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Review
. 2017 Oct;14(10):611-629.
doi: 10.1038/nrclinonc.2017.44. Epub 2017 Apr 11.

EMT, CSCs, and drug resistance: the mechanistic link and clinical implications

Tsukasa Shibue  1   2 , Robert A Weinberg  1   2   3
Affiliations
Review

EMT, CSCs, and drug resistance: the mechanistic link and clinical implications

Tsukasa Shibue et al. Nat Rev Clin Oncol. 2017 Oct.

Abstract

The success of anticancer therapy is usually limited by the development of drug resistance. Such acquired resistance is driven, in part, by intratumoural heterogeneity - that is, the phenotypic diversity of cancer cells co-inhabiting a single tumour mass. The introduction of the cancer stem cell (CSC) concept, which posits the presence of minor subpopulations of CSCs that are uniquely capable of seeding new tumours, has provided a framework for understanding one dimension of intratumoural heterogeneity. This concept, taken together with the identification of the epithelial-to-mesenchymal transition (EMT) programme as a critical regulator of the CSC phenotype, offers an opportunity to investigate the nature of intratumoural heterogeneity and a possible mechanistic basis for anticancer drug resistance. In fact, accumulating evidence indicates that conventional therapies often fail to eradicate carcinoma cells that have entered the CSC state via activation of the EMT programme, thereby permitting CSC-mediated clinical relapse. In this Review, we summarize our current understanding of the link between the EMT programme and the CSC state, and also discuss how this knowledge can contribute to improvements in clinical practice.

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Conflict of interest statement

Competing interests statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1. Morphological and physiological changes associated with the epithelial-to-mesenchymal transition (EMT)
a ∣ A schematic overview of EMT-associated changes in cell physiology. Activation of the EMT programme induces profound changes in various aspects of cell morphology and physiology, most notably in cell cell junctions, cytoskeletal composition, cellular interactions with the extracellular matrix (ECM), and cell polarity. b ∣ Summary of the physiological outcomes of EMT in carcinoma: the profile of the shapes illustrates how the extent of invasiveness, the tumour-initiating ability, and degree of drug resistance change across the spectrum of EMT-programme activation. Carcinoma cells invade surrounding tissues either by individual-cell migration or multicellular migration (as cell cohorts). In general, migration of individual cells, which requires the strong activation of the EMT programme, results in faster tissue invasion than occurs by multicellular migration, the mode of migration that predominates when the EMT programme is only weakly activated. The tumour-initiating ability of carcinoma cells is also affected by the level of EMT-programme activation, peaking at an intermediate level of EMT in these cells; extensive EMT activation is usually detrimental to tumour-initiating ability. The drug resistance of carcinoma cells also seems to be maximal at an intermediate level of EMT-programme activation, but plateaus (rather than declines) with further activation of this programme,. MET, mesenchymal-to-epithelial transition.
Figure 2
Figure 2. The patterns of epithelial-to-mesenchymal transition (EMT)-programme activation during carcinoma progression
a ∣ In primary tumours, activation of the EMT programme enables particular carcinoma cells to invade the surrounding stroma; some of these cells eventually enter the systemic circulation. b ∣ Circulating tumour cells can demonstrate epithelial and/or mesenchymal traits. Indeed, cancer cells in the circulation, whether solitary or in clusters, frequently exhibit signs of at least partial EMT. c ∣ Reversal of the EMT process — that is, activation of the mesenchymal-to-epithelial transition (MET) programme — following dissemination of carcinoma cells to distant tissues seems to be critical for the outgrowth of metastases from many types of carcinoma,.
Figure 3
Figure 3. The contribution of the tumour microenvironment to the activation of the epithelial-to-mesenchymal transition (EMT) programme
a ∣ Carcinoma-associated fibroblasts (CAFs) are frequently observed at the invasive front of tumours, and probably make an important contribution to the induction of EMT in nearby carcinoma cells by secreting various cytokines and enzymes. b ∣ The tumour microenvironment is often characterized by chronic inflammation; both soluble and cellular mediators of tumour-associated inflammation can contribute to the induction of an EMT programme in carcinoma cells. c ∣ Hypoxia is another common characteristic of the tumour microenvironment. HIF-1, the central mediator of the responses to tumour-associated hypoxia, has been demonstrated to trigger an EMT process, involving the prototypic transcription factors ZEB1/2, TCF-3, and TWIST1, in carcinoma cells. CCL18, C–C-motif chemokine 18; HGF, hepatocyte growth factor; HIF-1, hypoxia-inducible factor 1; MMP, matrix metalloproteinase; TGFβ, transforming growth factor β; TNFα, tumour necrosis factor α; uPA, urokinase plasminogen activator.
Figure 4
Figure 4. The mechanistic link between the epithelial-to-mesenchymal transition (EMT) programme and cancer stem cell (CSC) status
a ∣ The EMT programme enables carcinoma cells to interact productively with the surrounding extracellular matrix (ECM) proteins. Such changes in cell interactions with the ECM, in turn, reinforce the tumour-initiating ability of cancer cells with an active EMT programme. In particular, EMT enables the efficient development by carcinoma cells of integrin-containing mature adhesion plaques, and these plaques, once formed, trigger signalling pathways critical to the proliferation of cancer cells, such as those involving focal adhesion kinase (FAK) and extracellular signal-related kinase (ERK). b ∣ The activation of the EMT programme results in the establishment of several autocrine signalling loops, including the transforming growth factor β (TGFβ) and canonical and/or noncanonical Wnt pathways. These signalling loops contribute to the CSC properties of cells with an active EMT programme. BMPs, bone morphogenetic proteins; DKK1, Dickkopf-related protein 1; FLPs, filopodium-like protrusions; SFRP1, secreted Frizzled-related protein 1.
Figure 5
Figure 5. The mechanism underlying epithelial-to-mesenchymal transition (EMT)-dependent acquisition of therapeutic resistance
a ∣ EMT-associated downregulation of multiple apoptotic signalling pathways, enhanced drug efflux, and slow cell proliferation all contribute to enhance the general resistance of carcinoma cells to anticancer drugs. b ∣ In addition, the EMT-associated transcription factor Snail induces the expression of the AXL receptor tyrosine kinase on the surface of carcinoma cells. AXL signalling, triggered by the binding of its ligand growth arrest-specific protein 6 (GAS6), enables Snail-expressing carcinoma cells to override cytostatic effects of EGFR blockade with small-molecule inhibitors (such as erlotinib) or antagonistic monoclonal antibodies. c ∣ The EMT programme also activates several processes that enable carcinoma cells to evade the lethal effect of cytotoxic T cells. These changes include elevated expression of programmed cell death 1 ligand 1 (PD-L1), which binds to the programmed cell death protein 1 (PD-1) inhibitory immune-checkpoint receptor that is expressed by cytotoxic T cells and thereby diminishes their function; and increased secretion of thrombospondin-1 (TSP-1), which promotes the development of regulatory T cells within the tumour microenvironment that ultimately suppress the activity of cytotoxic T cells.
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