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Sensitivity of a novel model of mammary cancer stem cell-like cells to TNF-related death pathways

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Abstract

Cancer stem cells (CSC) are resistant to radiation and chemotherapy and play a significant role in cancer recurrence and metastatic disease. It is therefore important to identify alternative strategies, such as immunotherapies that can be used to control this refractory population. A CD44+CD24−/low subpopulation of cells within the B6 PyMT-MMTV transgenic mouse-derived AT-3 mammary carcinoma cell line was identified, which had CSC-like characteristics, including pluripotency and a resistance to chemo- and radiotherapy. Therefore, unlike xenograph models that require immunocompromised settings, this novel system may provide a means to study immune-mediated responses against CSC-like cells. The immunobiology of the AT-3 CSC-like cell population was studied by their surface molecule expression profile and their sensitivity to specified cell death pathways. Comparable levels of Rae-1, CD155, CD54 and higher levels of Fas and DR5 were expressed on the AT-3 CSC-like cells compared to non-CSC-like tumor cells. Expression correlated with an in vitro sensitivity to cell death by NK cells or through the ligation of the death receptors (Fas or DR5), by their ligands or anti-Fas and anti-DR5 mAbs. Indeed, compared to the rest of the AT-3 tumor cells, the CD44+CD24−/low subpopulation of cells were more sensitive to both Fas- and TRAIL-mediated cell death pathways. Therefore, despite the refractory nature of CSC to other conventional therapies, these CSC-like cells were not inherently resistant to specified forms of immune-mediated cell death. These results encourage the continued investigation into immunotherapeutic strategies as a means of controlling breast CSC, particularly through their cell death pathways.

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Acknowledgments

We would like to thank members of the Flow Cytometry core facility for their patience in obtaining the high number of CSC required for these investigations. This work is supported by the National Breast Cancer Foundation (Australia) and the Cancer Council of Victoria.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Cancer Immunology Research Program, Peter MacCallum Cancer Centre, Locked Bag#1, A’Beckett Street, Melbourne, VIC, 8006, Australia

    Ming Li, Deborah A. Knight, Mark J. Smyth & Trina J. Stewart

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  1. Ming Li
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  2. Deborah A. Knight
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  3. Mark J. Smyth
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  4. Trina J. Stewart
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Correspondence to Trina J. Stewart.

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Li, M., Knight, D.A., Smyth, M.J. et al. Sensitivity of a novel model of mammary cancer stem cell-like cells to TNF-related death pathways. Cancer Immunol Immunother 61, 1255–1268 (2012). https://doi.org/10.1007/s00262-012-1200-1

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  • DOI: https://doi.org/10.1007/s00262-012-1200-1

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