Understanding the cancer stem cell

Abstract

The last 15 years has seen an explosion of interest in the cancer stem cell (CSC). Although it was initially believed that only a rare population of stem cells are able to undergo self-renewing divisions and differentiate to form all populations within a malignancy, a recent work has shown that these cells may not be as rare as thought first, at least in some malignancies. Improved experimental models are beginning to uncover a less rigid structure to CSC biology, in which the concepts of functional plasticity and clonal evolution must be incorporated into the traditional models. Slowly the genetic programmes and biological processes underlying stem cell biology are being elucidated, opening the door to the development of drugs targeting the CSC. The aim of ongoing research to understand CSCs is to develop novel stem cell-directed treatments, which will reduce therapy resistance, relapse and the toxicity associated with current, non-selective agents.

Figure 1

The cancer stem cell theory of tumour development and relapse initiation. An initial oncogenic event (solid arrow) occurring in a normal cell may create a precancerous cell, or directly result in malignant transformation. The oncogenic event is likely to require a number of supporting genetic/epigenetic events (hashed arrows). By the point of clinical diagnosis, the heterogeneous tumour contains cells which have, or are able to activate their stem cell programme and may be able to evade standard therapy. Any cancer stem cells evading therapy are able to divide and differentiate to repopulate the tumour.

Figure 2

After oncogenesis, induced by an initial event (solid arrow) with or without supporting events (hashed arrow), cells differentiate to form a heterogeneous tumour. Two models have been proposed to explain this (A and B). The process of clonal evolution (C) is likely to underlie the ongoing development of certain tumour characteristics such as drug resistance. (A) Stochastic model. Variations in phenotype and biology result from intrinsic and extrinsic factors including niche interactions (=) and intercellular signalling (▴). These signals may be available to any cell at a particular time, with the correct combination of factors able to initiate the CSC programme, and therefore self-renewal (curved arrows) in any member of the population. (B) Hierarchy model. A tumour shows a hierarchy analogous to the normal tissue hierarchy, with a restricted pool of cells showing self-renewal (curved arrows) and differentiation potential. Differentiated tumour cells form the bulk of the tumour mass but are unable to self-renew. (C) Clonal evolution. An ongoing process, beginning before the clinical presentation, wherein sequential genetic and epigenetic changes result in a polyclonal population with differing survival potential under the selective pressure of therapy. Clonal evolution may be seen within tumours following either the stochastic or hierarchy model.