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.

  • Original Article
  • Published:

Inhibition of ovarian cancer metastasis by adeno-associated virus-mediated gene transfer of nm23H1 in an orthotopic implantation model

Cancer Gene Therapy volume 13, pages 266–272 (2006)Cite this article

Abstract

Ovarian cancer is one of the most threatening malignant tumors in females due to the frequent occurrence of metastasis that precedes diagnosis. The present study explored the possibility of preventing ovarian cancer metastasis by promoting nm23H1 expression through adeno-associated virus (AAV)-mediated gene transfer. A cell line of high metastatic potential, SW626-M4, was derived by in vivo selection and used to establish an ovarian cancer metastasis model in the mouse. Liver metastasis and animal survival time were measured after transfer of a recombinant adeno-associated viral vector expressing nm23H1 (AAV-nm23H1) into the aforementioned model. Intraperitoneal injection of AAV-nm23H1 into this orthotopic implantation model of ovarian cancer resulted in (1) expression of the exogenous gene in more than 95% of tumor cells in situ in nude mice; (2) a 60% reduction in the number of animals developing liver metastases; and (3) a 35-day prolongation of median survival time compared with the untreated host group. In conclusion, the results support the feasibility of induction of nm23H1 expression through gene transfer as a therapeutic strategy for preventing metastases and prolonging host survival time, and indicate that AAV vectors deserve attention in the design of future gene therapy approaches to achieving long-term expression of curative genes in vivo.

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
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Gutierrez A, Lemoine N, Sikora K . Gene therapy for cancer. Lancet 1992; 339: 715–721.

    Article  CAS  PubMed  Google Scholar 

  2. Leone A, Flatow U, VanHoutte K, Steeg P . Transfection of human nm23-H1 into the human MDA-MB-435 breast carcinoma cell line: effects on tumor metastatic potential, colonization and enzymatic activity. Oncogene 1993; 8: 2325–2333.

    CAS  PubMed  Google Scholar 

  3. Seraj M, Samant R, Verderame M, Welch D . Functional evidence for a novel human breast carcinoma metastasis suppressor BRMS1, encoded at chromosome 11q13. Cancer Res 2000; 60: 2764–2769.

    CAS  PubMed  Google Scholar 

  4. Lee J, Welch D . Suppression of metastasis in human breast carcinoma MDA-MB-435 cells after transfection with the metastasis suppressor gene, KiSS-1. Cancer Res 1997; 57: 2384–2387.

    CAS  PubMed  Google Scholar 

  5. Dong J, Lamb P, Rinker-Schaeffer C, Vukanovic J, Ichikawa T, Isaacs J et al. KAI1, a metastasis suppressor gene for prostate cancer on human chromosome 11p11. 2. Science 1995; 268: 884–886.

    Article  CAS  PubMed  Google Scholar 

  6. Takaoka A, Hinoda Y, Satoh S, Adachi Y, Itoh F, Adachi M et al. Suppression of invasive properties of colon cancer cells by a metastasis suppressor KAI1 gene. Oncogene 1998; 16: 1443–1453.

    Article  CAS  PubMed  Google Scholar 

  7. Leone A, Flatow U, King C, Sandeen M, Margulies I, Liotta L et al. Reduced tumor incidence, metastatic potential, and cytokine responsiveness of nm23-transfected melanoma cells. Cell 1991; 65: 25–35.

    Article  CAS  PubMed  Google Scholar 

  8. Kantor J, McCormick B, Steeg P, Zetter B . Inhibition of cell motility after nm23 transfection of human and murine tumor cells. Cancer Res 1993; 53: 1971–1973.

    CAS  PubMed  Google Scholar 

  9. Ohta S, Lai E, Pang A, Brouwers F, Chan W, Eisenhofer G et al. Downregulation of metastasis suppressor genes in malignant pheochromocytoma. Int J Cancer 2005; 114: 139–143.

    Article  CAS  PubMed  Google Scholar 

  10. Seifert M, Welter C, Mehraein Y, Seitz G . Expression of the nm23 homologues nm23-H4, nm23-H6, and nm23-H7 in human gastric and colon cancer. J Pathol 2005; 205: 623–632.

    Article  CAS  PubMed  Google Scholar 

  11. Backer J, Mendola C, Kovesdi I, Fairhurst J, O'Hara B, Eddy Jr RL et al. Chromosomal localization and nucleoside diphosphate kinase activity of human metastasis-suppressor genes NM23-1 and NM23-2. Oncogene 1993; 8: 497–502.

    CAS  PubMed  Google Scholar 

  12. Bhujwalla Z, Aboagye E, Gillies R, Chacko V, Mendola C, Backer J . Nm23-transfected MDA-MB-435 human breast carcinoma cells form tumors with altered phospholipid metabolism and pH: a 31P nuclear magnetic resonance study in vivo and in vitro. Magn Reson Med 1999; 41: 897–903.

    Article  CAS  PubMed  Google Scholar 

  13. Russell R, Pedersen A, Kantor J, Geisinger K, Long R, Zbieranski N et al. Relationship of nm23 to proteolytic factors, proliferation and motility in breast cancer tissues and cell lines. Br J Cancer 1998; 78: 710–717.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Baba H, Urano T, Okada K, Furukawa K, Nakayama E, Tanaka H et al. Two isotypes of murine nm23/nucleoside diphosphate kinase, nm23-M1 and nm23-M2, are involved in metastatic suppression of a murine melanoma line. Cancer Res 1995; 55: 1977–1981.

    CAS  PubMed  Google Scholar 

  15. Parhar R, Shi Y, Zou M, Farid N, Ernst P, al-Sedairy S . Effects of cytokine-mediated modulation of nm23 expression on the invasion and metastatic behavior of B16F10 melanoma cells. Int J Cancer 1995; 60: 204–210.

    Article  CAS  PubMed  Google Scholar 

  16. Miele M, De La Rosa A, Lee J, Hicks D, Dennis J, Steeg P et al. Suppression of human melanoma metastasis following introduction of chromosome 6 is independent of NME1 (Nm23). Clin Exp Metastasis 1997; 15: 259–265.

    Article  CAS  PubMed  Google Scholar 

  17. Tagashira H, Hamazaki K, Tanaka N, Gao C, Namba M . Reduced metastatic potential and c-myc overexpression of colon adenocarcinoma cells (Colon 26 line) transfected with nm23-R2/rat nucleoside diphosphate kinase alpha isoform. Int J Mol Med 1998; 2: 65–68.

    CAS  PubMed  Google Scholar 

  18. Miyazaki H, Fukuda M, Ishijima Y, Takagi Y, Iimura T, Negishi A et al. Overexpression of nm23-H2/NDP kinase B in a human oral squamous cell carcinoma cell line results in reduced metastasis, differentiated phenotype in the metastatic site, and growth factor-independent proliferative activity in culture. Clin Cancer Res 1999; 5: 4301–4307.

    CAS  PubMed  Google Scholar 

  19. Link CJ, Moorman D, Seregina T, Levy J, Schabold K . A phase I trial of in vivo gene therapy with the herpes simplex thymidine kinase/ganciclovir system for the treatment of refractory or recurrent ovarian cancer. Hum Gene Ther 1996; 7: 1161–1179.

    Article  PubMed  Google Scholar 

  20. Freeman S, Abboud C, Whartenby K, Packman C, Koeplin D, Moolten F et al. The ‘bystander effect’: tumor regression when a fraction of the tumor mass is genetically modified. Cancer Res 1993; 53: 5274–5283.

    CAS  PubMed  Google Scholar 

  21. Tanaka K, Isselbacher K, Khoury G, Jay G . Reversal of oncogenesis by the expression of a major histocompatibility complex class I gene. Science 1985; 228: 26–30.

    Article  CAS  PubMed  Google Scholar 

  22. Rosenfeld M, Wang M, Siegal G, Alvarez R, Mikheeva G, Krasnykh V et al. Adenoviral-mediated delivery of herpes simplex virus thymidine kinase results in tumor reduction and prolonged survival in a SCID mouse model of human ovarian carcinoma. J Mol Med 1996; 74: 455–462.

    Article  CAS  PubMed  Google Scholar 

  23. Kaplitt M, Leone P, Samulski R, Xiao X, Pfaff D, O'Malley K et al. Long-term gene expression and phenotypic correction using adeno-associated virus vectors in the mammalian brain. Nat Genet 1994; 8: 148–154.

    Article  CAS  PubMed  Google Scholar 

  24. Muzyczka N . Use of adeno-associated virus as a general transduction vector for mammalian cells. Curr Top Microbiol Immunol 1992; 158: 97–129.

    CAS  PubMed  Google Scholar 

  25. Yang Y, Nunes F, Berencsi K, Furth E, Gonczol E, Wilson J . Cellular immunity to viral antigens limits E1-deleted adenoviruses for gene therapy. Proc Natl Acad Sci USA 1994; 91: 4407–4411.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Yang Y, Li Q, Ertl H, Wilson J . 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 

  27. Snyder R, Miao C, Patijn G, Spratt S, Danos O, Nagy D et al. Persistent and therapeutic concentrations of human factor IX in mice after hepatic gene transfer of recombinant AAV vectors. Nat Genet 1997; 16: 270–276.

    Article  CAS  PubMed  Google Scholar 

  28. During M, Leone P . Adeno-associated virus vectors for gene therapy of neurodegenerative disorders. Clin Neurosci 1995–96; 3: 292–300.

    PubMed  Google Scholar 

  29. Xiao X, Li J, Samulski R . Production of high-titer recombinant adeno-associated virus vectors in the absence of helper adenovirus. J Virol 1998; 72: 2224–2232.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Xiao X, Li J, Samulski R . Efficient long-term gene transfer into muscle tissue of immunocompetent mice by adeno-associated virus vector. J Virol 1996; 70: 8098–8108.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Alvarez R, Curiel D . A phase I study of recombinant adenovirus vector-mediated intraperitoneal delivery of herpes simplex virus thymidine kinase (HSV-TK) gene and intravenous ganciclovir for previously treated ovarian and extraovarian cancer patients. Hum Gene Ther 1997; 8: 597–613.

    Article  CAS  PubMed  Google Scholar 

  32. During M, Xu R, Young D, Kaplitt M, Sherwin R, Leone P . Peroral gene therapy of lactose intolerance using an adeno-associated virus vector. Nat Med 1998; 4: 1131–1135.

    Article  CAS  PubMed  Google Scholar 

  33. Tamada Y, Aoki D, Nozawa S, Irimura T . Model for paraaortic lymph node metastasis produced by orthotopic implantation of ovarian carcinoma cells in athymic nude mice. Eur J Cancer 2004; 40: 158–163.

    Article  CAS  PubMed  Google Scholar 

  34. Deshane J, Siegal G, Wang M, Wright M, Bucy R, Alvarez R et al. Transductional efficacy and safety of an intraperitoneally delivered adenovirus encoding an anti-erbB-2 intracellular single-chain antibody for ovarian cancer gene therapy. Gynecol Oncol 1997; 63: 378–385.

    Article  Google Scholar 

  35. Kiguchi K, Kubota T, Aoki D, Udagawa Y, Yamanouchi S, Saga M et al. A patient-like orthotopic implantation nude mouse model of highly metastatic human ovarian cancer. Clin Exp Metastasis 1998; 16: 751–756.

    Article  CAS  PubMed  Google Scholar 

  36. Herrera-Gayol A, Jothy S . Adhesion proteins in the biology of breast cancer: contribution of CD44. Exp Mol Pathol 1999; 66: 149–156.

    Article  CAS  PubMed  Google Scholar 

  37. Zhao H, Jhanwar-Uniyal M, Datta P, Yemul S, Ho L, Khitrov G et al. Expression profile of genes associated with antimetastatic gene: nm23-mediated metastasis inhibition in breast carcinoma cells. Int J Cancer 2004; 109: 65–70.

    Article  CAS  PubMed  Google Scholar 

  38. Otsuki Y, Tanaka M, Yoshii S, Kawazoe N, Nakaya K, Sugimura H . Tumor metastasis suppressor nm23H1 regulates Rac1 GTPase by interaction with Tiam1. Proc Natl Acad Sci USA 2001; 98: 4385–4390.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Suzuki E, Ota T, Tsukuda K, Okita A, Matsuoka K, Murakami M et al. nm23-H1 reduces in vitro cell migration and the liver metastatic potential of colon cancer cells by regulating myosin light chain phosphorylation. Int J Cancer 2004; 108: 207–211.

    Article  CAS  PubMed  Google Scholar 

  40. Khan MH, Yasuda M, Higashino F, Haque S, Kohgo T, Nakamura M, Shindoh M et al. nm23-H1 suppresses invasion of oral squamous cell carcinoma-derived cell lines without modifying matrix metalloproteinase-2 and matrix metalloproteinase-9 expression. Am J Pathol 2001; 158: 1785–1791.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Chao H, Mao L, Bruce A, Walsh C . Sustained expression of human factor VIII in mice using a parvovirus-based vector. Blood 2000; 95: 1594–1599.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank X Xiao and DW Wang for the gift of adeno-associated virus (AAV) vector. We would like to thank Dr Paul Kretchmer at San Francisco Edit for his assistance in editing this manuscript. This work was supported by grants from the National Science Foundation of China (no. 30025017) and the ‘973’ Program of China (no. 2002CB513100 and 2002CB513107)

Author information

Author notes

  1. J Li and J Zhou: These two authors contributed equally to this work.

Authors and Affiliations

  1. Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, P.R. China

    J Li, J Zhou, G Chen, H Wang, S Wang, H Xing, Q Gao, Y Lu & D Ma

  2. Depatment of Ophthalmology, University of Texas Southwestern Medical Cencer at Dallas, TX, USA

    Y He

Authors
  1. J Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. G Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. H Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. H Xing
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Q Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Y Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Y He
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. D Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to D Ma.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Li, J., Zhou, J., Chen, G. et al. Inhibition of ovarian cancer metastasis by adeno-associated virus-mediated gene transfer of nm23H1 in an orthotopic implantation model. Cancer Gene Ther 13, 266–272 (2006). https://doi.org/10.1038/sj.cgt.7700899

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.cgt.7700899

Keywords

This article is cited by

Search

Advanced search

Quick links