Figure 7

Schematic depiction of the regulation of MYB expression, and hence proliferative rate (represented on the Y-axis) by ZEB1 at various metastatic stages (detailed on the X-axis). Hypoxia/EGF positioned at the apex of each MYB curve indicates the switching on of EMT signals by these factors. This may lead to the induction of a cascade of CDH1-repressor genes, resulting in ZEB1 induction, which acts to stabilize the mesenchymal phenotype, resulting in further protection from immune-derived apoptotic signals within the bloodstream. Thus, these clinically indolent tumor cells may circulate and/or remain disseminated until a suitable, perhaps normoxic, secondary niche is found. Combined with other factors, such as hormone fluctuations associated with age and/or pregnancy or inflammation, a more conducive tumor microenvironment is created, triggering the reexpression of MYB, which may in turn repress ZEB1. The net result is the reversion of EMT (MET), and the secondary tumor actively grows until the cycle is repeated.