Oncotarget

Research Papers:

Lgr6+ stem cells and their progeny in mouse epidermis under regimens of exogenous skin carcinogenesis, and their absence in ensuing skin tumors

Gerline C. van de Glind _, Heggert G. Rebel, Jacoba J. Out-Luiting, Wim Zoutman, Cornelis P. Tensen and Frank R. de Gruijl

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Oncotarget. 2016; 7:86740-86754. https://doi.org/10.18632/oncotarget.13436

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Abstract

Gerline C. van de Glind1, Heggert G. Rebel1, Jacoba J. Out-Luiting1, Wim Zoutman1, Cornelis P. Tensen1, Frank R. de Gruijl1

1Department of Dermatology, LUMC, Leiden, The Netherlands

Correspondence to:

Frank R. de Gruijl, email: [email protected]

Cornelis P. Tensen, email: [email protected]

Keywords: stem cells, Lgr6, lineage tracing, UV, skin carcinogenesis

Received: March 04, 2016    Accepted: October 31, 2016    Published: November 17, 2016

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.


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