Review
Cancer stem cells: Back to Darwin?

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Abstract

Current models of cancer propagation or ‘stem’ cells pay scant attention to the evolutionary dynamics of cancer or to the underlying genetic, mutational drivers. Recent genetic studies on acute lymphoblastic leukaemia at the single cell level reveal a complex non-linear, branching clonal architecture—with sub-clones having distinctive genetic signatures. Most cancers appropriately interrogated are found to have intra-clonal genetic heterogeneity indicative of divergent clonal evolution. These data further suggest that clonal architecture might be driven by genetic heterogeneity of propagating or ‘stem’ cells. When assayed for leukaemic regeneration in NOD/SCID/γ mice, genetically diverse ‘stem’ cells read-out, broadly reflecting the clonal architecture. This has suggested a ‘back to Darwin’ model for cancer propagation. In this, cells with self-renewal potency or ‘stem-ness’ provide genetically diverse units of evolutionary selection in cancer progression. The model has significant implications for targeted cancer therapy.

Section snippets

Cancer stem cells: now you see them, now you do not

The concept of cancer stem cells (CSCs) has sparked excitement and controversy in equal measure. The arguments touch on fundamental issues of cancer biology but also have potentially critical implications for therapy. The history of the idea has been chronicled elsewhere [1]: suffice to say that the development of the NOD/SCID in vivo assay for human leukaemic stem cells by John Dick and colleagues [2], [3] resurrected a stalled debate and sparked the current explosion of interest.

The concept

The missing link?

A particular anomaly in the cancer stem cell debate is that much of the underlying genetics of cancer tends to be ignored. Cancer development is fundamentally a dynamic, Darwinian process of mutational diversification and clonal selection [25], [26], [27], [28]. In this context, mutant cells with self-renewal or ‘stem’ cells could well be the crucial units of selection. But, in this context, they simply cannot be a fixed entity. They can be anticipated to differ in frequency and in phenotypic

Genetic diversity of cancer stem cells

Recent genome-wide sequencing has revealed that most epithelial carcinomas have extraordinarily complex genetic landscapes in which an undefined number of functionally relevant ‘driver’ mutations lie embedded in a sea of ‘passenger’ mutations or genetic noise [36], [37]. Distilling from this complexity the timing and sequence of critical genetic lesions is an enormous challenge. Also, these genomic portraits are usually presented as if they reflect the singular genotype of the particular cancer

A ‘back to Darwin’ model for cancer propagation

What kind of model of CSC then sits most comfortably with both the genetics and evolutionary biology of cancer? The three ideas preferred (Fig. 1), I suggest, are each inadequate as strict and exclusive alternatives. CSC could, under some circumstances, be developmentally positioned at the apex of a hierarchy but there is no reason to suppose that hierarchical structures are inherently stable and maintained with cancer progression. Some degree of stochastic and seemingly random variation in

Conflict of interest

The author declares that there is no conflict of interest.

Acknowledgements

The author is supported by Leukaemia & Lymphoma Research (UK) and the Kay Kendall Leukaemia Fund (UK).

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