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Basal Cell Carcinoma and Its Development: Insights from Radiation-Induced Tumors in Ptch1-Deficient Mice

TitoloBasal Cell Carcinoma and Its Development: Insights from Radiation-Induced Tumors in Ptch1-Deficient Mice
Tipo di pubblicazioneArticolo su Rivista peer-reviewed
Anno di Pubblicazione2004
AutoriMancuso, Mariateresa, Pazzaglia Simonetta, Tanori Mirella, Hahn H., Merola P., Rebessi S., Atkinson M.J., Di Majo V., Covelli V., and Saran Anna
RivistaCancer Research
Volume64
Paginazione934-941
ISSN00085472
Parole chiaveallele, Alleles, animal, animal experiment, animal model, animal tissue, Animals, article, Basal Cell, basal cell carcinoma, cancer incidence, cancer staging, carcinogenesis, Carcinoma, cell infiltration, cell proliferation, Cell Surface, controlled study, Disease Models, Epidermis, gene, gene mutation, Hedgehog Proteins, Humans, Intracellular Signaling Peptides and Proteins, irradiation, latent period, Loss of Heterozygosity, Membrane Proteins, Mice, mouse, mutation, Neoplasms, nonhuman, precancer, precursor, priority journal, ptch1 gene, radiation injury, Radiation-Induced, Receptors, signal transduction, Skin, skin epithelium, Skin Neoplasms, Trans-Activators, tumor growth, Tumor Suppressor Protein p53, X-Rays
Abstract

Loss-of-function mutations in Patched (Ptch1) are implicated in constitutive activation of the Sonic hedgehog pathway in human basal cell carcinomas (BCCs), and inherited Ptch1 mutations underlie basal cell nevus syndrome in which a typical feature is multiple BCC occurring with greater incidence in portals of radiotherapy. Mice in which one copy of Ptch1 is inactivated show increased susceptibility to spontaneous tumor development and hypersensitivity to radiation-induced tumorigenesis, providing an ideal in vivo model to study the typical pathologies associated with basal cell nevus syndrome. We therefore examined BCC development in control and irradiated Ptch1neo67/+ mice. We show that unirradiated mice develop putative BCC precursor lesions, i.e., basaloid hyperproliferation areas arising from both follicular and interfollicular epithelium, and that these lesions progress to nodular and infiltrative BCCs only in irradiated mice. Data of BCC incidence, multiplicity, and latency support the notion of epidermal hyperproliferations, nodular and infiltrative BCC-like tumors representing different stages of tumor development. This is additionally supported by the pattern of p53 protein expression observed in BCC subtypes and by the finding of retention of the normal remaining Ptch1 allele in all nodular, circumscribed BCCs analyzed compared with its constant loss in infiltrative BCCs. Our data suggest chronological tumor progression from basaloid hyperproliferations to nodular and then infiltrative BCC occurring in a stepwise fashion through the accumulation of sequential genetic alterations.

Note

cited By 85

URLhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-10744221671&doi=10.1158%2f0008-5472.CAN-03-2460&partnerID=40&md5=b54e037372024bdae31e22b61bfbd471
DOI10.1158/0008-5472.CAN-03-2460
Citation KeyMancuso2004934