title: Upregulation of CD26 expression in epithelial cells and stromal cells during wound-induced skin tumour formation.
abstract: We have previously described InvEE transgenic mice in which non-dividing, differentiating epidermal cells express oncogenically activated MAPK kinase 1 (MEK1). Skin wounding triggers tumour formation in InvEE mice via a mechanism that involves epidermal release of IL-1α and attraction of a pro-tumorigenic inflammatory infiltrate. To look for potential effects on the underlying connective tissue, we screened InvEE and wild-type epidermis for differential expression of cytokines and immune modulators. We identified a single protein, CD26 (dipeptidyl peptidase-4). CD26 serum levels were not increased in InvEE mice. In contrast, CD26 was upregulated in keratinocytes expressing mutant MEK1 and in the epithelial compartment of InvEE tumours, where it accumulated at cell-cell borders. CD26 expression was increased in dermal fibroblasts following skin wounding but was downregulated in tumour stroma. CD26 activity was stimulated by calcium-induced intercellular adhesion in keratinocytes, suggesting that the upregulation of CD26 in InvEE epidermis is due to expansion of the differentiated cell layers. IL-1α treatment of dermal fibroblasts stimulated CD26 activity, and therefore epidermal IL-1α release may contribute to the upregulation of CD26 expression in wounded dermis. Pharmacological blockade of CD26, via Sitagliptin, reduced growth of InvEE tumours, while combined inhibition of IL-1α and CD26 delayed tumour onset and reduced tumour incidence. Our results demonstrate that inappropriate activation of MEK1 in the epidermis leads to changes in dermal fibroblasts that, like the skin inflammatory infiltrate, contribute to tumour formation.
authors.affiliation: Cancer Research UK Cambridge Research Institute, Cambridge, UK.
authors.forename: E N
authors.initials: EN
authors.lastname: Arwert
authors.forename: R A
authors.initials: RA
authors.lastname: Mentink
authors.forename: R R
authors.initials: RR
authors.lastname: Driskell
authors.forename: E
authors.initials: E
authors.lastname: Hoste
authors.forename: S J
authors.initials: SJ
authors.lastname: Goldie
authors.forename: S
authors.initials: S
authors.lastname: Quist
authors.forename: F M
authors.initials: FM
authors.lastname: Watt
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000201:enzymology* / Q000473:pathology; D002478:Cells, Cultured; D018819:Dipeptidyl Peptidase 4 / Q000235:genetics / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology; D004817:Epidermis / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D004847:Epithelial Cells / Q000201:enzymology*; D005347:Fibroblasts / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D053582:Interleukin-1alpha / Q000378:metabolism; D015603:Keratinocytes; D048369:MAP Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010212:Papilloma / Q000201:enzymology* / Q000473:pathology; D011719:Pyrazines / Q000494:pharmacology; D000068900:Sitagliptin Phosphate; D012878:Skin Neoplasms / Q000201:enzymology* / Q000473:pathology; D017154:Stromal Cells / Q000201:enzymology*; D014230:Triazoles / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D053582:Interleukin-1alpha; D011719:Pyrazines; D014230:Triazoles; D048369:MAP Kinase Kinase 1; C482127:Map2k1 protein, mouse; D018819:Dipeptidyl Peptidase 4; C545245:Dpp4 protein, mouse; D000068900:Sitagliptin Phosphate