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Retention of Intrinsic Stem Cell Hierarchies in Carcinoma-Derived Cell Lines

Institute for Cell and Molecular Science, Queen Mary University of London, Whitechapel, London, United Kingdom

Requests for reprints: Ian C. Mackenzie, Institute for Cell and Molecular Science, Queen Mary University of London, 2 Newark Street, Whitechapel, London E1 2AT, United Kingdom. Phone: 0207-882-7159; Fax: 0207-882-7171; E-mail: i.c.mackenzie{at}qmul.ac.uk.

Recent work indicates that the growth and behavior of cancers are ultimately determined by a small subpopulation of malignant stem cells and that information about the properties of these cells is urgently needed to enable their targeting for therapeutic elimination. A key feature of normal stem cells is their asymmetrical division, the mechanism that allows stem cell self-renewal while producing hierarchies of amplifying and differentiating cells that form the bulk of the tissue. Most cancer deaths result from epithelial malignancies, but the extent to which the hierarchical proliferative stem and amplifying cell patterns of normal epithelia are actually retained in epithelial malignancies has been unclear. Here we show that even cell lines generated from carcinomas consistently produce in vitro colony patterns unexpectedly similar to those produced by the stem and amplifying cells of normal epithelia. From the differing types of colony morphologies formed, it is possible to predict both the growth potential of their constituent cells and their patterns of macromolecular expression. Maintenance of a subpopulation of stem cells during passage of cell lines indicates that the key stem cell property of asymmetrical division persists but is shifted towards enhanced stem cell self-renewal. The presence of malignant epithelial stem cells in vivo has been shown by serial transplantation of primary cancer cells and the present observations indicate that stem cell patterns are robust and persist even in cell lines. An understanding of this behavior should facilitate studies directed towards the molecular or pharmacologic manipulation of malignant stem cell survival.

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