Complexity in interpretation of embryonic epithelial-mesenchymal transition in response to transforming growth factor-beta signaling

Epithelial-mesenchymal transition (EMT) is a highly conserved and fundamental process that governs morphogenesis in development and may also contribute to cancer metastasis. Transforming growth factor (TGF-beta) is a potent inducer of EMT in various developmental and tumor systems. The analysis of TGF-beta signal transduction pathways is now considered a critically important area of biology, since many defects occur in these pathways in embryonic development. The complexity of TGF-beta signal transduction networks is overwhelming due to the large numbers of interacting constituents, complicated feedforward, feedback and crosstalk circuitry mechanisms that they involve in addition to the cellular kinetics and enzymatics that contribute to cell signaling. As a result of this complexity, apparently simple but highly important questions remain unanswered, that is, how do epithelial cells respond to such TGF-beta signals? System biology and cellular kinetics play a crucial role in cellular function; omissions of such a critical contributor may lead to inaccurate understanding of embryonic EMT. In this review, we identify and explain why certain conditions need to be considered for a true representation of TGF-beta signaling in vivo to better understand the controlled, yet delicate mechanism of embryonic EMT.