Notch and NF-кB modulate the effects of TGF-beta in cervical carcinoma cells

The phenomenon of epithelial to mesenchymal transition (EMT) refers to a process critical in multiple tissues undergoing morphogenetic alterations induced by a variety of extracellular signals. EMT has received much attention recently because of its importance in the process of tumor progression and metastasis. TGF-beta is one of the extracellular signals that can cause this wide spectrum of changes and it has been shown to induce EMT in epithelial cells of different origin. Consistent with the ability of TGF- beta to induce EMT in a variety of cell types, we have observed a strong induction of EMT in cervical cancer cell lines when lower concentrations of TGF-beta was used while its higher concentrations induced growth inhibition. But interestingly, we found that with cancer progression the tissue level and serum level of TGF-beta increases suggesting the cross talks of other pathways suppressing the growth inhibitory effects of TGF-beta and favoring its cancer promoting activities like EMT.
The classical TGF-beta signaling is mediated through Smads, where the R-Smads like Smad 2 and Smad 3 get phosphorylated and translocated to nucleus along with Smad 4 and the trimer binds to smad binding elements (SBE) of TGF-beta responsive genes. The present data suggests that the TGF-beta induced EMT is not mediated through classical Smad signaling pathway, but cooperate with Notch and NF-κB pathways. The non canonical Notch pathway through PI3K/AKT can activate NF-κB. The activation of NF-κB is noted in cervical carcinoma progression and this activated NF-κB block the inhibitory effects of TGF-beta and enhance EMT and invasion.
Recently we have developed sphere culture conditions to enrich the cancer initiating cells. This offers a system where you can study the conditions that modulate stemness. There are also recent reports suggesting that EMT can induce stemness. The role of TGF-beta mediated EMT in contributing stemness could be explored in future.