Notch tumor suppressor function

Abstract

Cancer development results from deregulated control of stem cell populations and alterations in their surrounding environment. Notch signaling is an important form of direct cell-cell communication involved in cell fate determination, stem cell potential and lineage commitment. The biological function of this pathway is critically context dependent. Here we review the pro-differentiation role and tumor suppressing function of this pathway, as revealed by loss-of-function in keratinocytes and skin, downstream of p53 and in cross-connection with other determinants of stem cell potential and/or tumor formation, such as p63 and Rho/CDC42 effectors. The possibility that Notch signaling elicits a duality of signals, involved in growth/differentiation control and cell survival will be discussed, in the context of novel approaches for cancer therapy.

Figure 1. Cross-regulation of Notch with other key signaling pathways in keratinocyte stem self renewal, differentiation and/or tumorigenesis

A dynamic equilibrium exists in the skin among keratinocyte stem cells, transit amplifying populations, and cells that have exited the cell cycle and are committed reversibly versus irreversibly to differentiation. As discussed in the text, such equilibrium is controlled by an inverse gradient and reciprocal negative regulation of p63 expression and Notch activity in the lower versus upper epidermal layers. p63 suppresses Notch signaling in epidermal cells with high self-renewal potential, while synergizing with other aspects of Notch function in early stages of differentiation. Notch1 and p21^WAF1/Cip1, a “canonical” Notch target in keratinocytes, suppress Wnt ligand expression and signaling, and function as negative regulator of stem cell potential and tumorigenesis. In fact, UV light exposure is a major etiological agent of human skin cancer, and the Notch1 gene is a p53 target with a key role in human keratinocyte tumor suppression.

Figure 2. Duality of Notch functions in keratinocyte commitment to differentiation and cell survival

Notch signaling impacts on, and is regulated by a complex signaling network with an important role in skin homeostasis and tumor development. Like Notch, many other components of this network exert a duality of functions, impinging on keratinocyte growth/differentiation control as well as cell survival. This has potentially important implications for cancer therapy. An attractive approach could be the use of selective inhibitors, which can suppress the Notch pro-survival function while leaving intact or enhancing its ability to induce differentiation. Alternatively, Notch inhibitors, or inducers, could be used as part of a combination therapy based on in conjunction with other compounds with growth inhibitory and/or pro-apoptotic functions.