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Tackling the cancer stem cells — what challenges do they pose?

Abstract

Since their identification in 1994, cancer stem cells (CSCs) have been objects of intensive study. Their properties and mechanisms of formation have become a major focus of current cancer research, in part because of their enhanced ability to initiate and drive tumour growth and their intrinsic resistance to conventional therapeutics. The discovery that activation of the epithelial-to-mesenchymal transition (EMT) programme in carcinoma cells can give rise to cells with stem-like properties has provided one possible mechanism explaining how CSCs arise and presents a possible avenue for their therapeutic manipulation. Here we address recent developments in CSC research, focusing on carcinomas that are able to undergo EMT. We discuss the signalling pathways that create these cells, cell-intrinsic mechanisms that could be exploited for selective elimination or induction of their differentiation, and the role of the tumour microenvironment in sustaining them. Finally, we propose ways to use our current knowledge of the complex biology of CSCs to design novel therapies to eliminate them.

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Figure 1: Why specific targeting of CSCs is important.
Figure 2: Signalling pathways used by CSCs: distinct combinations of paracrine and juxtracrine signals induce EMT in different contexts.
Figure 3: Impact of stromal cells and secreted factors on cancer stem cells.

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Acknowledgements

The authors thank B. Bierie, J. Krall, W. Leong Tam, K. Kober and other members of the Weinberg laboratory for helpful discussions. D.R.P. was supported by a C.J. Martin Overseas Biomedical Fellowship from the National Health and Medical Research Council of Australia. The Weinberg laboratory is supported by grants from the Breast Cancer Research Foundation (BCRF), the US National Institutes of Health (NIH; U54-CA163109), the Samuel Waxman Cancer Research Foundation, the Ludwig Center for Molecular Oncology at MIT and the US Department of Defense (Grant 1210095). R.A.W. is an American Cancer Society Research Professor and a Daniel K. Ludwig Cancer Research Professor.

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Correspondence to Robert A. Weinberg.

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Pattabiraman, D., Weinberg, R. Tackling the cancer stem cells — what challenges do they pose?. Nat Rev Drug Discov 13, 497–512 (2014). https://doi.org/10.1038/nrd4253

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