Figure 2.

Environmental stimuli of EMT and MET. Specific environmental stimuli lead to the initiation of EMT program during cancer development and progression. In the microenvironment of the primary lesion, soluble growth factors including transforming growth factor beta (TGF-β), epidermal growth factor (EGF), fibroblast growth factor (FGF), hepatocyte growth factor (HGF) secreted by stromal cells such as cancer-associated fibroblast, tumor-associated macrophage, and neutrophil activate several signaling pathways in cancer cells. These signaling pathways then regulate the EMT-related transcription factors (EMT-TFs) through epigenetic mechanisms. Hypoxic stress and altered metabolism from the microenvironment are also stimuli of EMT. For CTCs, in the absence of stroma-derived signaling cues that initiated EMT, platelet-derived TGF-β signals serve as the stimuli to sustain EMT. Although the external stimuli of MET are currently largely unknown, it has been proposed that MET can be triggered by stromal cells from the microenvironment including cancer-associated fibroblast, endothelial cells, and myeloid progenitor cells, or passively result from the absence of EMT-inducing signals from the primary tumor microenvironment.