Hair cycle-dependent basal cell carcinoma tumorigenesis in Ptc1neo67/+ mice exposed to radiation.
We examined the effects of hair cycle phase on basal cell carcinoma (BCC) tumorigenesis induced by radiation in mice lacking one Patched allele (Ptc1(neo67/+)). Our results show that Ptc1(neo67/+) mouse skin irradiated in early anagen is highly susceptible to tumor induction, as a 3.2-fold incidence of visible BCC-like tumors was observed in anagen-irradiated compared with telogen-irradiated mice. Microscopic nodular BCC-like tumors were also enhanced by irradiation during active hair-follicle growth phases. Interestingly, histologic examination of the tumors revealed a qualitative difference in BCC tumorigenesis depending on hair growth phase at the time of exposure. In fact, in addition to typical BCC-like tumors, we observed development of a distinct basal cell tumor subtype characterized by anti-cytokeratin 14 and anti-smooth muscle actin reactivity. These tumors showed relatively short latency and rapid growth and were strictly dependent on age at irradiation, as they occurred only in mice irradiated in early anagen phase. Examination of anatomic and immunohistochemical relationships revealed a close relation of these tumors with the follicular outer root sheath of anagen skin. In contrast, there are strong indications for the derivation of typical, smooth muscle actin-negative BCC-like tumors from cell progenitors of interfollicular epidermis. These results underscore the role of follicular bulge stem cells and their progeny with high self-renewal capacity in the formation of basal cell tumors and contribute to clarify the relationship between target cell and tumor phenotype in BCC tumorigenesis induced by radiation.
Mancuso
Mariateresa
M
Biotechnology and Radiation Protection Unit, Ente per le Nuove Tecnologie, l'Energia e l'Ambiente, CR-Casaccia, Via Anguillarese 301, 00060 Rome, Italy.
Leonardi
Simona
S
Tanori
Mirella
M
Pasquali
Emanuela
E
Pierdomenico
Maria
M
Rebessi
Simonetta
S
Di Majo
Vincenzo
V
Covelli
Vincenzo
V
Pazzaglia
Simonetta
S
Saran
Anna
A
D022981:Allelic Imbalance; D000818:Animals; D002280:Basal Cell Carcinoma / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D019070:Cell Lineage; D005260:Female; D018859:Hair Follicle / Q000473:pathology / Q000528:radiation effects*; D051741:Kruppel-Like Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D019656:Loss of Heterozygosity; D008297:Male; D051379:Mice; D009381:Neoplasms, Radiation-Induced / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics*; D012867:Skin / Q000528:radiation effects; D012878:Skin Neoplasms / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D013234:Stem Cells / Q000473:pathology; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2
C498520:Gli1 protein, mouse; C000618551:Gli2 protein, mouse; D051741:Kruppel-Like Transcription Factors; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2