Basal cell carcinoma and its development: insights from radiation-induced tumors in Ptch1-deficient mice.

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 Ptch1(neo67/+) 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.

• Authors: Mariateresa Mancuso, Simonetta Pazzaglia, Mirella Tanori, Heidi Hahn, Paola Merola, Simonetta Rebessi, Michael J Atkinson, Vincenzo Di Majo, Vincenzo Covelli, Anna Saran
• Journal: Cancer research (Cancer Res) Vol. 64 Issue 3 Pg. 934-41 (Feb 01 2004) ISSN: 0008-5472 [Print] United States
• PMID: 14871823 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Hedgehog Proteins
• Intracellular Signaling Peptides and Proteins
• Membrane Proteins
• PTCH1 protein, human
• Patched Receptors
• Patched-1 Receptor
• Ptch1 protein, mouse
• Receptors, Cell Surface
• SHH protein, human
• Trans-Activators
• Tumor Suppressor Protein p53

Topics

• Alleles
• Animals
• Carcinoma, Basal Cell (etiology, genetics, metabolism)
• Disease Models, Animal
• Hedgehog Proteins
• Humans
• Intracellular Signaling Peptides and Proteins
• Loss of Heterozygosity
• Membrane Proteins (deficiency, genetics)
• Mice
• Mutation
• Neoplasms, Radiation-Induced (etiology, genetics, metabolism)
• Patched Receptors
• Patched-1 Receptor
• Receptors, Cell Surface
• Signal Transduction (physiology)
• Skin (radiation effects)
• Skin Neoplasms (etiology, genetics, metabolism)
• Trans-Activators (physiology)
• Tumor Suppressor Protein p53 (biosynthesis, genetics)
• X-Rays