Abstract
Adult stem cells may serve as powerful cellular vehicles to deliver therapeutic genes for cancer therapy. In such applications, effective and safe transduction to load stem cells with genes of interest is essential. To examine whether baculovirus can be used to fulfill this task, we tested a range of baculoviral vectors in human bone marrow mesenchymal stem cells (MSCs). A vector using the human cytomegalovirus immediate-early gene promoter to drive transgene expression and the woodchuck hepatitis virus posttranscriptional regulatory element to enhance translation was able to transduce MSCs with efficiency close to 80%. Following the observation that baculoviral transduction did not significantly affect surface marker expression of the stem cells, we tested the feasibility of using baculovirus-transduced MSCs for targeted cancer therapy. We transduced cells with a baculoviral vector harboring the herpes simplex virus thymidine kinase gene, and performed tail vein injection of the transduced cells into mice preinoculated subcutaneously with human U87 glioma cells. After ganciclovir prodrug injection, we observed inhibition of tumor growth and significantly prolonged survival of tumor-inoculated animals. Our findings suggest that baculoviral transduction of MSCs is an attractive option to generate targeting vehicles for systemic cancer therapy.
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References
Devine SM, Cobbs C, Jennings M, Bartholomew A, Hoffman R . Mesenchymal stem cells distribute to a wide range of tissues following systemic infusion into nonhuman primates. Blood 2003; 101: 2999–3001.
Spaeth E, Klopp A, Dembinski J, Andreeff M, Marini F . Inflammation and tumor microenvironments: defining the migratory itinerary of mesenchymal stem cells. Gene Ther 2008; 15: 730–738.
Bexell D, Gunnarsson S, Tormin A, Darabi A, Gisselsson D, Roybon L et al. Bone marrow multipotent mesenchymal stroma cells act as pericyte-like migratory vehicles in experimental gliomas. Mol Ther 2009; 17: 183–190.
Studeny M, Marini FC, Champlin RE, Zompetta C, Fidler IJ, Andreeff M . Bone marrow-derived mesenchymal stem cells as vehicles for interferon-beta delivery into tumors. Cancer Res 2002; 62: 3603–3608.
Pereboeva L, Komarova S, Mikheeva G, Krasnykh V, Curiel DT . Approaches to utilize mesenchymal progenitor cells as cellular vehicles. Stem Cells 2003; 21: 389–404.
Nakamura K, Ito Y, Kawano Y, Kurozumi K, Kobune M, Tsuda H et al. Antitumor effect of genetically engineered mesenchymal stem cells in a rat glioma model. Gene Ther 2004; 11: 1155–1164.
Nakamizo A, Marini F, Amano T, Khan A, Studeny M, Gumin J et al. Human bone marrow–derived mesenchymal stem cells in the treatment of gliomas. Cancer Res 2005; 65: 3307–3318.
Miletic H, Fischer Y, Litwak S, Giroglou T, Waerzeggers Y, Winkeler A et al. Bystander killing of malignant glioma by bone marrow–derived tumor-infiltrating progenitor cells expressing a suicide gene. Mol Ther 2007; 15: 1373–1381.
Chan J, O’Donoghue K, de la Fuente J, Roberts IR, Kumar S, Morgan JE et al. Human fetal mesenchymal stem cells as vehicles for gene delivery. Stem Cells 2005; 23: 93–102.
Damme AV, Thorrez L, Ma L, Vandenburgh H, Eyckmans J, Dell’Accio F et al. Efficient lentiviral transduction and improved engraftment of human bone marrow mesenchymal cells. Stem Cells 2006; 24: 896–907.
Uchibori R, Okada T, Ito T, Urabe M, Mizukami H, Kume A et al. Retroviral vector-producing mesenchymal stem cells for targeted suicide cancer gene therapy. J Gene Med 2009; 11: 373–381.
Hacein-Bey-Abina S, Von Kalle C, Schmidt M, McCormack MP, Wulffraat N, Leboulch P et al. LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science 2003; 302: 415–419.
McMahon JM, Conroy S, Lyons M, Greiser U, O'shea C, Strappe P et al. Gene transfer into rat mesenchymal stem cells: a comparative study of viral and nonviral vectors. Stem Cells Dev 2006; 15: 87–96.
Ren C, Kumar S, Chanda D, Chen J, Mountz JD, Ponnazhagan S . Therapeutic potential of mesenchymal stem cells producing interferon-alpha in a mouse melanoma lung metastasis model. Stem Cells 2008; 26: 2332–2338.
Xu G, Jiang XD, Xu Y, Zhang J, Huang FH, Chen ZZ et al. Adenoviral-mediated interleukin-18 expression in mesenchymal stem cells effectively suppresses the growth of glioma in rats. Cell Biol Int 2009; 33: 466–474.
Bessis N, GarciaCozar FJ, Boissier MC . Immune responses to gene therapy vectors: influence on vector function and effector mechanisms. Gene Ther 2004; 11 (Suppl 1): S10–S17.
Ho YC, Chung YC, Hwang SM, Wang KC, Hu YC . Transgene expression and differentiation of baculovirus-transduced human mesenchymal stem cells. J Gene Med 2005; 7: 860–868.
Ho YC, Lee HP, Hwang SM, Lo WH, Chen HC, Chung CK et al. Baculovirus transduction of human mesenchymal stem cell-derived progenitor cells: variation of transgene expression with cellular differentiation states. Gene Ther 2006; 13: 1471–1479.
Chuang CK, Wong TH, Hwang SM, Chang YH, Chen GY, Chiu YC et al. Baculovirus transduction of mesenchymal stem cells: in vitro responses and in vivo immune responses after cell transplantation. Mol Ther 2009; 17: 889–896.
Chuang CK, Sung LY, Hwang SM, Lo WH, Chen HC, Hu YC . Baculovirus as a new gene delivery vector for stem cell engineering and bone tissue engineering. Gene Ther 2007; 14: 1417–1424.
Balani P, Boulaire J, Zhao Y, Zeng J, Lin J, Wang S . High mobility group box2 promoter-controlled suicide gene expression enables targeted glioblastoma treatment. Mol Ther 2009; 17: 1003–1011.
Zeng J, Du J, Zhao Y, Palanisamy N, Wang S . Baculoviral vector-mediated transient and stable transgene expression in human embryonic stem cells. Stem Cells 2007; 25: 1055–1061.
Zeng J, Du J, Lin J, Bak XY, Wu C, Wang S . High-efficiency transient transduction of human embryonic stem cell-derived neurons with baculoviral vectors. Mol Ther 2009; 17: 1585–1593.
Du J, Zeng J, Zhao Y, Boulaire J, Wang S . The combined use of viral transcriptional and post-transcriptional regulatory elements to improve baculovirus-mediated transient gene expression in human embryonic stem cells. J Biosci Bioeng 2010; 109: 1–8.
Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini FC, Krause DS et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006; 8: 315–317.
Tomchuck SL, Zwezdaryk KJ, Coffelt SB, Waterman RS, Danka ES, Scandurro AB . Toll-like receptors on human mesenchymal stem cells drive their migration and immunomodulating responses. Stem Cells 2008; 26: 99–107.
Fillat C, Carrio M, Cascante A, Sangro B . Suicide gene therapy mediated by the Herpes Simplex virus thymidine kinase gene/Ganciclovir system: fifteen years of application. Curr Gene Ther 2003; 3: 13–26.
Maestroni GJ, Hertens E, Galli P . Factor(s) from nonmacrophage bone marrow stromal cells inhibit Lewis lung carcinoma and B16 melanoma growth in mice. Cell Mol Life Sci 1999; 55: 663–667.
Hombauer H, Minguell JJ . Selective interactions between epithelial tumour cells and bone marrow mesenchymal stem cells. Br J Cancer 2000; 82: 1290–1296.
Condreay JP, Witherspoon SM, Clay WC, Kost TA . Transient and stable gene expression in mammalian cells transduced with a recombinant baculovirus vector. Proc Natl Acad Sci USA 1999; 96: 127–132.
Merrihew RV, Clay WC, Condreay JP, Witherspoon SM, Dallas WS, Kost TA . Chromosomal integration of transduced recombinant baculovirus DNA in mammalian cells. J Virol 2001; 75: 903–909.
Strauss R, Hüser A, Ni S, Tuve S, Kiviat N, Sow PS et al. Baculovirus-based vaccination vectors allow for efficient induction of immune responses against plasmodium falciparum circumsporozoite protein. Mol Ther 2007; 15: 193–202.
Kucerova L, Altanerova V, Matuskova M, Tyciakova S, Altaner C . Adipose tissue-derived human mesenchymal stem cells mediated prodrug cancer gene therapy. Cancer Res 2007; 67: 6304–6313.
Cavarretta IT, Altanerova V, Matuskova M, Kucerova L, Culig Z, Altaner C . Adipose tissue-derived mesenchymal stem cells expressing prodrug-converting enzyme inhibit human prostate tumor growth. Mol Ther 2010; 18: 223–231.
Trinh QT, Austin EA, Murray DM, Knick VC, Huber BE . Enzyme/prodrug gene therapy: comparison of cytosine deaminase/5-fluorocytosine versus thymidine kinase/ganciclovir enzyme/prodrug systems in a human colorectal carcinoma cell line. Cancer Res 1995; 55: 4808–4812.
Rogers RP, Ge JQ, Holley-Guthrie E, Hoganson DK, Comstock KE, Olsen JC et al. Killing Epstein-Barr virus-positive B lymphocytes by gene therapy: comparing the efficacy of cytosine deaminase and herpes simplex virus thymidine kinase. Hum Gene Ther 1996; 7: 2235–2245.
Kuriyama S, Mitoro A, Yamazaki M, Tsujinoue H, Nakatani T, Akahane T et al. Comparison of gene therapy with the herpes simplex virus thymidine kinase gene and the bacterial cytosine deaminase gene for the treatment of hepatocellular carcinoma. Scand J Gastroenterol 1999; 34: 1033–1041.
Uckert W, Kammertons T, Haack K, Qin Z, Gebert J, Schendel DJ et al. Double suicide gene (cytosine deaminase and herpes simplex virus thymidine kinase) but not single gene transfer allows reliable elimination of tumor cells in vivo. Hum Gene Ther 1998; 9: 855–865.
Xia K, Liang D, Tang A, Feng Y, Zhang J, Pan Q et al. A novel fusion suicide gene yeast CDglyTK plays a role in radio-gene therapy of nasopharyngeal carcinoma. Cancer Gene Ther 2004; 11: 790–796.
Boucher PD, Im MM, Freytag SO, Shewach DS . A novel mechanism of synergistic cytotoxicity with 5-fluorocytosine and ganciclovir in double suicide gene therapy. Cancer Res 2006; 66: 3230–3237.
Acknowledgements
This work was supported by Institute of Bioengineering and Nanotechnology, Biomedical Research Council, Agency for Science, Technology and Research (A*STAR) in Singapore and by the grants from the National Medical Research Council in Singapore (NMRC/1119/2007) and the Ministry of Education of Singapore (T206B3110).
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Bak, X., Yang, J. & Wang, S. Baculovirus-transduced bone marrow mesenchymal stem cells for systemic cancer therapy. Cancer Gene Ther 17, 721–729 (2010). https://doi.org/10.1038/cgt.2010.32
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DOI: https://doi.org/10.1038/cgt.2010.32
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