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.

Clinically applicable human adipose tissue-derived mesenchymal stem cells delivering therapeutic genes to brainstem gliomas

Subjects

Abstract

Pediatric brainstem glioma is an incurable malignancy because of its inoperability. As a result of their extensive tropism toward cancer and the possibility of autologous transplantation, human adipose-derived mesenchymal stem cells (hAT-MSC) are attractive vehicles to deliver therapeutic genes to brainstem gliomas. In this study, in a good manufacturing practice (GMP) facility, we established clinically applicable hAT-MSCs expressing therapeutic genes and investigated their therapeutic efficacy against brainstem glioma in mice. For feasible clinical applications, (1) primary hAT-MSCs were cultured from human subcutaneous fat to make autologous transplantation possible, (2) hAT-MSCs were genetically engineered to express carboxyl esterase (CE) and (3) a secreted form of the tumor necrosis factor-related apoptosis-inducing ligand (sTRAIL) expression vector for synergistic effects was delivered by a gene transfer technology that did not result in genomic integration of the vector. (4) Human CE and sTRAIL sequences were utilized to avoid immunological side effects. The hAT-MSCs expressing CE±sTRAIL showed significant therapeutic effects against brainstem gliomas in vitro and in vivo. However, the simultaneous expression of CE and sTRAIL had no synergistic effects in vivo. The results indicate that non-viral transient single sTRAIL gene transfer to autologous hAT-MSCs is a clinically applicable stem cell-based gene therapy for brainstem gliomas in terms of therapeutic effects and safety.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

References

  1. Jemal A, Murray T, Samuels A, Ghafoor A, Ward E, Thun MJ . Cancer statistics, 2003. CA Cancer J Clin 2003; 53: 5–26.

    Article  PubMed  Google Scholar 

  2. Jennings MT, Freeman ML, Murray MJ . Strategies in the treatment of diffuse pontine gliomas: the therapeutic role of hyperfractionated radiotherapy and chemotherapy. J Neuro-Oncology 1996; 28: 207–222.

    CAS  Article  Google Scholar 

  3. Okada H, Low KL, Kohanbash G, McDonald HA, Hamilton RL, Pollack IF . Expression of glioma-associated antigens in pediatric brain stem and non-brain stem gliomas. J Neuro-Oncology 2008; 88: 245–250.

    CAS  Article  Google Scholar 

  4. Baksh D, Song L, Tuan RS . Adult mesenchymal stem cells: characterization, differentiation, and application in cell and gene therapy. J Cell Mol Med 2004; 8: 301–316.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. Strem BM, Hicok KC, Zhu M, Wulur I, Alfonso Z, Schreiber RE et al. Multipotential differentiation of adipose tissue-derived stem cells. Keio J Med 2005; 54: 132–141.

    CAS  Article  PubMed  Google Scholar 

  6. Birnbaum T, Roider J, Schankin CJ, Padovan CS, Schichor C, Goldbrunner R et al. Malignant gliomas actively recruit bone marrow stromal cells by secreting angiogenic cytokines. J Neuro-Oncology 2007; 83: 241–247.

    CAS  Article  Google Scholar 

  7. 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.

    CAS  Article  PubMed  Google Scholar 

  8. Safford KM, Rice HE . Stem cell therapy for neurologic disorders: therapeutic potential of adipose-derived stem cells. Curr Drug Targets 2005; 6: 57–62.

    CAS  Article  PubMed  Google Scholar 

  9. Choi SA, Lee JY, Wang KC, Phi JH, Song SH, Song J et al. Human adipose tissue-derived mesenchymal stem cells: characteristics and therapeutic potential as cellular vehicles for prodrug gene therapy against brainstem gliomas. Eur J Cancer 2012; 48: 129–137.

    CAS  Article  PubMed  Google Scholar 

  10. Choi SA, Hwang SK, Wang KC, Cho BK, Phi JH, Lee JY et al. Therapeutic efficacy and safety of TRAIL-producing human adipose tissue-derived mesenchymal stem cells against experimental brainstem glioma. Neuro-Oncology 2011; 13: 61–69.

    CAS  Article  PubMed  Google Scholar 

  11. 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.

    CAS  Article  PubMed  Google Scholar 

  12. Danks MK, Yoon KJ, Bush RA, Remack JS, Wierdl M, Tsurkan L et al. Tumor-targeted enzyme/prodrug therapy mediates long-term disease-free survival of mice bearing disseminated neuroblastoma. Cancer Res 2007; 67: 22–25.

    CAS  Article  PubMed  Google Scholar 

  13. Bobis S, Jarocha D, Majka M . Mesenchymal stem cells: characteristics and clinical applications. Folia histochemica et cytobiologica/Pol Acad Sci Pol Histochem Cytochem Soc 2006; 44: 215–230.

    CAS  Google Scholar 

  14. Utsunomiya T, Shimada M, Imura S, Morine Y, Ikemoto T, Mori H et al. Human adipose-derived stem cells: potential clinical applications in surgery. Surg Today 2011; 41: 18–23.

    Article  PubMed  Google Scholar 

  15. Szegezdi E, O'Reilly A, Davy Y, Vawda R, Taylor DL, Murphy M et al. Stem cells are resistant to TRAIL receptor-mediated apoptosis. J Cell Mol Med 2009; 13: 4409–4414.

    CAS  Article  PubMed  Google Scholar 

  16. Grisendi G, Bussolari R, Cafarelli L, Petak I, Rasini V, Veronesi E et al. Adipose-derived mesenchymal stem cells as stable source of tumor necrosis factor-related apoptosis-inducing ligand delivery for cancer therapy. Cancer Res 2010; 70: 3718–3729.

    CAS  Article  PubMed  Google Scholar 

  17. Pulkkanen KJ, Yla-Herttuala S . Gene therapy for malignant glioma: current clinical status. Mol Ther 2005; 12: 585–598.

    CAS  Article  PubMed  Google Scholar 

  18. Vredenburgh JJ, Desjardins A, Reardon DA, Friedman HS . Experience with irinotecan for the treatment of malignant glioma. Neuro-Oncology 2009; 11: 80–91.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. Satoh T, Hosokawa M, Atsumi R, Suzuki W, Hakusui H, Nagai E . Metabolic activation of CPT-11, 7-ethyl-10-[4-(1-piperidino)-1- piperidino]carbonyloxycamptothecin, a novel antitumor agent, by carboxylesterase. Biol Pharm Bull 1994; 17: 662–664.

    CAS  Article  PubMed  Google Scholar 

  20. Rivory LP, Bowles MR, Robert J, Pond SM . Conversion of irinotecan (CPT-11) to its active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38), by human liver carboxylesterase. Biochem Pharmacol 1996; 52: 1103–1111.

    CAS  Article  PubMed  Google Scholar 

  21. Kawato Y, Aonuma M, Hirota Y, Kuga H, Sato K . Intracellular roles of SN-38, a metabolite of the camptothecin derivative CPT-11, in the antitumor effect of CPT-11. Cancer Res 1991; 51: 4187–4191.

    CAS  PubMed  Google Scholar 

  22. Aboody KS, Najbauer J, Schmidt NO, Yang W, Wu JK, Zhuge Y et al. Targeting of melanoma brain metastases using engineered neural stem/progenitor cells. Neuro-Oncology 2006; 8: 119–126.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. Potter PM, Pawlik CA, Morton CL, Naeve CW, Danks MK . Isolation and partial characterization of a cDNA encoding a rabbit liver carboxylesterase that activates the prodrug irinotecan (CPT-11). Cancer Res 1998; 58: 2646–2651.

    CAS  PubMed  Google Scholar 

  24. Song JH, Song DK, Pyrzynska B, Petruk KC, Van Meir EG, Hao C . TRAIL triggers apoptosis in human malignant glioma cells through extrinsic and intrinsic pathways. Brain Pathol 2003; 13: 539–553.

    CAS  Article  PubMed  Google Scholar 

  25. Nagane M, Pan G, Weddle JJ, Dixit VM, Cavenee WK, Huang HJ . Increased death receptor 5 expression by chemotherapeutic agents in human gliomas causes synergistic cytotoxicity with tumor necrosis factor-related apoptosis-inducing ligand in vitro and in vivo. Cancer Res 2000; 60: 847–853.

    CAS  PubMed  Google Scholar 

  26. Roth W, Isenmann S, Naumann U, Kugler S, Bahr M, Dichgans J et al. Locoregional Apo2L/TRAIL eradicates intracranial human malignant glioma xenografts in athymic mice in the absence of neurotoxicity. Biochem Biophys Res Commun 1999; 265: 479–483.

    CAS  Article  PubMed  Google Scholar 

  27. Lee J, Hampl M, Albert P, Fine HA . Antitumor activity and prolonged expression from a TRAIL-expressing adenoviral vector. Neoplasia 2002; 4: 312–323.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. Griffith TS, Stokes B, Kucaba TA, Earel JK Jr., VanOosten RL, Brincks EL et al. TRAIL gene therapy: from preclinical development to clinical application. Curr Gene Ther 2009; 9: 9–19.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. Rieger J, Naumann U, Glaser T, Ashkenazi A, Weller M . APO2 ligand: a novel lethal weapon against malignant glioma? FEBS Lett 1998; 427: 124–128.

    CAS  Article  PubMed  Google Scholar 

  30. Pavet V, Beyrath J, Pardin C, Morizot A, Lechner MC, Briand JP et al. Multivalent DR5 peptides activate the TRAIL death pathway and exert tumoricidal activity. Cancer Res 2010; 70: 1101–1110.

    CAS  Article  PubMed  Google Scholar 

  31. Shah K, Tung CH, Yang K, Weissleder R, Breakefield XO . Inducible release of TRAIL fusion proteins from a proapoptotic form for tumor therapy. Cancer Res 2004; 64: 3236–3242.

    CAS  Article  PubMed  Google Scholar 

  32. Griffith TS, Anderson RD, Davidson BL, Williams RD, Ratliff TL . Adenoviral-mediated transfer of the TNF-related apoptosis-inducing ligand/Apo-2 ligand gene induces tumor cell apoptosis. J Immunol 2000; 165: 2886–2894.

    CAS  Article  PubMed  Google Scholar 

  33. Caretti V, Zondervan I, Meijer DH, Idema S, Vos W, Hamans B et al. Monitoring of tumor growth and post-irradiation recurrence in a diffuse intrinsic pontine glioma mouse model. Brain Pathol 2011; 21: 441–451.

    Article  PubMed  Google Scholar 

  34. Griffith TS, Rauch CT, Smolak PJ, Waugh JY, Boiani N, Lynch DH et al. Functional analysis of TRAIL receptors using monoclonal antibodies. J Immunol 1999; 162: 2597–2605.

    CAS  PubMed  Google Scholar 

  35. Mahalingam D, Szegezdi E, Keane M, de Jong S, Samali A . TRAIL receptor signalling and modulation: are we on the right TRAIL? Cancer Treat Rev 2009; 35: 280–288.

    CAS  Article  PubMed  Google Scholar 

  36. Kaliberov SA, Chiz S, Kaliberova LN, Krendelchtchikova V, Della Manna D, Zhou T et al. Combination of cytosine deaminase suicide gene expression with DR5 antibody treatment increases cancer cell cytotoxicity. Cancer Gene Ther 2006; 13: 203–214.

    CAS  Article  PubMed  Google Scholar 

  37. Nagane M, Shimizu S, Mori E, Kataoka S, Shiokawa Y . Predominant antitumor effects by fully human anti-TRAIL-receptor 2 (DR5) monoclonal antibodies in human glioma cells in vitro and in vivo. Neuro-Oncology 2010; 12: 687–700.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. Aoki Y, Hashizume R, Ozawa T, Banerjee A, Prados M, James CD et al. An experimental xenograft mouse model of diffuse pontine glioma designed for therapeutic testing. J Neuro-Oncology 2012; 108: 29–35.

    Article  Google Scholar 

  39. Altaner C . Prodrug cancer gene therapy. Cancer Lett 2008; 270: 191–201.

    CAS  Article  PubMed  Google Scholar 

  40. Kim SK, Kim SU, Park IH, Bang JH, Aboody KS, Wang KC et al. Human neural stem cells target experimental intracranial medulloblastoma and deliver a therapeutic gene leading to tumor regression. Clin Cancer Res 2006; 12: 5550–5556.

    CAS  Article  PubMed  Google Scholar 

  41. Kim SU . Human neural stem cells genetically modified for brain repair in neurological disorders. Neuropathology 2004; 24: 159–171.

    Article  PubMed  Google Scholar 

  42. 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.

    CAS  Article  PubMed  Google Scholar 

  43. Lee DH, Ahn Y, Kim SU, Wang KC, Cho BK, Phi JH et al. Targeting rat brainstem glioma using human neural stem cells and human mesenchymal stem cells. Clin Cancer Res 2009; 15: 4925–4934.

    CAS  Article  PubMed  Google Scholar 

  44. Gutova M, Najbauer J, Chen MY, Potter PM, Kim SU, Aboody KS . Therapeutic targeting of melanoma cells using neural stem cells expressing carboxylesterase, a CPT-11 activating enzyme. Curr Stem Cell Res Ther 2010; 5: 273–276.

    CAS  Article  PubMed  Google Scholar 

  45. Rath P, Shi H, Maruniak JA, Litofsky NS, Maria BL, Kirk MD . Stem cells as vectors to deliver HSV/tk gene therapy for malignant gliomas. Curr Stem Cell Res Ther 2009; 4: 44–49.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. Niu J, Xing C, Yan C, Liu H, Cui Y, Peng H et al. Lentivirus-mediated CD/TK fusion gene transfection neural stem cell therapy for C6 glioblastoma. Tumour Biol 2013; 34: 3731–3741.

    CAS  Article  PubMed  Google Scholar 

  47. Lee JY, Lee DH, Kim HA, Choi SA, Lee HJ, Park CK et al. Double suicide gene therapy using human neural stem cells against glioblastoma: double safety measures. J Neuro-Oncology 2014; 116: 49–57.

    CAS  Article  Google Scholar 

  48. Danks MK, Morton CL, Krull EJ, Cheshire PJ, Richmond LB, Naeve CW et al. Comparison of activation of CPT-11 by rabbit and human carboxylesterases for use in enzyme/prodrug therapy. Clin Cancer Res 1999; 5: 917–924.

    CAS  PubMed  Google Scholar 

  49. Wang Y, Zhu S, Cloughesy TF, Liau LM, Mischel PS . p53 disruption profoundly alters the response of human glioblastoma cells to DNA topoisomerase I inhibition. Oncogene 2004; 23: 1283–1290.

    CAS  Article  PubMed  Google Scholar 

  50. Kuroda J, Kuratsu J, Yasunaga M, Koga Y, Saito Y, Matsumura Y . Potent antitumor effect of SN-38-incorporating polymeric micelle, NK012, against malignant glioma. International journal of cancer. J Int Cancer 2009; 124: 2505–2511.

    CAS  Article  Google Scholar 

  51. Metz MZ, Gutova M, Lacey SF, Abramyants Y, Vo T, Gilchrist M et al. Neural stem cell-mediated delivery of irinotecan-activating carboxylesterases to glioma: implications for clinical use. Stem Cells Transl Med 2013; 2: 983–992.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. Yin J, Kim JK, Moon JH, Beck S, Piao D, Jin X et al. hMSC-mediated concurrent delivery of endostatin and carboxylesterase to mouse xenografts suppresses glioma initiation and recurrence. Mol Ther 2011; 19: 1161–1169.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This study was supported by a grant of the Korea Health technology R&D Project, Ministry of Health and Welfare, Republic of Korea (A120446) and by a grant no. 30-2014-0270 from the Seoul National University Hospital Research Fund.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to K M Joo or S-K Kim.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on Cancer Gene Therapy website

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Choi, S., Lee, Y., Kwak, P. et al. Clinically applicable human adipose tissue-derived mesenchymal stem cells delivering therapeutic genes to brainstem gliomas. Cancer Gene Ther 22, 302–311 (2015). https://doi.org/10.1038/cgt.2015.25

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/cgt.2015.25

Further reading

Search

Quick links