¹Department of Pathology, McGowan Institute for Regenerative Medicine, University of Pittsburgh Medical School, Pittsburgh, PA, USA

Correspondence: Professor E Lagasse, Department of Pathology, McGowan Institute for Regenerative Medicine, University of Pittsburgh Medical School, Pittsburgh, PA 15219-3130, USA. E-mail: Lagasse@pitt.edu

Received 18 September 2007; Revised 15 October 2007; Accepted 15 October 2007; Published online 8 November 2007.

Abstract

Our understanding of the role of stem cells in cancer development is evolving quickly. In the course of tumor expansion, a subpopulation of tumor cells with stem cell-like features has been noted. These cancer stem cells give rise to transit amplifying tumor cells, which comprise the majority of the tumor mass prior to terminal differentiation. Combining this finding with genetic instability, a well-known engine for cancer development and metastases, a new model emerges for cancer where normal stem cells and their cellular pathway acquire stochastic malignant abilities. In this model, when cancer stem cells self-renew, many genetic variants are produced. Just as microbes 'learn' to defeat antibiotics, genetically heterogeneous cancer stem cells may possibly acquire resistance to various chemotherapeutic approaches. Drug-resistant microorganisms selected by spontaneous mutation of bacterial DNA may not be so different than the drug-resistant and genetically instable cancer stem cells recurring after chemotherapeutic treatment. In this gloomy view of cancer, cancer stem cells with genetic instability can be considered as 'the best vehicle with the best engine', a formidable challenge for the future development of new anticancer therapies.