Molecular requirements for epithelial–mesenchymal transition during tumor progression
Introduction
During recent years, the epithelial–mesenchymal transition (EMT), where cells undergo a developmental switch from a polarized, epithelial phenotype to a highly motile fibroblastoid or mesenchymal phenotype, has emerged as a central process during embryonic development and chronic inflammation and fibrosis, as well as cancer progression [1, 2, 3, 4, 5, 6, 7]. During metazoan development, EMTs are required for morphogenetic movements underlying parietal endoderm formation and gastrulation, as well as during the formation of a range of organs and tissues, such as the neural crest, heart, musculoskeletal system, craniofacial structures and peripheral nervous system [1]. In the context of tumorigenesis, EMT has been studied with increasing intensity in tissue culture models of epithelial cells and transgenic mouse tumor models (reviewed in [2, 3, 7, 8]). EMT can require the cooperation of oncogenic Ras or receptor tyrosine kinases (RTKs) — both of which induce downstream, hyperactive Raf/MAPK signaling — with endogenous TGFβR signaling [3]. Sustained TGFβR signaling (caused e.g. by an autocrine TGFβ loop) can be required for the maintenance of EMT in epithelial cells and for metastasis in several mouse models [3, 9] (see Figure 1a).
It has also become clear that the term ‘EMT’ comprises a wide spectrum of changes in epithelial plasticity. These ‘subtypes’ of EMT can be induced by different agents or combinations thereof, are often dependent on particular cellular models, can be reversible or metastable and can enhance or repress the progression of the epithelial cell's gene expression program towards a mesenchymal phenotype to a varying extent (Figure 1b; reviewed in [2, 3, 7, 8]). Among these EMT subtypes, ‘complete EMT’, defined by a metastable, fibroblastoid phenotype plus loss of E-cadherin and gain of vimentin, was most closely correlated with local invasion and metastasis [3].
In this review, we discuss new molecular players and pathways that form the emerging, complex molecular network underlying EMT. The evolutionarily conserved mechanisms involved, central to both development and cancer progression, are expected to ultimately modulate similarly conserved molecular machines governing both epithelial — or cellular — polarity [10] and cellular motility [11]. Since the impact of the tumor stroma on EMT and tumor progression has been recently reviewed [6, 12], this important issue will not be covered here.
Section snippets
Induction of EMT: signal input, transduction and integration
In the majority of epithelial cell types tested — and in transgenic mouse tumor models — TGFβ signaling cooperates with oncogenic Ras or RTKs to cause EMT and metastasis [3, 13, 14, 15, 16]. Obviously, effectors upstream (e.g. SHIP1 [2]) or downstream of Ras (e.g. Crk, Fos; [17, 18]) could substitute for activated RTKs or Ras in working with TGFβ signaling to cause EMT. Recently, several additional signal transduction pathways emerged as important for EMT, often correlating with tumor
Regulation of E-cadherin expression: the network expands
Lost, nonpolar or cytoplasmic expression of E-cadherin protein and/or transcriptional repression of its mRNA are hallmarks of EMT, both in embryonic development and in cancer progression [1, 2]. During tumor progression, E-cadherin can be functionally inactivated or silenced by different mechanisms [22, 32]. Besides post-translational control (Figure 4), these mechanisms include somatic mutations (frequent in lobular breast carcinomas), downregulation of gene expression through promoter
Novel key regulators of EMT: how do they fit in ?
During the past two years, several major new regulators of EMT have been identified. Besides regulating pathway-specific events, an emerging general function might be the control of E-cadherin expression/function, often via the Snail/ZEB families (Figure 3, Figure 4), further exemplifying the convergence of studies on development and cancer. In addition, most of these regulators show intimate cross-talk with both RTK/Ras and TGFβ signaling (Figure 3).
The EMT ‘transcriptome’
Several studies have employed transcriptomic gene expression technologies to profile well-characterized models of EMT and metastasis as a basis for characterizing these events in unprecedented detail, yielding new candidate markers and regulators of EMT [21•, 40••, 55]. Comparative expression profiling of multiple derivatives of a polarized mammary epithelial cell line, showing various epithelial plasticity phenotypes and reflecting distinct events during tumor progression in vivo, serves as an
When and how during metastasis does EMT take place?
Metastasis is a complex, multistep process, involving basement membrane destruction and local invasion, intravasation and survival in the bloodstream, extravasation into distant organs and survival plus proliferation at the metastatic site [63]. Since loss of E-cadherin expression or function is a hallmark of metastasis, most of the above molecular players and pathways should regulate one or more of these steps. It is not fully known, however, at which steps EMT-like epithelial plasticity
Conclusions and future directions
Our understanding of basic cellular and molecular processes governing EMT has grown immensely during the past few years. Several developmentally important genes and pathways that induce EMT are activated in tumor models and promote EMT in the context of tumor progression, forming an increasingly complex network (Figure 2, Figure 3). Future work may clarify whether this — still actively growing — list of molecular players and pathways may ultimately converge on a few, basic molecular machines
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
Parts of this work were supported by the Austrian Ministry of Education, Science and Arts (GEN-AU program, MH; NK), the Austrian ‘Fonds zur Förderung der wissenschaftlichen Forschung’ (HB; FWF, SFB-006) and the Austrian ‘Forschungsförderungsfonds der gewerblichen Wirtschaft’ (HB; FFF806693).
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Margit A Huber and Norbert Kraut contributed equally to this work.