EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer

Abstract

Tumors are cellularly and molecularly heterogeneous, with subsets of undifferentiated cancer cells exhibiting stem cell-like features (CSCs). Epithelial to mesenchymal transitions (EMT) are transdifferentiation programs that are required for tissue morphogenesis during embryonic development. The EMT process can be regulated by a diverse array of cytokines and growth factors, such as transforming growth factor (TGF)-beta, whose activities are dysregulated during malignant tumor progression. Thus, EMT induction in cancer cells results in the acquisition of invasive and metastatic properties. Recent reports indicate that the emergence of CSCs occurs in part as a result of EMT, for example, through cues from tumor stromal components. Recent evidence now indicates that EMT of tumor cells not only causes increased metastasis, but also contributes to drug resistance. In this review, we will provide potential mechanistic explanations for the association between EMT induction and the emergence of CSCs. We will also highlight recent studies implicating the function of TGF-beta-regulated noncoding RNAs in driving EMT and promoting CSC self-renewal. Finally we will discuss how EMT and CSCs may contribute to drug resistance, as well as therapeutic strategies to overcome this clinically.

Figure 1

(Panel A) EMT in the context of pathophysiological conditions, such as during the repair of injured tissue. Tissue injury promotes the recruitment of mesenchymal stem cells (MSCs), which can secrete EMT-inducing cytokines such as TGF-β, resulting in dissolution of cell-cell contacts and accompanying morphogenetic changes. In cooperation with additional EMT inducers such as Wnt, epithelial cells transform to a fully mesenchymal phenotype, associated with increased motility and invasiveness through basement membranes.

Figure 2

(Panel A) Cancer stem cells (CSCs) with tumor-initiating capability can be identified by the expression of a distinct set of marker proteins, such as the ABC family transporter ABCG2, CD133, EpCAM or ALDH1. These CSCs can self-renew and differentiate into a number of cell types to generate the heterogeneity of the originating tumor. (Panel B) EMT can induce a CSC-like phenotype. Inducers of EMT such as TGF-β, Wnt or Notch cause cells to acquire a CD44^high CD24^low phenotype, reminiscent of breast CSCs.

Figure 3

(Panel A) TGF-β induced cell death can be blocked by concomitant upregulation of microRNAs. Mir-17–92 can block expression of the pro-apoptotic protein Bim. Pro-survival PI3K signaling can be activated ablation of PTEN expression via mir-216a and mir-217a. (Panel B) Regulation of EMT and CSC “stemness” by microRNAs. TGF-β-induced EMT can be potentiated by expression of mir-155, which targets RhoA, resulting in breakdown of tight junctions. TGF-β-mediated repression of mir-200 family members and mir-205 results in increased Zeb protein expression, leading to E-cadherin repression and breakdown of adherens junctions. Zeb expression also represses mir-200/mir-205 expression, which is associated with CSC renewal via upregulation of the mir-200 targets Sox2 and Klf4. Finally, TGF-β can upregulate the activity of HMGA2, which can aid in E-cadherin repression. HMAG2 is negatively regulated by the let-7 microRNA, a microRNA that can block the self-renewal of breast CSCs. Thus, let-7 mediated depletion of HMGA2 provides a link between TGF-β signaling, EMT and the emergence of CSCs.

Figure 4

(Panel A) Effective cancer therapy may require combination treatments. A putative “Drug X” may selectively kill bulk tumor cells that are well-differentiated. This could be combined with “Drug Y” to kill cells with a CSC phenotype. Cancer cells treated with Drug X may undergo EMT to acquire CSC-like properties, in which case co-administration of Drug Y would kill both pre-existing CSCs and those that emerge via treatment with Drug X. (Panel B) A novel strategy to eliminate CSCs could be to induce their differentiation, which could lead to intrinsic apoptotic cell death or could sensitize the resulting differentiated cells to existing therapies. This differentiation switch could be facilitated with compounds such as salinomycin, HDAC inhibitors or TGF-β pathway inhibitors. Finally, differentiation could also be promoted by administration of therapeutic microRNAs, such as mir-200 family members.