival by gene transferred vesicular stomatitis virus matrix protein in nude mice. Ann Oncol 19:1584–1591CrossRefPubMedGoogle Scholar
  42. 42.
    Siders WM, Vergillis K, Johnson C, Scheule RK, Kaplan JM (2002) Tumor treatment with complexes of cationic lipid and noncoding plasmid DNA results in the induction of cytotoxic T cells and systemic tumor elimination. Mol Ther 6:519–27CrossRefPubMedGoogle Scholar
  43. 43.
    Sternlicht MD, Werb Z (2001) How matrix metalloproteinases regulate cell behavior. Annu. Rev Cell. Dev Biol 17:307–323CrossRefGoogle Scholar
  44. 44.
    Egeblad M, Werb Z (2002) New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2:161–174CrossRefPubMedGoogle Scholar
  45. 45.
    Hlatky L, Hahnfeldt P, Folkman J (2002) Clinical application of antiangiogenic therapy: microvessel density, what it does and doesn’t tell us. J N C I 94:883–893Google Scholar
  46. 46.
    Shweiki D, Itin A, Soffer D, Keshet E (1992) Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 359:843–845CrossRefPubMedGoogle Scholar
  47. 47.
    Berzofsky JA, Terabe M, Oh SK, Belyakov IM, Ahlers JD, Janik JE, Morris JC (2004) Progress on new vaccine strategies for the immunotherapy and prevention of cancer. J Clin Invest 113:1515–1525PubMedGoogle Scholar
  48. 48.
    Liu JY, Wei YQ, Yang L (2003) Immunotherapy of tumors with vaccine based on quail homologous vascular endothelial growth factor receptor-2. Blood 102:1815–1823CrossRefPubMedGoogle Scholar
  49. 49.
    Lu Y, Wei YQ, Tian L (2003) Immunogene therapy of tumors with vaccine based on xenogeneic epidermal growth factor receptor. J Immunol 170:3162–3170PubMedGoogle Scholar
  50. 50.
    Weidner N, Semple JP, Welch WR, Folkman J (1991) Tumor angiogenesis and metastasis: correlation in invasive breast carcinoma. N Engl J Med 324:1–8PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Wei Shi
    • 1
  • Qingqing Tang
    • 1
  • Xiancheng Chen
    • 1
  • Ping Cheng
    • 1
  • Peidu Jiang
    • 1
  • Xiaomei Jing
    • 1
  • Xiang Chen
    • 1
  • Ping Chen
    • 1
  • Yongsheng Wang
    • 1
  • Yuquan Wei
    • 1
  • Yanjun Wen
    • 1
    Email author
  1. 1.National Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical SchoolSichuan UniversityChengduThe People’s Republic of China

Personalised recommendations