Emerging role of Notch signaling in epidermal differentiation and skin cancer

Signaling mediated by the Notch receptor governs tissue development during embryonal organogenesis, while in adult tissues it contributes to maintenance of cellular differentiation, proliferation and apoptosis. In addition, control by the Notch pathway of stem cell self-renewal and multi-potency points to an expanding role of Notch signaling in the progression of solid tumors. Notch and its ligands are abundantly expressed in the epidermis, where Notch signaling functions as a molecular switch that intervenes in cell transition between different skin layers during the epidermal differentiation process. More recent findings obtained in melanoma and non-melanoma skin cancers show that Notch signaling has a dual action (either as an oncogene or as a tumor suppressor), depending on the tumor cell type and the synchronous activation of other intracellular signaling mechanisms. In this Review, we highlight the pleiotropic roles of the Notch signaling pathway in normal skin homeostasis and differentiation and focus on its altered regulation in the tumorigenesis of melanoma and non-melanoma skin cancer. Further understanding of the roles of Notch signaling in specific skin cancer types may provide a rationale for novel Notch-based therapeutic strategies.