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
Epithelial – mesenchymal plasticity is an important concept that is critical to understanding EMT as it relates to cancer progression and metastasis. In contrast to the complete loss of epithelial markers concomitant with the acquisition of well-defined mesenchymal markers – migratory and invasive properties typical of cells that have undergone a ‘complete EMT’ (Kalluri, 2009; Nieto, 2013) – it is now evident that cancer cells that initiate an EMT programme often reside in a state in which newly acquired mesenchymal traits are expressed simultaneously with existing epithelial traits: a state often termed a ‘partial EMT’ (Nieto, 2013; Tam and Weinberg, 2013; Pattabiraman and Weinberg, 2014). Indeed, activation of the EMT programme in cancer usually results in tumour cells displaying a spectrum of phenotypes intermediate between the fully differentiated epithelial state and the completely mesenchymal state, the two opposing extremes (Tam and Weinberg, 2013). Thus, cancer cells can advance to different points along the EMT pathway (Figure 6.3). In cancer, these phenotypic shifts are initiated by a multitude of contextual signals present in the tumour microenvironment. Those cells capable of a high degree of epithelial – mesenchymal plasticity and which undergo partial EMT are the most likely to metastasize effectively, as they maintain the capacity to profoundly and reversibly change their phenotype and behaviour in order to successfully complete the various steps in the metastatic cascade. In contrast, cancer cells that undergo a complete EMT may lose the phenotypic plasticity required for tumour-initiating properties (Pattabiraman and Weinberg, 2014). Therefore, the progression of epithelial cancer cells through an EMT programme, together with the reversion of such cells to an epithelial state through MET, must be viewed as a highly plastic, dynamic process that ultimately provides epithelial cancer cells with the biological properties required for invasion and metastasis (Scheel and Weinberg, 2012).
The functional aspects of epithelial – mesenchymal plasticity rely, at least in part, on the recently elucidated connection between paracrine signals from the tumour stroma and autocrine signals produced by the cancer cells themselves (Pattabiraman and Weinberg, 2014) (Figure 6.3). Paracrine signals produced by the stroma, including ECM components, soluble factors such as TGF-β and the Wnt proteins and environmental conditions such as hypoxia and acidosis, serve to trigger the EMT programme. Autocrine signals are then produced by the tumour cells, perpetuating the presence of mesenchymal traits in the absence of further signals from the stromal compartment. The introduction of a cell-autonomous mechanism for the maintenance of mesenchymal traits provides a way for individual invading tumour cells to disseminate and produce metastases (Pattabiraman and Weinberg, 2014). Furthermore, it has been suggested that autocrine signalling loops may be important to preventing epithelial cells from activating EMT through the inhibition of EMT-promoting mediators, including TGF-β and Wnt, and that repression of these inhibitors enables pro-EMT autocrine signalling (Pattabiraman and Weinberg, 2014). The complex interplay between paracrine and autocrine signalling creates a vast array of signalling possibilities, which may dictate the extent to which cells move along the EMT continuum (Pattabiraman and Weinberg, 2014).