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Nat Cell Biol ; 14(12): 1282-94, 2012 Dec.
Article in English | MEDLINE | ID: mdl-23178882

ABSTRACT

Basal cell carcinoma, the most frequent human skin cancer, arises from activating hedgehog (HH) pathway mutations; however, little is known about the temporal changes that occur in tumour-initiating cells from the first oncogenic hit to the development of invasive cancer. Using an inducible mouse model enabling the expression of a constitutively active Smoothened mutant (SmoM2) in the adult epidermis, we carried out transcriptional profiling of SmoM2-expressing cells at different times during cancer initiation. We found that tumour-initiating cells are massively reprogrammed into a fate resembling that of embryonic hair follicle progenitors (EHFPs). Wnt/ ß-catenin signalling was very rapidly activated following SmoM2 expression in adult epidermis and coincided with the expression of EHFP markers. Deletion of ß-catenin in adult SmoM2-expressing cells prevents EHFP reprogramming and tumour initiation. Finally, human basal cell carcinomas also express genes of the Wnt signalling and EHFP signatures.


Subject(s)
Carcinoma, Basal Cell/pathology , Hair Follicle/cytology , Neoplastic Stem Cells/cytology , Animals , Carcinoma, Basal Cell/metabolism , Flow Cytometry , Hair Follicle/metabolism , Immunohistochemistry , Keratinocytes/cytology , Keratinocytes/metabolism , Mice , Mice, Transgenic , Neoplastic Stem Cells/metabolism , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , beta Catenin/metabolism
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