Transcriptional crosstalk between TGFβ and stem cell pathways in tumor cell invasion Role of EMT promoting Smad complexes

Tumor cells undergoing the epithelial-mesenchymal transition (EMT) acquire the capacity to migrate, invade the stroma and metastasize. EMT cells also acquire stem cell characteristics suggesting crosstalk between EMT and pathways involved in promoting cellular stemness (stem cell pathways) and that EMT may contribute to the generation of cancer stem cells. indeed, transforming growth factor-beta (TGF beta), a major inducer of EMT, cooperates with stem cell pathways like Wnt, Ras, Hedgehog and Notch to induce EMT. A molecular basis for this cooperative signaling is indicated by recent data showing that many EMT associated transcription factors like Snail1, Zeb1/2, Twist, beta-catenin, Lef/TCF, Foxc2 and AP-1 interact with Smads and form EMT promoting Smad complexes (EPSC) engaged in either repressing epithelial genes or activating mesenchymal genes. Thus, formation and activation of EPSC represents a point of convergence between EMT and stem cell pathways. Here, we review our current understanding of the mechanisms involved in the transcriptional crosstalk between TGF beta and stem cell pathways and discuss how a fundament for the activation of these mechanisms may lead to the induction of EMT in tumors.