Review
Cancer stem cells and epithelial–mesenchymal transition: Concepts and molecular links

https://doi.org/10.1016/j.semcancer.2012.04.001Get rights and content

Abstract

The epithelial–mesenchymal transition (EMT) confers mesenchymal properties on epithelial cells and has been closely associated with the acquisition of aggressive traits by carcinoma cells. EMT programs are orchestrated by a set of pleiotropically acting transcription factors (TFs). The actions of these EMT-TFs enable the early steps of metastasis: local invasion and subsequent dissemination of carcinoma cells to distant sites. However, in most malignancies, the subsequent outgrowth of micrometastatic deposits into macroscopic metastases has the greatest impact on clinical progression. Such metastatic “colonization” reflects the ability of disseminated tumor cells to adapt to a foreign tissue microenvironment. The outgrowth of a metastasis is also thought to be associated with self-renewal, the defining cellular trait of cancer stem cells (CSCs), also termed tumor-initiating cells. Importantly, molecular links between EMT-TFs and self-renewal have emerged, suggesting that EMT programs play critical roles both early and late in the metastatic cascade. The genetic and epigenetic mechanisms that regulate the activation of EMT-TFs and the traits they induce are areas under intensive investigation. Such studies may provide new opportunities for therapeutic intervention and help to overcome tumor heterogeneity and therapeutic resistance.

Introduction

In many tumor types, the presence of distant metastases marks stage IV and indicates, almost invariably, incurable disease and relatively short overall survival [1]. On a biological level, our understanding of metastasis has been greatly advanced by viewing it as a series of distinct steps that together comprise the “invasion–metastasis cascade” [2], [3]. As the first step, cancer cells in the primary tumor acquire the ability to invade into the surrounding tissue: in carcinomas, this requires breaching of the basement membrane that confines the epithelial compartment. Tumor cells then must gain access to lymphatic and blood vessels, enter into the lumina of these vessels (intravasation), survive transport through these vessels, and exit from the vasculature (extravasation). Finally, in a process often termed colonization, small cell clumps or singly disseminated tumor cells (micrometastases) must acquire the ability to survive and proliferate in the microenvironment of a foreign tissue in order to form macroscopic metastases.

The complexity of the metastatic process raises a major conceptual problem: how do tumor cells acquire all of the individual properties that together comprise the metastatic cascade? A mechanistic solution to this conundrum is provided by the existence of a multi-faceted cell-biological program that enables carcinoma cells to acquire a number of the traits required to accomplish the initial steps of metastatic cascade. Hence, rather than being pieced together one-by-one, many of the cell-biological traits needed to complete the metastatic cascade can be choreographed by small numbers of centrally acting, pleiotropic regulators; this greatly simplifies how we conceptualize this complex multi-step process. Thus, the epithelial–mesenchymal transition (EMT) represents a cellular program that confers on neoplastic epithelial cells the biological traits needed to accomplish most of the steps of the invasion–metastasis cascade [4], [5], [6].

In this review, we discuss the mechanisms through which EMT programs enable different steps of the metastatic cascade and the emerging connection between EMT programs and the traits displayed by CSCs. More specifically, we focus on the dual roles of certain transcription factors (TFs) that orchestrate EMT programs (EMT-TFs) and thereby impart traits required both for physical dissemination and entrance into the CSC state. Finally, we discuss the relevance of these connections between EMT and self-renewal for developing new strategies to overcome therapeutic resistance.

Section snippets

EMT programs and the early steps of metastasis

EMT programs were first observed in the context of embryonic development, where they function as transdifferentiation programs that effect critical morphogenetic steps, such as gastrulation and neural crest formation [7], [8]. Specifically, EMTs generate mesenchymal cell types from epithelial and endothelial precursors. These epithelial–mesenchymal conversions are crucial for cell movements that take place during morphogenesis, such as neural crest migration. This explains why the EMTs

Cancer stem cells and the metastatic cascade

The last step of the invasion–metastasis cascade – colonization – is likely to require adaptation of a disseminated cancer cells to the microenvironment of a foreign tissue. This represents a complex topic in and on itself and will not be covered in this review [18]. It seems unlikely that these adapative steps are enabled by EMT programs and thus may require additional changes to cells.

In addition, the trait of self-renewal also seems to be essential. In the narrowest sense, self-renewal

Conclusion and perspectives

One key implication for the development of therapies directed against high-grade malignancies is the necessity to identify agents and therapeutic strategies that specifically target CSCs, since these appear to be major sources of therapeutic resistance and tumor regrowth. Some initial steps have been made in this direction [87], and indeed many others are likely to follow. This strategy, attractive as it is in concept, may be complicated by one critical problem implicit in the earlier

Conflict of interest

The authors declare no conflict of interest.

Acknowledgements

The authors thank members of the Weinberg lab for insightful discussion. Research in the Weinberg lab is supported by the NIH/NCI (R.A.W.: CA12515 and DE020817), MIT Ludwig Center for Molecular Oncology (R.A.W.), Ludwig Fellowship for Metastasis Research (C.S.), Breast Cancer Research Foundation (R.A.W.), Harvard Breast Cancer SPORE (R.A.W.) and DoD BCRP Idea Award (R.A.W.).

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