title: Sonic hedgehog signaling in Basal cell nevus syndrome.
abstract: The hedgehog (Hh) signaling pathway is considered to be a major signal transduction pathway during embryonic development, but it usually shuts down after birth. Aberrant Sonic hedgehog (Shh) activation during adulthood leads to neoplastic growth. Basal cell carcinoma (BCC) of the skin is driven by this pathway. Here, we summarize information related to the pathogenesis of this neoplasm, discuss pathways that crosstalk with Shh signaling, and the importance of the primary cilium in this neoplastic process. The identification of the basic/translational components of Shh signaling has led to the discovery of potential mechanism-driven druggable targets and subsequent clinical trials have confirmed their remarkable efficacy in treating BCCs, particularly in patients with nevoid BCC syndrome (NBCCS), an autosomal dominant disorder in which patients inherit a germline mutation in the tumor-suppressor gene Patched (Ptch). Patients with NBCCS develop dozens to hundreds of BCCs due to derepression of the downstream G-protein-coupled receptor Smoothened (SMO). Ptch mutations permit transposition of SMO to the primary cilium followed by enhanced expression of transcription factors Glis that drive cell proliferation and tumor growth. Clinical trials with the SMO inhibitor, vismodegib, showed remarkable efficacy in patients with NBCCS, which finally led to its FDA approval in 2012.
authors.affiliation: Department of Dermatology, University of Alabama at Birmingham, Birmingham, Alabama. mathar@uab.edu.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Athar
authors.affiliation: Department of Dermatology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Changzhao
authors.initials: C
authors.lastname: Li
authors.affiliation: Columbia University Medical Center, Irving Cancer Research Center, New York, New York.
authors.forename: Arianna L
authors.initials: AL
authors.lastname: Kim
authors.affiliation: University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Vladimir S
authors.initials: VS
authors.lastname: Spiegelman
authors.affiliation: Columbia University Medical Center, Irving Cancer Research Center, New York, New York.
authors.forename: David R
authors.initials: DR
authors.lastname: Bickers
mesh_terms: D000818:Animals; D001478:Basal Cell Nevus Syndrome / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D048708:Cell Growth Processes / Q000502:physiology; D004195:Disease Models, Animal; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D011956:Receptors, Cell Surface / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D053823:Hedgehog Proteins; D011956:Receptors, Cell Surface