Epithelial–mesenchymal transitions (EMT) are embryonic morphogenetic programs whereby epithelial cells are converted into mesenchymal cells. Diverse molecular and phenotypic changes occur during this transition; cells lose their epithelial characteristics and acquire mesenchymal traits. The molecular hallmarks of EMT programs are loss of epithelial cadherin and other junction proteins and de novo expression of mesenchymal markers, such as vimentin, N-cadherin and S100A4.1, 2 EMT programs operate at early (gastrulation, neural crest delamination) or late (organ formation) stages of embryonic development downstream of several signaling pathways, such as Wnt, TGFβ, BMP, Notch, FGF, etc.3 The reverse process, a mesenchymal–epithelial transition (MET), has also been shown to play an important role in development by generating epithelial tissues from mesenchymal progenitors. In pathological conditions, aberrant activation of various EMT/MET programs contributes to fibrosis and cancer metastases. Several pleiotropically activated transcription factors acting downstream of EMT pathways are categorized as master regulators of EMT (MR-EMT). MR-EMT include Zn finger transcription factors of the SNAIL (SNAI1 and SNAI2) and ZEB (ZEB1 and ZEB2) families, the basic helix-loop-helix (bHLH) proteins E47, TWIST1, TWIST2, a forkhead transcription factor FOXC2 and a few other less comprehensively studied candidates.4 These factors interact with promoters of target genes and recruit transcriptional corepressors, coactivators and chromatin remodeling complexes to regulate transcription.3, 5 Upon ectopic expression in epithelial cells, these factors induce complete redifferentiation and generate individually migrating and highly invasive cells. In recent years, MR-EMT have been shown to control different key cancer-related features such as cell cycle progression,6–8 cell survival,9, 10 escape from cellular senescence,11 drug resistance,10, 12 DNA damage response13 and stemness.14, 15 This multifunctionality may be important at different stages of tumorigenesis, including oncogenic transformation, metastatic dissemination, escape from oncogene addiction and drug resistance. In particular, these activities of MR-EMT have been discussed in the context of the parallel model of tumor progression.9, 16 This model envisages epithelial cell plasticity to be a driving force for the formation of dormant micrometastases, which then escape dormancy and evolve into secondary tumors.17, 18 Cells in growing primary tumors accumulate genetic defects and produce late metastases, which are therefore genetically dissimilar to those generated during the early waves of dissemination. MR-EMT have been suggested to regulate virtually every step in tumor development including early and late metastatic dissemination.9, 16
In recent years, the cancer-related pathways controlling the expression and function of particular MR-EMT have been identified in an overwhelming number of reports. These studies demonstrate crosstalk between EMT and signaling pathways which are considered to be active at both early and late tumorigenic stages. Therefore, these data indirectly support the view of MR-EMT as factors which are active throughout the entire process of tumorigenesis. As an exploration of novel data on all MR-EMT is beyond the scope of this review we will focus on two proteins, ZEB1 and ZEB2 and discuss their involvement in several signal transduction pathways fundamental for different cancer stages, initiation, progression and spread.