Abstract
Tumor cells demonstrate substantial plasticity in their genotypic and phenotypic characteristics. Epithelial-mesenchymal plasticity (EMP) can be characterized into dynamic intermediate states and can be orchestrated by many factors, either intercellularly via epigenetic reprograming, or extracellularly via growth factors, inflammation and/or hypoxia generated by the tumor stromal microenvironment. EMP has the capability to alter phenotype and produce heterogeneity, and thus by changing the whole cancer landscape can attenuate oncogenic signaling networks, invoke anti-apoptotic features, defend against chemotherapeutics and reprogram angiogenic and immune recognition functions. We discuss here the role of phenotypic plasticity in tumor initiation, progression and metastasis and provide an update of the modalities utilized for the molecular characterization of the EMT states and attributes of cellular behavior, including cellular metabolism, in the context of EMP. We also summarize recent findings in dynamic EMP studies that provide new insights into the phenotypic plasticity of EMP flux in cancer and propose therapeutic strategies to impede the metastatic outgrowth of phenotypically heterogeneous tumors.
Highlights
SIGNIFICANCE OF Epithelial-mesenchymal plasticity (EMP) AND HYBRID EMT STATESEpithelial–mesenchymal transition, is not a two-step event through which cancer cells lose epithelial markers and acquire mesenchymal traits between two rigid phenotypes
Specialty section: This article was submitted to Molecular Diagnostics and Therapeutics, a section of the journal Frontiers in Molecular Biosciences
We summarize recent findings in dynamic Epithelial-mesenchymal plasticity (EMP) studies that provide new insights into the phenotypic plasticity of EMP flux in cancer and propose therapeutic strategies to impede the metastatic outgrowth of phenotypically heterogeneous tumors
Summary
Epithelial–mesenchymal transition, is not a two-step event through which cancer cells lose epithelial markers and acquire mesenchymal traits between two rigid phenotypes. Hybrid epithelial-mesenchymal features of carcinoma cells have been observed in various invasive carcinoma model systems (Lee et al, 2006; Klymkowsky and Savagner, 2009), in which individual cells co-express markers of both epithelial and mesenchymal lineages, and circulating tumor cells (CTCs) in particular have been shown to exhibit a spectrum of EMP states (Armstrong et al, 2011; Yu et al, 2014; Khoo et al, 2015; Bourcy et al, 2016); reviewed in McInnes et al (2015); Hassan et al (2020). The hybrid EMP state seen in carcinomas and CTCs, in which individual cells co-express markers of both epithelial and mesenchymal lineages, is predicted to have the highest tumourigenicity and metastatic potential (Lee et al, 2006; Klymkowsky and Savagner, 2009; Jolly et al, 2016; Kroger et al, 2019; Pastushenko and Blanpain, 2019). An emerging challenge is to decipher correctly the contribution that intermediate states of the EMT spectrum make to tumor evolution for therapeutic interventions
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