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
Normal tissue-specific stem cells crossreact with their microenvironment in a bidirectional manner during normal development, as well as in responses to pathological insults. A developing tumour also recruits a multitude of cell types to make up the diverse microenvironment via neovascularization through interactions between the tumour cells and their niche (Polyak et al., 2009). In addition to genetic mutations, recent studies have implicated epigenetic alterations driven by signals from the tumour microenvironment in tumour development and progression (Baylin and Ohm, 2006; Korkaya et al., 2011a). The co-evolution of tumours and the niche may result from genetic and epigenetic changes caused by the reciprocal interactions within this microenvironment (Ma et al., 2009; Polyak et al., 2009).
In recent years, functional characterization of CSCs (in multiple solid tumours) has indeed reinvigorated the ‘seed and soil’ concept first proposed by Paget, which suggests that tumour seeds must first find favourable soil in order to establish a viable metastasis (Paget et al., 1989). This concept is well supported by many studies exploring the significance of the microenvironment in cancer progression (Littlepage et al., 2005; Albini and Sporn, 2007). By definition, a CSC must be capable of initiating tumours when inoculated into experimental animals at limiting dilutions (Clarke et al., 2006; Burness and Sipkins, 2010). CSCs, like their normal counterparts, are also influenced by bidirectional interactions with their niche, which comprises a diversity of cell types and associated signalling pathways (Calabrese et al., 2007; Vermeulen et al., 2008). Thus, identification of signals originating from the microenvironment may provide an attractive molecular target for CSC-specific therapeutics (Korkaya et al., 2011a).
The breast cancer stroma, like that of other solid tumours, contains an array of cell types, including mesenchymal cells, endothelial cells, lymphocytes, macrophages, neutrophils, fibroblasts and pericytes, which interact with tumour cells via chemokine networks (Jones and Wagers, 2008). The role of these cells in the development of the tumour has been extensively studied, and recently the importance of multipotent mesenchymal cells resident in the tumour microenvironment known as mesenchymal stem cells (MSCs) has been widely recognized (Bhowmick et al., 2004; Arendt et al., 2010; Liu et al., 2011; Yan et al., 2012). MSCs have been defined as multipotent cells that have the ability to differentiate into multiple lineages, including bone, cartilage, stroma, adipose tissue, connective tissue, muscle and tendon (Pittenger et al., 1999; Deans and Moseley, 2000). MSCs can secrete various factors and function in a wide range of physiological responses, such as homing to the site of injury, suppressing immune reactions and repairing and regenerating damaged tissues (Pittenger et al., 2002; Chamberlain et al., 2007; Xia et al., 2012). MSCs are considered to be integral components of the cancer stroma in experimental as well as clinical settings (Chamberlain et al., 2007; Karnoub et al., 2007). Interestingly, disseminated tumour cells from the primary tumour home to microanatomical areas surrounded by MSCs – a process that may contribute to the metastatic process (Trumpp and Wiestler, 2008). These micrometastatic CSCs might recapitulate tumours in distant organs by utilizing microenvironmental signals (Croker and Allan, 2008). A recent study has reported that the homing and engraftment of both the normal HSCs and leukaemic stem cells require specialized microenvironments of bone marrow (i.e. the periendosteal region) (Sipkins et al., 2005). On the whole, the importance of the CSC niche in regulating the fate of CSC supports the concept that targeting the unique microenvironment of CSCs may represent a compelling therapeutic strategy.
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