title: Lgr5+ stem cells and their progeny in mouse epidermis under regimens of exogenous skin carcinogenesis, and their absence in ensuing skin tumors.
abstract: Actively proliferating Lgr5+ skin stem cells are found deep in the hair follicle (HF). These cells renew the HF and drive its expansion in anagen phase. Their long residence and continuous mitotic activity make them prime candidates to transform into skin tumor-initiating cells. This was investigated by subjecting Lgr5-EGFP-Ires-CreERT2/R26R-LacZ mice (haired and hairless) to chemical and UV carcinogenic regimens. In the course of these regimens Lgr5+ cells (EGFP+) remained exclusively located in HFs, and in deep-seated cysts of hairless skin. In haired mice, progeny of Lgr5+ stem cells (LacZ+ after a pulse of tamoxifen) appeared in the interfollicular epidermis upon UV-induced sunburn and in TPA-induced hyperplasia. In hairless mice the progeny remained located in deep-seated cysts and in HF remnants. Progeny in hairless skin was only detected interfollicularly at a late stage, in between outgrowing tumors. Lgr5+ stem cells were absent in the ultimate tumor masses, and no tumor appeared to be a (clonal) expansion of Lgr5+ cells (52 tumors with tamoxifen at the start of carcinogenesis, 42 tumors with tamoxifen late during tumor outgrowth). In contrast to CD34/K15+ quiescent bulge stem cells, actively proliferating Lgr5+ stem cells do therefore not appear to be tumor drivers in experimental skin carcinogenesis.
authors.affiliation: Department of Dermatology, LUMC, Leiden, 2333RC, The Netherlands.
authors.forename: Gerline C
authors.initials: GC
authors.lastname: van de Glind
authors.affiliation: Department of Dermatology, LUMC, Leiden, 2333RC, The Netherlands.
authors.forename: Jacoba J
authors.initials: JJ
authors.lastname: Out-Luiting
authors.affiliation: Department of Dermatology, LUMC, Leiden, 2333RC, The Netherlands.
authors.forename: Heggert G
authors.initials: HG
authors.lastname: Rebel
authors.affiliation: Department of Dermatology, LUMC, Leiden, 2333RC, The Netherlands.
authors.forename: Cornelis P
authors.initials: CP
authors.lastname: Tensen
authors.affiliation: Department of Dermatology, LUMC, Leiden, 2333RC, The Netherlands.
authors.forename: Frank R
authors.initials: FR
authors.lastname: de Gruijl
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D004817:Epidermis / Q000473:pathology; D018859:Hair Follicle / Q000473:pathology*; D051379:Mice; D008812:Mice, Hairless; D008822:Mice, Transgenic; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D012878:Skin Neoplasms / Q000473:pathology*; D013234:Stem Cells / Q000473:pathology*
chemical_list: C493597:Lgr5 protein, mouse; D043562:Receptors, G-Protein-Coupled
keywords: Lgr5; UV; lineage tracing; skin carcinogenesis; stem cells