Human Neural Stem Cell Tropism to Metastatic Breast Cancer§

Authors

  • Donghong Zhao,

    Corresponding author
    1. Department of Neurosciences, City of Hope National Medical Center and Beckman Research Institute, Duarte, California, USA
    • Department of Neurosciences, City of Hope National Medical Center and Beckman Research Institute, 1500 E. Duarte Road, Duarte, California 91010-3000, USA
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    • Telephone: 626-359-8111x60163; Fax: 626-930-5416

  • Joseph Najbauer,

    1. Department of Neurosciences, City of Hope National Medical Center and Beckman Research Institute, Duarte, California, USA
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  • Alexander J. Annala,

    1. Department of Neurosciences, City of Hope National Medical Center and Beckman Research Institute, Duarte, California, USA
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  • Elizabeth Garcia,

    1. Department of Neurosciences, City of Hope National Medical Center and Beckman Research Institute, Duarte, California, USA
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  • Marianne Z. Metz,

    1. Department of Neurosciences, City of Hope National Medical Center and Beckman Research Institute, Duarte, California, USA
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  • Margarita Gutova,

    1. Department of Neurosciences, City of Hope National Medical Center and Beckman Research Institute, Duarte, California, USA
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  • Monika D. Polewski,

    1. Department of Neurosciences, City of Hope National Medical Center and Beckman Research Institute, Duarte, California, USA
    2. Irell and Manella Graduate School of Biological Sciences, City of Hope National Medical Center and Beckman Research Institute, Duarte, California, USA
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  • Megan Gilchrist,

    1. Department of Neurosciences, City of Hope National Medical Center and Beckman Research Institute, Duarte, California, USA
    2. Department of Biological Sciences, California State University, Long Beach, California, USA
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  • Carlotta A. Glackin,

    1. Department of Neurosciences, City of Hope National Medical Center and Beckman Research Institute, Duarte, California, USA
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  • Seung U. Kim,

    1. Division of Neurology, Department of Medicine, UBC Hospital, University of British Columbia, Vancouver, British Columbia, Canada
    2. Medical Research Institute, Chung-Ang University College of Medicine, Seoul, Korea
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  • Karen S. Aboody

    Corresponding author
    1. Department of Neurosciences, City of Hope National Medical Center and Beckman Research Institute, Duarte, California, USA
    2. Division of Neurosurgery, City of Hope National Medical Center and Beckman Research Institute, Duarte, California, USA
    • Department of Neurosciences and Division of Neurosurgery, City of Hope National Medical Center and Beckman Research Institute, 1500 E. Duarte Road, Duarte, California 91010-3000, USA
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    • Telephone: 626-471-7177; Fax: 626-301-8857


  • This article is dedicated to the loving memory of Monica Bartow Aboody.

  • Author contributions: D.Z.: conception and design, collection and assembly of data, data analysis and interpretation, and manuscript writing; J.N.: conception and design, data analysis and interpretation, and manuscript writing; A.J.A.: data analysis and interpretation and manuscript editing; E.G. and M.Z.M.: technical support, contributed to experimental design; M.G., M.D.P., and M.G.: collection and assembly of data and manuscript editing; C.A.G. and S.U.K.: provision of study material; K.S.A.: conception and design, data analysis, financial support, and editing and final approval of manuscript.

  • §

    Disclosure of potential conflicts of interest is found at the end of this article.

  • First published online in STEM CELLSEXPRESS Nov 14, 2011.

Abstract

Metastasis to multiple organs is the primary cause of mortality in breast cancer patients. The poor prognosis for patients with metastatic breast cancer and toxic side effects of currently available treatments necessitate the development of effective tumor-selective therapies. Neural stem cells (NSCs) possess inherent tumor tropic properties that enable them to overcome many obstacles of drug delivery that limit effective chemotherapy strategies for breast cancer. We report that increased NSC tropism to breast tumor cell lines is strongly correlated with the invasiveness of cancer cells. Interleukin 6 (IL-6) was identified as a major cytokine mediating NSC tropism to invasive breast cancer cells. We show for the first time in a preclinical mouse model of metastatic human breast cancer that NSCs preferentially target tumor metastases in multiple organs, including liver, lung, lymph nodes, and femur, versus the primary intramammary fat pad tumor. For proof-of-concept of stem cell-mediated breast cancer therapy, NSCs were genetically modified to secrete rabbit carboxylesterase (rCE), an enzyme that activates the CPT-11 prodrug to SN-38, a potent topoisomerase I inhibitor, to effect tumor-localized chemotherapy. In vitro data demonstrate that exposure of breast cancer cells to conditioned media from rCE-secreting NSCs (NSC.rCE) increased their sensitivity to CPT-11 by 200-fold. In vivo, treatment of tumor-bearing mice with NSC.rCE cells in combination with CPT-11 resulted in reduction of metastatic tumor burden in lung and lymph nodes. These data suggest that NSC-mediated enzyme/prodrug therapy may be more effective and less toxic than currently available chemotherapy strategies for breast cancer metastases. STEM CELLS 2012; 30:314–325.

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