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The metastatic spread of tumor epithelial cells accounts for over 90% of cancer-specific mortality; however, the molecular mechanisms that govern tumor spread and distant recolonization remain unclear. In this issue of JCI, Rokavec and colleagues shine light on this murky aspect of tumor biology by focusing through the lens of microenvironmental contributions, namely inflammation, as driving signals that set off a delicate, intracellular feedback loop among cytokine receptors, transcription factors and miRNAs. This study provides in vivo evidence and identifies molecular players behind the elusive switch that drives the epithelial-to-mesenchymal transition and the mesenchymal-to-epithelial transition.
EMT/MET switch
The migratory capacity conferred on cells following the epithelial-to-mesenchymal transition (EMT) is a developmental necessity that has become a predominant hypothesis to explain epithelial cancer metastases and therapeutic resistance (1). In the simplest terms, selective pres- sures (e.g., nutrient deprivation, hypoxia, therapeutics, etc.) on epithelial tumor cells activate dormant signaling pathways that allow these tumor cells to lose epithelial characteristics and take on mesenchymal properties, including migration and inva- sion that are advantageous for tumor sur- vival. The concept that EMT promotes can- cer metastasis is supported by the reality that mesenchymal tumors, such as sarco- mas, are some of the most difficult tumors to treat. However, if mesenchymal proper- ties are so advantageous for cancer spread, why then do most metastatic lesions dis- play epithelial properties similar to those of the primary tumor?
A predominant answer to this question resides in the mesenchymal-to-epithelial transition (MET), which would allow transformed mesenchymal-like cells to regain their epithelial characteristics, a state that is perhaps more advantageous for survival in a foreign microenviron- ment. As obvious as this explanation appears to be, there are many unanswered questions that remain. For instance, there is a lack of solid in vivo evidence to sup- port the induction of MET following metastasis. Furthermore, if MET does occur, what are the molecular pathways involved in promoting tumor aggressive- ness (EMT), and how can these pathways be dialed back enough to reestablish epi- thelial characteristics? Furthermore, what are the unique aspects of the primary...