title: CD34 expression by hair follicle stem cells is required for skin tumor development in mice.
abstract: The cell surface marker CD34 marks mouse hair follicle bulge cells, which have attributes of stem cells, including quiescence and multipotency. Using a CD34 knockout (KO) mouse, we tested the hypothesis that CD34 may participate in tumor development in mice because hair follicle stem cells are thought to be a major target of carcinogens in the two-stage model of mouse skin carcinogenesis. Following initiation with 200 nmol 7,12-dimethylbenz(a)anthracene (DMBA), mice were promoted with 12-O-tetradecanoylphorbol-13-acetate (TPA) for 20 weeks. Under these conditions, CD34KO mice failed to develop papillomas. Increasing the initiating dose of DMBA to 400 nmol resulted in tumor development in the CD34KO mice, albeit with an increased latency and lower tumor yield compared with the wild-type (WT) strain. DNA adduct analysis of keratinocytes from DMBA-initiated CD34KO mice revealed that DMBA was metabolically activated into carcinogenic diol epoxides at both 200 and 400 nmol. Chronic exposure to TPA revealed that CD34KO skin developed and sustained epidermal hyperplasia. However, CD34KO hair follicles typically remained in telogen rather than transitioning into anagen growth, confirmed by retention of bromodeoxyuridine-labeled bulge stem cells within the hair follicle. Unique localization of the hair follicle progenitor cell marker MTS24 was found in interfollicular basal cells in TPA-treated WT mice, whereas staining remained restricted to the hair follicles of CD34KO mice, suggesting that progenitor cells migrate into epidermis differently between strains. These data show that CD34 is required for TPA-induced hair follicle stem cell activation and tumor formation in mice.
authors.affiliation: Cancer Biology Group, Laboratory of Molecular Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA. trempus@niehs.nih.gov
authors.forename: Carol S
authors.initials: CS
authors.lastname: Trempus
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Morris
authors.forename: Matthew
authors.initials: M
authors.lastname: Ehinger
authors.forename: Amy
authors.initials: A
authors.lastname: Elmore
authors.forename: Carl D
authors.initials: CD
authors.lastname: Bortner
authors.forename: Mayumi
authors.initials: M
authors.lastname: Ito
authors.forename: George
authors.initials: G
authors.lastname: Cotsarelis
authors.forename: Joanne G W
authors.initials: JG
authors.lastname: Nijhof
authors.forename: John
authors.initials: J
authors.lastname: Peckham
authors.forename: Norris
authors.initials: N
authors.lastname: Flagler
authors.forename: Grace
authors.initials: G
authors.lastname: Kissling
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Humble
authors.forename: Leon C
authors.initials: LC
authors.lastname: King
authors.forename: Linda D
authors.initials: LD
authors.lastname: Adams
authors.forename: Dhimant
authors.initials: D
authors.lastname: Desai
authors.forename: Shantu
authors.initials: S
authors.lastname: Amin
authors.forename: Raymond W
authors.initials: RW
authors.lastname: Tennant
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D018952:Antigens, CD34 / Q000096:biosynthesis* / Q000235:genetics; D002453:Cell Cycle / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D005260:Female; D018859:Hair Follicle / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012878:Skin Neoplasms / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D013234:Stem Cells / Q000378:metabolism* / Q000473:pathology; D013755:Tetradecanoylphorbol Acetate
chemical_list: D018952:Antigens, CD34; D015127:9,10-Dimethyl-1,2-benzanthracene; D013755:Tetradecanoylphorbol Acetate