Principles of stem cell biology and cancer: future applications and therapeutics. Edited by T. Regad, T. J. Sayers and R. C. Rees. John Wiley & Sons (2015)
Part II. Cancer stem cells
Modern anticancer drug discovery began in the mid-19th century, with cytotoxic chemotherapeutic agents targeting cancer cells with high proliferative rates. It is well known, however, that cancers are composed of heterogeneous cell types (Virchow, 1855; Cogngeim, 1867), suggesting that the nature of the target cells suffering the effects of the oncogenic activity might play an important role in the control of oncogenesis. In contrast with conventional views of cancer, in which all cells are tumourigenic, the cancer stem cell (CSC) hypothesis proposed a decade ago (Reya et al., 2001; Pardal et al., 2003) that tumours contain a subset of cells that both self-renew and give rise to a differentiated progeny. While many aspects of this theory remain speculative and are still evolving, CSCs are viewed as those cells at the apex of the tumour hierarchy, highlighting the role of aberrant differentiation in tumourigenesis. In analogy to normal adult tissue stem cells, CSCs are the driving force of the tumour. In particular, CSCs are usually defined by two minimal properties. The first is the ability to regrow the tumour from which they were isolated or identified, which implies that the tumour-initiating cells can only be defined experimentally in vivo. The use of serial transplantation to validate a candidate CSC subpopulation allows the capability to recapitulate the heterogeneity of the primary tumour to be monitored. Both xenoand syngeneic transplantations might, however, misrepresent the real network of interactions with diverse support, such as fibroblasts, endothelial cells, macrophages, mesenchymal stem cells and many of the cytokines and receptors involved in these interactions (La Porta, 2009). As a consequence of this, contrasting results have appeared in the literature for the frequency of CSCs in xenograft tumours. In a recent paper, our group suggested that the number of CSCs should not be stated in absolute terms, but only relative to the animal model used (La Porta, 2009). The second property necessary to define CSCs is the multipotency of lineage differentiation. In addition to these properties, there are at least two aspects of CSCs that are not completely clear: their origin and their frequency in vivo. The use of the correct panel of markers is necessary to demonstrate their origin. The second issue is particularly difficult to address, for two obvious reasons: if CSCs are few, there are problems connected to the sensitivity of the technique and/or the small portion of biopsy analysed. Moreover, the behaviour and frequency of tumour-initiating cells in vivo and in animal models could be influenced by various environmental factors. For example, haematopoietic stem cells grow asymmetrically, and the probability of asymmetric cell division depends on the presence of certain cytokines (Brummendorf et al., 1998; Takano et al., 2004; La Porta, 2010). Interestingly, haematopoietic stem cells, along with oligodendrocyte precursors, show an intrinsic property of asymmetric growth and appear to be regulated only in a permissive way by extrinsic factors (Gao and Raff, 1997; Brummendorf et al., 1998). Furthermore, some proteins have been shown to be asymmetrically distributed during haematopoietic stem cell division (Fonseca et al., 2008). A recent review analysed the developmental signalling pathways involved in the self-renewal of haematopoietic stem cells, such as the Notch pathway and Wnt and TGF-Я signalling, as well as chemical regulators like retinoic acid (Zon, 2008). It is important to highlight that ‘stemness’ does not necessarily involve a set of genes common to all stem cells, since the gene expression patterns of stem cells in distinct tissues differ widely (Klein et al., 2007).
Another important aspect is the mechanism by which stem cells decide whether to remain in the niche or to leave. This could be a major factor in the balancing act between stem cell self-renewal and differentiation (Wallenfang and Matunis, 2003). In this connection, melanocyte growth is controlled by keratinocytes and melanoma seems to escape from this control through different mechanisms, including downregulation of receptors (E-cadherin, P-cadherin and desmoglein), upregulation of receptors and signalling molecules important for melanoma cell and melanoma cell – fibroblast interactions (N-cadherin, zanula occludens protein 1) and deregulation of morphogenesis (Notch receptors and their ligands). The investigation of normal melanocyte homeostasis might help us to define how melanoma and, in particular, melanoma CSCs escape the microenvironment created by epidermal keratinocytes and how they develop new cellular partners in fibroblasts and endothelial cells that support their growth and invasion (Haas and Herlyn, 2005).
Finally, the role of senescence in the dynamics of CSCs proliferation has been considered in recent years. Cancer cells are characterized by their persistent proliferation, but just like normal cells (Hayflick and Moorhead, 1961), tumour cells can go senescent, halting their growth (Di Micco et al., 2006; Collado and Serrano, 2010). The molecular basis for the induction of senescence appears to be a combination of several mechanisms, including telomerase shortening, DNA damage and oxidative stress (Collado and Serrano, 2010). It has been suggested that senescence should be present only in preneoplastic cells (Collado and Serrano, 2010), but there is evidence that senescence markers increase during tumour progression (Wasco et al., 2008). Recently, our group investigated this aspect, formulating cancer growth in mathematical terms and obtaining predictions for the evolution of senescence (La Porta et al., 2012). We also performed experiments in human melanoma cells that are compatible with the hierarchical model and showed that senescence is a reversible process, controlled by survivin (La Porta et al., 2012). Our findings show that enhancing senescence is unlikely to provide a useful therapeutic strategy for fighting cancer, unless CSCs are specifically targeted (La Porta et al., 2012). Another important result of our paper is that slightly different assay conditions lead to different CSC fractions, which can sometimes be relatively large (Quintana et al., 2008). There is, in fact, no reason to believe that the CSC population must be small. This idea comes from the analogy with tissue stem cells, which replicate homeostatically, keeping their population constant either by asymmetric division or stochastically (Clayton et al., 2007; Lopez-Garcia et al., 2010), leading to a vanishing concentration of stem cells in the total cell population. CSCs do not replicate homeostatically and therefore their population grows exponentially. Changes in assay conditions can change the duplication rate of CSCs, leading under extreme conditions (e.g. the use of matrigel, mice permissive conditions, etc.) to a relatively large concentration of CSCs, perhaps resolving previous controversies (Quintana et al., 2008, 2010; Boiko et al., 2010).
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