title: CXCR3 enhances a T-cell-dependent epidermal proliferative response and promotes skin tumorigenesis.
abstract: The chemokine receptor CXCR3 has been proposed to play a critical role in host antitumor responses. In this study, we defined CXCR3-expressing immune cell infiltration in human skin squamous cell carcinomas and then used CXCR3-deficient mice to assess the contribution of CXCR3 to skin tumorigenesis. Our studies employed two established protocols for chemical skin carcinogenesis [methylcholanthrene (MCA) or 7,12-dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA) models]. CXCR3 deletion did not affect tumor development in the MCA model; however, CXCR3 was important in the DMBA/TPA model where gene deletion reduced the incidence of skin tumors. This decreased incidence of skin tumors did not reflect differences in epidermal development but rather was associated with reduced epidermal thickness and proliferation in CXCR3(-/-) mice, implicating the CXCR3 pathway in DMBA/TPA-induced epidermal inflammation and proliferation. Notably, CXCR3 expressed in CD4(+) and CD8(+) T cells was found to be important for enhanced epidermal proliferation. Specifically, CXCR3-deficient mice reconstituted with T cells isolated from wild-type mice treated with DMBA/TPA restored wild-type levels of epidermal proliferation in the mutant mice. Taken together, our findings establish that CXCR3 promotes epidermal tumorigenesis likely through a T-cell-dependent induction of keratinocyte proliferation.
authors: Department of Otolaryngology, and John Cochran VA Medical Center, St. Louis, Missouri, USA.
authors: Ashley E
authors: AE
authors: Winkler
authors: Joshua J
authors: JJ
authors: Brotman
authors: Meredith E
authors: ME
authors: Pittman
authors: Nancy P
authors: NP
authors: Judd
authors: James S
authors: JS
authors: Lewis
authors: Robert D
authors: RD
authors: Schreiber
authors: Ravindra
authors: R
authors: Uppaluri
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000494:pharmacology; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D004817:Epidermis / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008748:Methylcholanthrene / Q000494:pharmacology; D051379:Mice; D008817:Mice, Mutant Strains; D054367:Receptors, CXCR3 / Q000235:genetics / Q000276:immunology*; D012878:Skin Neoplasms / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
chemical_list: C515188:Cxcr3 protein, mouse; D054367:Receptors, CXCR3; D008748:Methylcholanthrene; D015127:9,10-Dimethyl-1,2-benzanthracene; D013755:Tetradecanoylphorbol Acetate