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NPJ Breast Cancer. 2017 Apr 19;3:14. doi: 10.1038/s41523-017-0012-z. eCollection 2017.

Cell state plasticity, stem cells, EMT, and the generation of intra-tumoral heterogeneity.

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The Salk Institute for Biological Studies, 10010 N. Torrey Pines Road, La Jolla, CA 92037 USA.
Huntsman Cancer Institute, The University of Utah, 2000 Circle of Hope, Salt Lake City, UT 84112 USA.


Cellular heterogeneity in cancer represents a significant challenge. In order to develop effective and lasting therapies, it is essential to understand the source of this heterogeneity, and its role in tumor progression and therapy resistance. Here, we consider not only genetic and epigenetic mechanisms, but also inflammation and cell state reprogramming in creating tumor heterogeneity. We discuss similarities between normal mammary epithelial developmental states and various breast cancer molecular sub-types, and the cells that are thought to propagate them. We emphasize that while stem cell phenotypes and mesenchymal character have often been conflated, existing data suggest that the combination of intrinsic genetic and epigenetic changes, and microenvironmental influences generate multiple types of tumor propagating cells distinguishable by their positions along a continuum of epithelial to mesenchymal, stem to differentiated and embryonic to mature cell states. Consequently, in addition to the prospect of stem cell-directed tumor therapies, there is a need to understand interrelationships between stem cell, epithelial-mesenchymal, and tumor-associated reprogramming events to develop new therapies that mitigate cell state plasticity and minimize the evolution of tumor heterogeneity.

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