Figure 1.

Epigenetic regulation of epithelial to mesenchymal transition in cancer metastatic cascade. In the primary tumor, for local migration, epithelial tumor cells initiate EMT program by activating signaling pathways responsive to specific environmental stimuli. As a result, EMT-related transcription factors (EMT-TFs) are induced, whose expression can be regulated by DNA methylation, histone modifications, and RNA-mediated epigenetic regulation. Next, EMT-TFs collaborate with various epigenetic proteins to regulate the expression of downstream EMT effectors. It is assumed that tumor cells undergo partial EMT instead of complete EMT to improve their metastatic ability. After local migration, tumor cells disseminate into the circulation, known as circulating tumor cells (CTCs). CTCs interact with platelets through different cell surface receptors and ligands, by which they sustain EMT via platelet-derived TGFβ signals in the absence of stroma-derived signaling cues that initiated EMT in the microenvironment of the primary lesion. CTC clusters and single CTCs have been demonstrated to exhibit distinct DNA methylation patterns of EMT-associated genes. In addition, members of miR-200 family have been acknowledged as key regulators of EMT maintenance in CTCs by forming double-negative feedback loops with EMT TFs, in which they reciprocally repress each other’s translation or transcription. The extravasation mechanisms of CTCs vary widely depending on the flow direction and organ-specific vascular structure. Upon reaching the distant sites, the vast majority of carcinoma cells will not survive, while a small minority persist in a quiescence state as dormant cancer cells until reinitiate growth and form colonization. It is proposed that invasive cells need to undergo MET to acquire the capability of macrometastatic growth. MET is mainly triggered and regulated by contextual signals from microenvironment or due to the absence of EMT-inducing signals from the primary tumor microenvironment, resulting in downregulation of several EMT-TFs. The negative feedback loops consisting of pairs of miRNAs and EMT-TFs are also considered the driving force underpinning this state reversibility. Both EMT-TFs and micro RNAs in these loops have also been shown to be elaborately regulated by epigenetic mechanisms including DNA methylation and histone modifications.