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.

  • Research Article
  • Published:

Antitumor effect of genetically engineered mesenchymal stem cells in a rat glioma model

Gene Therapy volume 11, pages 1155–1164 (2004)Cite this article

Abstract

The prognosis of patients with malignant glioma is extremely poor, despite the extensive surgical treatment that they receive and recent improvements in adjuvant radio- and chemotherapy. In the present study, we propose the use of gene-modified mesenchymal stem cells (MSCs) as a new tool for gene therapy of malignant brain neoplasms. Primary MSCs isolated from Fischer 344 rats possessed excellent migratory ability and exerted inhibitory effects on the proliferation of 9L glioma cell in vitro. We also confirmed the migratory capacity of MSCs in vivo and showed that when they were inoculated into the contralateral hemisphere, they migrated towards 9L glioma cells through the corpus callosum. MSCs implanted directly into the tumor localized mainly at the border between the 9L tumor cells and normal brain parenchyma, and also infiltrated into the tumor bed. Intratumoral injection of MSCs caused significant inhibition of 9L tumor growth and increased the survival of 9L glioma-bearing rats. Gene-modification of MSCs by infection with an adenoviral vector encoding human interleukin-2 (IL-2) clearly augmented the antitumor effect and further prolonged the survival of tumor-bearing rats. Thus, gene therapy employing MSCs as a targeting vehicle would be promising as a new therapeutic approach for refractory brain tumor.

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
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Surawicz TS et al. Brain tumor survival: results from the National Cancer Data Base. J Neurooncol 1998; 40: 151–160.

    Article  CAS  PubMed  Google Scholar 

  2. Dunn IF, Black PM . The neurosurgeon as local oncologist: cellular and molecular neurosurgery in malignant glioma therapy. Neurosurgery 2003; 52: 1411–1422; discussion 1422–1414.

    Article  PubMed  Google Scholar 

  3. Black PM, Loeffler J . Cancer of the Nervous System. Oxford: Blackwell, 1997.

    Google Scholar 

  4. Shinoura N et al. Transduction of a fiber-mutant adenovirus for the HSVtk gene highly augments the cytopathic effect towards gliomas. Jpn J Cancer Res 2000; 91: 1028–1034.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Chen SH et al. Gene therapy for brain tumors: regression of experimental gliomas by adenovirus-mediated gene transfer in vivo. Proc Natl Acad Sci USA 1994; 91: 3054–3057.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Kambara H et al. Combined radiation and gene therapy for brain tumors with adenovirus-mediated transfer of cytosine deaminase and uracil phosphoribosyltransferase genes. Cancer Gene Ther 2002; 9: 840–845.

    Article  CAS  PubMed  Google Scholar 

  7. Adachi Y et al. Experimental gene therapy for brain tumors using adenovirus-mediated transfer of cytosine deaminase gene and uracil phosphoribosyltransferase gene with 5-fluorocytosine. Hum Gene Ther 2000; 11: 77–89.

    Article  CAS  PubMed  Google Scholar 

  8. Eck SL et al. Treatment of recurrent or progressive malignant glioma with a recombinant adenovirus expressing human interferon-beta (H5.010CMVhIFN-beta): a phase I trial. Hum Gene Ther 2001; 12: 97–113.

    Article  CAS  PubMed  Google Scholar 

  9. Trask TW et al. Phase I study of adenoviral delivery of the HSV-tk gene and ganciclovir administration in patients with current malignant brain tumors. Mol Ther 2000; 1: 195–203.

    Article  CAS  PubMed  Google Scholar 

  10. Aboody KS 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 

  11. Benedetti S et al. Gene therapy of experimental brain tumors using neural progenitor cells. Nat Med 2000; 6: 447–450.

    Article  CAS  PubMed  Google Scholar 

  12. Ehtesham M et al. The use of interleukin 12-secreting neural stem cells for the treatment of intracranial glioma. Cancer Res 2002; 62: 5657–5663.

    CAS  PubMed  Google Scholar 

  13. Ehtesham M et al. Induction of glioblastoma apoptosis using neural stem cell-mediated delivery of tumor necrosis factor-related apoptosis-inducing ligand. Cancer Res 2002; 62: 7170–7174.

    CAS  PubMed  Google Scholar 

  14. Singh G . Sources of neuronal material for implantation. Neuropathology 2001; 21: 110–114.

    Article  CAS  PubMed  Google Scholar 

  15. Tsuda H et al. Efficient BMP2 gene transfer and bone formation of mesenchymal stem cells by a fiber-mutant adenoviral vector. Mol Ther 2003; 7: 354–365.

    Article  CAS  PubMed  Google Scholar 

  16. Beresford JN et al. Evidence for an inverse relationship between the differentiation of adipocytic and osteogenic cells in rat marrow stromal cell cultures. J Cell Sci 1992; 102 (Part 2): 341–351.

    CAS  PubMed  Google Scholar 

  17. Dennis JE, Haynesworth SE, Young RG, Caplan AI . Osteogenesis in marrow-derived mesenchymal cell porous ceramic composites transplanted subcutaneously: effect of fibronectin and laminin on cell retention and rate of osteogenic expression. Cell Transplant 1992; 1: 23–32.

    Article  CAS  PubMed  Google Scholar 

  18. Liechty KW et al. Human mesenchymal stem cells engraft and demonstrate site-specific differentiation after in utero transplantation in sheep. Nat Med 2000; 6: 1282–1286.

    Article  CAS  PubMed  Google Scholar 

  19. Woodbury D, Schwarz EJ, Prockop DJ, Black IB . Adult rat and human bone marrow stromal cells differentiate into neurons. J Neurosci Res 2000; 61: 364–370.

    Article  CAS  PubMed  Google Scholar 

  20. Deng W, Obrocka M, Fischer I, Prockop DJ . In vitro differentiation of human marrow stromal cells into early progenitors of neural cells by conditions that increase intracellular cyclic AMP. Biochem Biophys Res Commun 2001; 282: 148–152.

    Article  CAS  PubMed  Google Scholar 

  21. Sanchez-Ramos J et al. Adult bone marrow stromal cells differentiate into neural cells in vitro. Exp Neurol 2000; 164: 247–256.

    Article  CAS  PubMed  Google Scholar 

  22. Kobune M et al. Telomerized human multipotent mesenchymal cells can differentiate into hematopoietic and cobblestone area-supporting cells. Exp Hematol 2003; 31: 715–722.

    Article  CAS  PubMed  Google Scholar 

  23. Li Y et al. Human marrow stromal cell therapy for stroke in rat: neurotrophins and functional recovery. Neurology 2002; 59: 514–523.

    Article  CAS  PubMed  Google Scholar 

  24. Kopen GC, Prockop DJ, Phinney DG . Marrow stromal cells migrate throughout forebrain and cerebellum, and they differentiate into astrocytes after injection into neonatal mouse brains. Proc Natl Acad Sci USA 1999; 96: 10711–10716.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Zhao LR et al. Human bone marrow stem cells exhibit neural phenotypes and ameliorate neurological deficits after grafting into the ischemic brain of rats. Exp Neurol 2002; 174: 11–20.

    Article  PubMed  Google Scholar 

  26. Woodbury D, Reynolds K, Black IB . Adult bone marrow stromal stem cells express germline, ectodermal, endodermal, and mesodermal genes prior to neurogenesis. J Neurosci Res 2002; 69: 908–917.

    Article  CAS  PubMed  Google Scholar 

  27. Tille JC, Pepper MS . Mesenchymal cells potentiate vascular endothelial growth factor-induced angiogenesis in vitro. Exp Cell Res 2002; 280: 179–191.

    Article  CAS  PubMed  Google Scholar 

  28. Rhines LD et al. Local immunotherapy with interleukin-2 delivered from biodegradable polymer microspheres combined with interstitial chemotherapy: a novel treatment for experimental malignant glioma. Neurosurgery 2003; 52: 872–879; discussion 879–880.

    Article  PubMed  Google Scholar 

  29. Iwadate Y et al. Induction of immunity in peripheral tissues combined with intracerebral transplantation of interleukin-2-producing cells eliminates established brain tumors. Cancer Res 2001; 61: 8769–8774.

    CAS  PubMed  Google Scholar 

  30. Wang L et al. MCP-1, MIP-1, IL-8 and ischemic cerebral tissue enhance human bone marrow stromal cell migration in interface culture. Hematology 2002; 7: 113–117.

    Article  CAS  PubMed  Google Scholar 

  31. Wang L et al. Ischemic cerebral tissue and MCP-1 enhance rat bone marrow stromal cell migration in interface culture. Exp Hematol 2002; 30: 831–836.

    Article  CAS  PubMed  Google Scholar 

  32. Yu J, Ustach C, Kim HR . Platelet-derived growth factor signaling and human cancer. J Biochem Mol Biol 2003; 36: 49–59.

    CAS  PubMed  Google Scholar 

  33. Hellstrom M et al. Role of PDGF-B and PDGFR-beta in recruitment of vascular smooth muscle cells and pericytes during embryonic blood vessel formation in the mouse. Development 1999; 126: 3047–3055.

    CAS  PubMed  Google Scholar 

  34. Andrades JA et al. A recombinant human TGF-beta1 fusion protein with collagen-binding domain promotes migration, growth, and differentiation of bone marrow mesenchymal cells. Exp Cell Res 1999; 250: 485–498.

    Article  CAS  PubMed  Google Scholar 

  35. De Palma M, Venneri MA, Roca C, Naldini L . Targeting exogenous genes to tumor angiogenesis by transplantation of genetically modified hematopoietic stem cells. Nat Med 2003; 9: 789–795.

    Article  CAS  PubMed  Google Scholar 

  36. Coussens LM, Werb Z . Inflammation and cancer. Nature 2002; 420: 860–867.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Weaver VM, Fischer AH, Peterson OW, Bissell MJ . The importance of the microenvironment in breast cancer progression: recapitulation of mammary tumorigenesis using a unique human mammary epithelial cell model and a three-dimensional culture assay. Biochem Cell Biol 1996; 74: 833–851.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Hombauer H, Minguell JJ . Selective interactions between epithelial tumour cells and bone marrow mesenchymal stem cells. Br J Cancer 2000; 82: 1290–1296.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. 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.

    Article  CAS  PubMed  Google Scholar 

  40. Kimura S et al. Growth control of C6 glioma in vivo by nerve growth factor. J Neurooncol 2002; 59: 199–205.

    Article  PubMed  Google Scholar 

  41. Stoeltzing O et al. Angiopoietin-1 inhibits vascular permeability, angiogenesis, and growth of hepatic colon cancer tumors. Cancer Res 2003; 63: 3370–3377.

    CAS  PubMed  Google Scholar 

  42. Conget PA, Minguell JJ . Adenoviral-mediated gene transfer into ex vivo expanded human bone marrow mesenchymal progenitor cells. Exp Hematol 2000; 28: 382–390.

    Article  CAS  PubMed  Google Scholar 

  43. Marx JC et al. High-efficiency transduction and long-term gene expression with a murine stem cell retroviral vector encoding the green fluorescent protein in human marrow stromal cells. Hum Gene Ther 1999; 10: 1163–1173.

    Article  CAS  PubMed  Google Scholar 

  44. Allay JA et al. LacZ and interleukin-3 expression in vivo after retroviral transduction of marrow-derived human osteogenic mesenchymal progenitors. Hum Gene Ther 1997; 8: 1417–1427.

    Article  CAS  PubMed  Google Scholar 

  45. Dehari H et al. Enhanced antitumor effect of RGD fiber-modified adenovirus for gene therapy of oral cancer. Cancer Gene Ther 2003; 10: 75–85.

    Article  CAS  PubMed  Google Scholar 

  46. Nakamura T, Sato K, Hamada H . Effective gene transfer to human melanomas via integrin-targeted adenoviral vectors. Hum Gene Ther 2002; 13: 613–626.

    Article  CAS  PubMed  Google Scholar 

  47. Ferguson TA, Green DR, Griffith TS . Cell death and immune privilege. Int Rev Immunol 2002; 21: 153–172.

    Article  PubMed  Google Scholar 

  48. Dranoff G et al. Vaccination with irradiated tumor cells engineered to secrete murine granulocyte–macrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity. Proc Natl Acad Sci USA 1993; 90: 3539–3543.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Studeny M et al. Bone marrow-derived mesenchymal stem cells as vehicles for interferon-beta delivery into tumors. Cancer Res 2002; 62: 3603–3608.

    CAS  PubMed  Google Scholar 

  50. Yamauchi A et al. Pre-administration of angiopoietin-1 followed by VEGF induces functional and mature vascular formation in a rabbit ischemic model. J Gene Med 2003; 5: 994–1004.

    Article  CAS  PubMed  Google Scholar 

  51. Namba H et al. Evaluation of the bystander effect in experimental brain tumors bearing herpes simplex virus-thymidine kinase gene by serial magnetic resonance imaging. Hum Gene Ther 1996; 7: 1847–1852.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank H Isogai at the Institute for Animal Experimentation of Sapporo Medical University for help in animal experiments. This work was supported in part by a grant to HH from the Ministry of Education and Science.

Author information

Authors and Affiliations

  1. Department of Molecular Medicine, Sapporo Medical University, Sapporo, Japan

    K Nakamura, Y Ito, Y Kawano, K Kurozumi, M Kobune, H Tsuda & H Hamada

  2. Division of Gene Therapy, Sapporo Medical University, Sapporo, Japan

    Y Ito

  3. 4th Department of Internal Medicine, Sapporo Medical University, Sapporo, Japan

    Y Kawano, M Kobune & Y Niitsu

  4. Department of Neurological Surgery, Field of Neuroscience, Branch of Biophysical Science, Graduate School of Medicine and Dentistry, Okayama University, Okayama, Japan

    K Kurozumi

  5. Department of Neurosurgery, Sapporo Medical University, Sapporo, Japan

    A Bizen & O Honmou

Authors
  1. K Nakamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Y Ito
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Y Kawano
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. K Kurozumi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M Kobune
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. H Tsuda
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. A Bizen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. O Honmou
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Y Niitsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. H Hamada
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nakamura, K., Ito, Y., Kawano, Y. et al. Antitumor effect of genetically engineered mesenchymal stem cells in a rat glioma model. Gene Ther 11, 1155–1164 (2004). https://doi.org/10.1038/sj.gt.3302276

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gt.3302276

Keywords

This article is cited by

Search

Advanced search

Quick links