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:

Human neural stem cells expressing carboxyl esterase target and inhibit tumor growth of lung cancer brain metastases

Cancer Gene Therapy volume 20, pages 678–682 (2013)Cite this article

Subjects

Abstract

Neural stem cells (NSCs) led to the development of a novel strategy for delivering therapeutic genes to brain tumors. Human NSCs expressing rabbit carboxyl esterase (F3.CE), which activates CPT-11, significantly inhibit the growth of A549 human non-small cell lung adenocarcinoma cells in the presence of CPT-11 in vitro and in vivo. F3.CE cells migrated selectively into the brain metastases located in the opposite hemisphere. The treatment also significantly decreased tumor volume in immune-deficient mice bearing lung cancer when F3.CE cells were transplanted into the contralateral hemisphere. The survival of tumor-bearing animals was significantly prolonged by the treatment with F3.CE and CPT-11. This strategy could be considered as an effective treatment regimen for lung cancer brain metastases.

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. Gavrilovic IT, Posner JB . Brain metastases: epidemiology and pathophysiology. J Neurooncol 2005; 75: 5–14.

    Article  Google Scholar 

  2. Schuette W . Treatment of brain metastases from lung cancer: chemotherapy. Lung Cancer 2004; 45 (Suppl 2): S253–S257.

    Article  Google Scholar 

  3. Shaffrey ME, Mut M, Asher AL, Burri SH, Chahlavi A, Chang SM et al. Brain metastases. Curr Probl Surg 2004; 41: 665–741.

    Article  Google Scholar 

  4. 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. NeuroOncol 2006; 8: 119–126.

    CAS  Google Scholar 

  5. Schmidt NO, Przyleck W, Yang W, Ziu M, Teng Y, Kim SU et al. Brain tumor tropism of transplanted human neural stem cells is induced by vascular endothelial growth factor. Neoplasia 2005; 7: 623–629.

    Article  CAS  Google Scholar 

  6. Kim SU . Neural stem cell-based gene therapy for brain tumors. Stem Cell Rev 2010; 7: 130–140.

    Article  Google Scholar 

  7. 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; 15: 5550–5556.

    Article  Google Scholar 

  8. Shimato S, Natsume A, Takeuchi H, Wakabayashi T, Fujii M, Ito M et al. Human neural stem cells target and deliver therapeutic gene to experimental leptomeningeal medulloblastoma. Gene Ther 2007; 15: 1132–1142.

    Article  Google Scholar 

  9. Kendall S, Najbauer J, Johnston HF, Metz M, Li S, Bowers M et al. Neural stem cell targeting of glioma is dependent on PI3K signaling. Stem Cells 2008; 26: 11575–11586.

    Article  Google Scholar 

  10. Joo K, Park IH, Shin JY, Jin J, Kang BG, Kim SY et al. Human neural stem cells target and deliver therapeutic genes to breast cancer brain metastasis. Mol Ther 2009; 17: 570–575.

    Article  CAS  Google Scholar 

  11. Kim JH, Lee JE, Kim SU, Cho KG . Stereological analysis on migration of human neural stem cells in the brain of rats bearing glioma. Neurosurgery 2010; 66: 333–342.

    Article  Google Scholar 

  12. Aboody KS, Bush RA, Garcia E, Metz MZ, Najbauer J, Justus KA et al. Development of a tumor-selective approach to treat metastatic cancer. PLoS One 2006; 1: e23.

    Article  Google Scholar 

  13. Danks MK, Yoon KJ, Bush RA, Remack JS, Weird 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.

    Article  CAS  Google Scholar 

  14. Yi BR, Kim SU, Kim YB, Lee HJ, Cho MH, Choi KC . Antitumor effects of genetically engineered stem cells expressing yeast cytosine deaminase in lung cancer brain metastases via their tumor-tropic properties. Oncol Rep 2012; 27: 1823–1828.

    CAS  PubMed  Google Scholar 

  15. Lim SH, Choi SA, Lee JY, Wang KC, Phi JH, Lee DH et al. Therapeutic targeting of subdural medulloblastomas using human neural stem cells expressing carboxylesterase. Cancer Gene Ther 2011; 18: 817–824.

    Article  CAS  Google Scholar 

  16. Seol HJ, Jin J, Seong DH, Joo KM, Kang W, Yang H et al. Genetically engineered human neural stem cells with rabbit carboxyl esterase can target b rain metastasis from breast cancer. Cancer Lett 2011; 311: 152–159.

    Article  CAS  Google Scholar 

  17. Zhao D, Najbauer J, Annala AJ, Garcia E, Metz MZ, Gutova M et al. Human neural stem cell tropism to metastatic breast cancer. Stem Cells 2012; 30: 314–325.

    Article  CAS  Google Scholar 

  18. Wang C, Natsume A, Lee HJ, Motomura M, Nishimira Y, Ohno Y et al. Neural stem cell-based dual suicide gene delivery for metastatic brain tumors. Cancer Gene Ther 2012; 19: 796–801.

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  20. Lee HJ, Kim KS, Kim EJ, Lee KH, Choi HB, Park IH et al. Brain transplantation of human neural stem cells promotes functional recovery in mouse intracerebral hemorrhage stroke model. Stem Cells 2007; 25: 211–224.

    Article  Google Scholar 

  21. Kim SU, Nagai A, Nakagawa E, Choi HB, Bang JH, Lee HJ et al. Production and characterization of immortal human neural stem cell line with multipotent differentiation property. Methods Mol Biol 2008; 438: 103–121.

    Article  CAS  Google Scholar 

  22. 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 

  23. Aboody KS, Najbauer J, Danks MK . Stem and progenitor cell-mediated tumor selective gene therapy. Gene Ther 2008; 15: 739–752.

    Article  CAS  Google Scholar 

  24. Prados MD, Lamborn K, Yung WK, Jaeckle K, Robins HI, Mehta M et al. A phase II trial of irinotecan (CPT-11) in patients with recurrent malignant glioma: a North American Brain Tumor Consortium study. Neuro Oncol 2006; 8: 189–193.

    Article  CAS  Google Scholar 

  25. Quinn JA, Jiang SX, Reardon DA, Desjardins A, Vredenburgh JJ, Friedman AH et al. Phase II trial of temozolomide (TMZ) plus irinotecan (CPT-11) in adults with newly diagnosed glioblastoma multiforme before radiotherapy. J Neurooncol 2009; 95: 393–400.

    Article  CAS  Google Scholar 

  26. de Groot JF, Yung WK . Bevacizumab and irinotecan in the treatment of recurrent malignant gliomas. Cancer J 2008; 14: 279–285.

    Article  CAS  Google Scholar 

  27. Poulsen HS, Grunnet K, Sorensen M, Olsen P, Hasselbalch B, Nelausen K et al. Bevacizumab plus irinotecan in the treatment patients with progressive recurrent malignant brain tumours. Acta Oncol 2009; 48: 52–58.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by grants from Korea Healthcare Technology R&D Project (A092255) and R&D Program for Cancer Control, Korean Ministry of Health & Welfare (SUK), Asan Life Science Institute (2008-436), Seoul, Korea (SHH), and Canadian Myelin Research Initiative (SUK).

Author information

Author notes

  1. S H Hong and H J Lee: These authors contributed equally to the work.

Authors and Affiliations

  1. Department of Neurosurgery, Ulsan University College of Medicine Asan Medical Center, Seoul, Korea

    S H Hong

  2. Medical Research Institute, Chung-Ang University College of Medicine, Seoul, Korea

    H J Lee, J An & S U Kim

  3. Department of Physiology, Chung-Ang University College of Medicine, Seoul, Korea

    I Lim

  4. Department of Neurosurgery, University of South Florida College of Medicine, Tampa, FL, USA

    C Borlongan

  5. Department of Neurosciences, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA, USA

    K S Aboody

  6. Division of Neurology, Department of Medicine, UBC Hospital, University of British Columbia, Vancouver, BC, Canada

    S U Kim

Authors
  1. S H Hong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. H J Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J An
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. I Lim
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. C Borlongan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. K S Aboody
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. S U Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S U Kim.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hong, S., Lee, H., An, J. et al. Human neural stem cells expressing carboxyl esterase target and inhibit tumor growth of lung cancer brain metastases. Cancer Gene Ther 20, 678–682 (2013). https://doi.org/10.1038/cgt.2013.69

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/cgt.2013.69

Keywords

This article is cited by

Search

Advanced search

Quick links