Cancer stem cells: problems for therapy?

Abstract

Many, if not all, tumours contain a sub-population of self-renewing and expanding stem cells known as cancer stem cells (CSCs). The symmetric division of CSCs is one mechanism enabling expansion in their numbers as tumours grow, while epithelial-mesenchymal transition (EMT) is an increasingly recognized mechanism to generate further CSCs endowed with a more invasive and metastatic phenotype. Putative CSCs are prospectively isolated using methods based on either a surface marker or an intracellular enzyme activity and then assessed by a 'sphere-forming' assay in non-adherent culture and/or by their ability to initiate new tumour growth when xenotransplanted into immunocompromised mice-hence, these cells are often referred to as tumour-propagating cells (TPCs). Cell sub-populations enriched for tumour-initiating ability have also been found in murine tumours, countering the argument that xenografting human cells merely select human cells with an ability to grow in mice. Cancer progression can be viewed as an evolutionary process that generates new/multiple clones with a fresh identity; this may be a major obstacle to successful cancer stem cell eradication if treatment targets only a single type of stem cell. In this review, we first briefly discuss evidence that cancer can originate from normal stem cells or closely related descendants. We then outline the attributes of CSCs and review studies in which they have been identified in various cancers. Finally, we discuss the implications of these findings for successful cancer therapies, concentrating on the self-renewal pathways (Wnt, Notch, and Hedgehog), aldehyde dehydrogenase activity, EMT, miRNAs, and other epigenetic modifiers as potential targets for therapeutic manipulation.

Prognostic impact of the expression of ALDH1 and SOX2 in urothelial cancer of the upper urinary tract

“…44 On the basis of the abilities for tumor initiation, self-renewal and differentiation, various putative cancer stem-like cell/tumor-initiating cell markers have been used. 45 As these markers (such as side population, CD44 þ /CD24-, CD133 þ , ALDH1, SOX2, Oct3/4, etc.) show distinct properties of cancer stem cells, tumor tissues can show heterogeneity when multiple markers are examined.…”

Cancer cells in epithelial-to-mesenchymal transition and tumor-propagating–cancer stem cells: distinct, overlapping or same populations

“…Other properties have been ascribed to them, such as resistance to chemotherapy and irradiation, which could, in part, result from their assumed quiescence (Kong et al, 2010;Alison et al, 2011). However, breast cancers treated by chemotherapy display a drop rather than an increase in CD44/CD24-high cells (Aulmann et al, 2010).…”

“…We do not use the term CSC-tumorinitiating cell, as this term (Mani et al, 2008) could lead to a confusion with the cells in which the cancer was initiated in vivo. The highly productive concept of CSC-TPC (Lapidot et al, 1994;Clarke and Fuller, 2006;Kelly et al, 2007;Hong et al, 2008;Alison et al, 2011) has represented a major advance in cancer research.…”

Targeted therapy aimed at cancer stem cells: Wilms’ tumor as an example

“…3). There are several mechanisms that may mediate CSC resistance to chemotherapy and radiation, these include: the quiescent nature of CSCs shown in several malignancies, their presence in hypoxic niches into which therapies fail to penetrate, the up-regulation of DNA damage response mechanisms by these cells, and their increased drug efflux capacity [41]. Identifying the CSCs and understanding the mechanisms involved may assist unraveling new therapeutic targets and creating new improved specific treatments (Fig.…”