Abstract
Epithelial/mesenchymal transition (EMT) has emerged as a key regulator of metastasis by facilitating tumor cell invasion and dissemination to distant organs. Recent evidences support that the reverse mesenchymal/epithelial transition (MET) is required for metastatic outgrowth; moreover, the existence of hybrid epithelial/mesenchymal (E/M) phenotypes is increasingly being reported in different tumor contexts. The accumulated data strongly support that plasticity between epithelial and mesenchymal states underlies the dissemination and metastatic potential of carcinoma cells. However, the translation into the clinics of EMT and epithelial plasticity processes presents enormous challenges and still remains a controversial issue. In this review, we will evaluate current evidences for translational applicability of EMT and depict an overview of the most recent EMT in vivo models, EMT marker analyses in human samples as well as potential EMT therapeutic approaches and ongoing clinical trials. We foresee that standardized analyses of EMT markers in solid and liquid tumor biopsies in addition to innovative tools targeting the E/M states will become promising strategies for future translation to the clinical setting.
Highlights
An additional concern regarding some mouse models genetically modified for Epithelial/mesenchymal transition (EMT)-TFs expression is that they rely on the alteration of a particular epithelial/mesenchymal transition transcription factor (EMT-TF), underestimating the contribution of epithelial plasticity and hybrid E/M states to the metastatic cascade
Sorafenib reverses histone modifications related to EMT in lung carcinoma cells (Zhang et al, 2013), and mocetinostat is a histone deacetylase (HDAC) inhibitor able to reverse the EMT phenotype and sensitize resistant prostate cancer (PCa) cells to docetaxel by restoring miR-203 expression and promoting ZEB1 inhibition (Meidhof et al, 2015)
Preclinical genetic mouse models and innovative intravital imaging have helped to demonstrate the plasticity of the process in vivo and highlighted the nonredundant and complementary functions of EMT-TFs and their specificity in distinct tumors
Summary
Since the beginning of the present century, a plethora of in vitro studies have firmly established that activation of the EMT program promotes tumor cell invasion and metastasis and have defined the molecular players, environmental cues, and signaling pathways implicated in EMT induction (Chaffer et al, 2016; De Craene and Berx, 2013; Lambert et al, 2017; Lamouille et al, 2014; Nieto, 2013; Nieto and Cano, 2012; Nieto et al, 2016; Peinado et al, 2007; Thiery, 2002; Thiery et al, 2009; Yang and Weinberg, 2008). The EMT process within the tumor context is highly dynamic, implying transient and reversible states, resembling embryonic development where multiple rounds of EMT and the reverse mesenchymal/epithelial transition (MET) processes occur as necessary steps for early embryogenesis and morphogenesis (Nieto, 2013; Nieto et al, 2016; Thiery et al, 2009). This reversibility might be an essential feature of the metastatic cascade. Most of the current genetic models are based on the manipulation to knock-out/knock-in key regulators of EMT (i.e., EMT-TF genes) and/or in EMT lineage tracing models (Fig. 1)
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