title: Lgr6+ stem cells and their progeny in mouse epidermis under regimens of exogenous skin carcinogenesis, and their absence in ensuing skin tumors.
abstract: Lgr6+ cells have been identified as a novel class of proliferating (Ki67+) stem cells in mouse epidermis. We investigated their response to UV exposure in Lgr6-EGFP-Ires-CreERT2/R26R-LacZ haired and hairless mice and whether they become initiating cells of UV- or chemically induced skin tumors. UV overexposure erased Lgr6+ cells (EGFP+) from the interfollicular epidermis (IFE), but - as after wounding - they apparently repopulated the IFE from the hair follicles. Under sub-sunburn chronic UV exposure, Lgr6+ cells and their progeny (LacZ+ after pulse of tamoxifen) diminished strongly in the IFE. Although the inter-tumoral IFE clearly showed Lgr6 progeny, none of the UV- or chemically induced tumors (n = 22 and 41, respectively) appeared to be clonal expansions of Lgr6+ stem cells; i.e. no Lgr6+ cells or progeny in the proliferating tumor bulk. In checking for promoter methylation we found it to occur stochastically for the EGFP-Cre cassette. Lgr6 mRNA measured by qPCR was found to be diminished in skin tumors (also in UV tumors from wt type mice). The ratio of Lgr6/Ki67 was significantly reduced, pointing at a loss of Lgr6+ cells from the proliferative pool. Our data show that Lgr6+ cells are not major tumor-initiating cells in skin carcinogenesis.
authors.affiliation: Department of Dermatology, LUMC, Leiden, The Netherlands.
authors.forename: Gerline C
authors.initials: GC
authors.lastname: van de Glind
authors.affiliation: Department of Dermatology, LUMC, Leiden, The Netherlands.
authors.forename: Heggert G
authors.initials: HG
authors.lastname: Rebel
authors.affiliation: Department of Dermatology, LUMC, Leiden, The Netherlands.
authors.forename: Jacoba J
authors.initials: JJ
authors.lastname: Out-Luiting
authors.affiliation: Department of Dermatology, LUMC, Leiden, The Netherlands.
authors.forename: Wim
authors.initials: W
authors.lastname: Zoutman
authors.affiliation: Department of Dermatology, LUMC, Leiden, The Netherlands.
authors.forename: Cornelis P
authors.initials: CP
authors.lastname: Tensen
authors.affiliation: Department of Dermatology, LUMC, Leiden, The Netherlands.
authors.forename: Frank R
authors.initials: FR
authors.lastname: de Gruijl
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D019175:DNA Methylation / Q000187:drug effects / Q000528:radiation effects; D004817:Epidermis / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D018859:Hair Follicle / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D008812:Mice, Hairless; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000378:metabolism; D012867:Skin / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism*; D014466:Ultraviolet Rays
chemical_list: C548022:Lgr6 protein, mouse; D043562:Receptors, G-Protein-Coupled
keywords: Lgr6; UV; lineage tracing; skin carcinogenesis; stem cells