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Tumor cells as cellular vehicles to deliver gene therapies to metastatic tumors

Abstract

A long-pursued goal in cancer treatment is to deliver a therapy specifically to metastases. As a result of the disseminated nature of the metastatic disease, carrying the therapeutic agent to the sites of tumor growth represents a major step for success. We hypothesized that tumor cells injected intravenously (i.v.) into an animal with metastases would respond to many of the factors driving the metastatic process, and would target metastases. Using a model of spontaneous metastases, we report here that i.v. injected tumor cells localized on metastatic lesions. Based on this fact, we used genetically transduced tumor cells for tumor targeting of anticancer agents such as a suicide gene or an oncolytic virus, with evident antitumoral effect and negligible systemic toxicity. Therefore, autologous tumor cells may be used as cellular vehicles for systemic delivery of anticancer therapies to metastatic tumors.

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References

  1. Rosenberg SA . Progress in human tumour immunology and immunotherapy. Nature. 2001;411:380–384.

    Article  CAS  PubMed  Google Scholar 

  2. Carter P . Improving the efficacy of antibody-based cancer therapies. Nat Rev Cancer. 2001;1:118–129.

    Article  CAS  PubMed  Google Scholar 

  3. Arap W, Pasqualini R, Ruoslahti E . Cancer treatment by targeted drug delivery to tumor vasculature in a mouse model. Science. 1998;279:377–380.

    Article  CAS  PubMed  Google Scholar 

  4. Hood JD, Bednarski M, Frausto R, et al. Tumor regression by targeted gene delivery to the neovasculature. Science. 2002;296:2404–2407.

    Article  CAS  PubMed  Google Scholar 

  5. Lyden D, Hattori K, Dias S, et al. Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nat Med. 2001;7:1194–1201.

    Article  CAS  PubMed  Google Scholar 

  6. Sznol M, Lin SL, Bermudes D, et al. Use of preferentially replicating bacteria for the treatment of cancer. J Clin Invest. 2000;105:1027–1030.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Dang LH, Bettegowda C, Huso DL, et al. Combination bacteriolytic therapy for the treatment of experimental tumors. Proc Natl Acad Sci USA. 2001;98:15155–15160.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Alemany R, Balague C, Curiel DT . Replicative adenoviruses for cancer therapy. Nat Biotechnol. 2000;18:723–727.

    Article  CAS  PubMed  Google Scholar 

  9. Bell JC, Garson KA, Lichty BD, et al. Oncolytic viruses: programmable tumour hunters. Curr Gene Ther. 2002;2:243–254.

    Article  CAS  PubMed  Google Scholar 

  10. Shayakhmetov DM, Li ZY, Ni S, et al. Targeting of adenovirus vectors to tumor cells does not enable efficient transduction of breast cancer metastases. Cancer Res. 2002;62:1063–1068.

    CAS  PubMed  Google Scholar 

  11. Liotta LA, Kleinerman J, Saidel GM . Quantitative relationships of intravascular tumor cells, tumor vessels, and pulmonary metastases following tumor implantation. Cancer Res. 1974;34:997–1004.

    CAS  PubMed  Google Scholar 

  12. Fidler IJ . Metastasis: quantitative analysis of distribution and fate of tumor embolilabeled with 125 I-5-iodo-2'-deoxyuridine. J Natl Cancer Inst. 1970;45:773–782.

    CAS  PubMed  Google Scholar 

  13. Nicolson GL . Organ specificity of tumor metastasis: role of preferential adhesion, invasion and growth of malignant cells at specific secondary sites. Cancer Metastasis Rev. 1988;7:143–188.

    Article  CAS  PubMed  Google Scholar 

  14. Liao F, Li Y, O'Connor W, et al. Monoclonal antibody to vascular endothelial-cadherin is a potent inhibitor of angiogenesis, tumor growth, and metastasis. Cancer Res. 2000;60:6805–6810.

    CAS  PubMed  Google Scholar 

  15. Ruoslahti E, Giancotti FG . Integrins and tumor cell dissemination. Cancer Cells. 1989;1:119–126.

    CAS  PubMed  Google Scholar 

  16. Muller A, Homey B, Soto H, et al. Involvement of chemokine receptors in breast cancer metastasis. Nature. 2001;410:50–56.

    Article  CAS  PubMed  Google Scholar 

  17. Felding-Habermann B, O'Toole TE, Smith JW, et al. Integrin activation controls metastasis in human breast cancer. Proc Natl Acad Sci USA. 2001;98:1853–1858.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Lillo R, Ramirez M, Alvarez A, et al. Efficient and nontoxic adenoviral purging method for autologous transplantation in breast cancer patients. Cancer Res. 2002;62:5013–5018.

    CAS  PubMed  Google Scholar 

  19. Coukos G, Makrigiannakis A, Kang EH, et al. Use of carrier cells to deliver a replication-selective herpes simplex virus-1 mutant for the intraperitoneal therapy of epithelial ovarian cancer. Clin Cancer Res. 1999;5:1523–1537.

    CAS  PubMed  Google Scholar 

  20. Al-Mehdi AB, Tozawa K, Fisher AB, et al. Intravascular origin of metastasis from the proliferation of endothelium-attached tumor cells: a new model for metastasis. Nat Med. 2000;6:100–102.

    Article  CAS  PubMed  Google Scholar 

  21. Liotta LA, Kohn EC . The microenvironment of the tumour–host interface. Nature. 2001;411:375–379.

    Article  CAS  PubMed  Google Scholar 

  22. Cameron MD, Schmidt EE, Kerkvliet N, et al. Temporal progression of metastasis in lung: cell survival, dormancy, and location dependence of metastatic inefficiency. Cancer Res. 2000;60:2541–2546.

    CAS  PubMed  Google Scholar 

  23. Horino K, Kindezelskii AL, Elner VM, et al. Tumor cell invasion of model 3-dimensional matrices: demonstration of migratory pathways, collagen disruption, and intercellular cooperation. FASEB J. 2001;15:932–939.

    Article  CAS  PubMed  Google Scholar 

  24. Aboody KS, Brown A, Rainov NG, et al. Neural stem cells display extensive tropism for pathology in adult brain: evidence from intracranial gliomas. Proc Natl Acad Sci USA. 2000;97:12846–12851.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Harrington K, Alvarez-Vallina L, Crittenden M, et al. Cells as vehicles for cancer gene therapy: the missing link between targeted vectors and systemic delivery? Hum Gene Ther. 2002;13:1263–1280.

    Article  CAS  PubMed  Google Scholar 

  26. Holder JW, Elmore E, Barrett JC . Gap junction function and cancer. Cancer Res. 1993;53:3475–3485.

    CAS  PubMed  Google Scholar 

  27. Mullen CA, Coale MM, Lowe R, et al. Tumors expressing the cytosine deaminase suicide gene can be eliminated in vivo with 5-fluorocytosine and induce protective immunity to wild type tumor. Cancer Res. 1994;54:1503–1506.

    CAS  PubMed  Google Scholar 

  28. 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 

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Acknowledgements

We thank Isabel de los Santos, Pilar Hernández and Sergio García for technical assistance, and Dr José M. Martínez for his help with analyzing image files. This work was supported in part by Fundación Leucemia Linfoma (MR) and Fundación Oncohematología Infantil (JGC, LM and MR).

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Correspondence to Manuel Ramírez.

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Supplementary information accompanies the paper on Cancer Gene Therapy website (http://www.nature.com/cgt).

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García-Castro, J., Martínez-Palacio, J., Lillo, R. et al. Tumor cells as cellular vehicles to deliver gene therapies to metastatic tumors. Cancer Gene Ther 12, 341–349 (2005). https://doi.org/10.1038/sj.cgt.7700801

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