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Translational and Clinical Research
Article first published online: 18 JAN 2012
Copyright © 2011 AlphaMed Press
Volume 30, Issue 2, pages 314–325, February 2012
How to Cite
Zhao, D., Najbauer, J., Annala, A. J., Garcia, E., Metz, M. Z., Gutova, M., Polewski, M. D., Gilchrist, M., Glackin, C. A., Kim, S. U. and Aboody, K. S. (2012), Human Neural Stem Cell Tropism to Metastatic Breast Cancer. STEM CELLS, 30: 314–325. doi: 10.1002/stem.784
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.
- Issue published online: 18 JAN 2012
- Article first published online: 18 JAN 2012
- Accepted manuscript online: 14 NOV 2011 03:14PM EST
- Manuscript Accepted: 25 OCT 2011
- Manuscript Received: 6 JUN 2011
- Department of Defense-Breast Cancer Concept Award. Grant Number: BC087425
- Rosalinde and Arthur Gilbert Foundation
- STOP CANCER Foundation
- CIRM Stem Cell Research Biotechnology Training Program
- CSULB. Grant Number: TB1-01182
- Breast cancer metastasis;
- Cancer invasion;
- Neural stem cells;
- Stem cell tropism;
- Stem cell-mediated therapy;
- Gene therapy
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.