The role of Notch signaling in human cervical cancer: implications for solid tumors.

The detection of intracellular forms of Notch1 in human cervical cancers more than a decade ago prompted an investigation into the possible role of this pathway in driving these cancers. These tumors are consistently characterized by features of deregulated ligand-dependent signaling. Although Notch signaling complements the function of papillomavirus oncogenes in transformation assays of human keratinocytes, there are dose-dependent effects, which inhibit growth of established cervical cancer cell lines. Two pro-oncogenic effector mechanisms that have been suggested to operate in this context by Notch signaling are the activation of PI3K/Akt pathway and the upregulation of c-Myc. Collectively, there is a complex interplay between Notch signaling and papillomaviruses in the context of cervical carcinogenesis. Better animal model systems and identification of human cervical cancer stem cells should help clarify the possible stage specific and pleiotropic effects and regulation of Notch signaling.