title: The barrier function of organotypic non-melanoma skin cancer models.
abstract: Non-melanoma skin cancer (NMSC) is the most frequent human cancer with continuously rising incidences worldwide. Herein, we investigated the molecular basis for the impaired skin barrier function of organotypic NMSC models. We unraveled disturbed epidermal differentiation by reflectance confocal microscopy and histopathological evaluation. While the presence of claudin-4 and occludin were distinctly reduced, zonula occludens protein-1 was more wide-spread, and claudin-1 was heterogeneously distributed within the NMSC models compared with normal reconstructed human skin. Moreover, the cancer altered stratum corneum lipid packing and profile with decreased cholesterol content, increased phospholipid amount, and altered ceramide subclasses. These alterations contributed to increased surface pH and to 1.5 to 2.6-fold enhanced caffeine permeability of the NMSC models. Three topical applications of ingenol mebutate gel (0.015%) caused abundant epidermal cell necrosis, decreased Ki-67 indices, and increased lactate dehydrogenase activity. Taken together, our study provides new biological insights into the microenvironment of organotypic NMSC models, improves the understanding of the disease model by revealing causes for impaired skin barrier function in NMSC models at the molecular level, and fosters human cell-based approaches in preclinical drug evaluation.
authors.affiliation: Institute for Pharmacy, Freie Universität Berlin, Königin-Luise-Str. 2+4, 14195 Berlin, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Zoschke
authors.affiliation: Collegium Medicum Berlin, Luisenstr. 54, 10117 Berlin, Germany; Department of Dermatology, Venereology and Allergology, Skin Cancer Center Charité, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Ulrich
authors.affiliation: Faculty of Pharmacy, Charles University in Prague, Akademika Heyrovského 1203, 50005 Hradec Králové, Czech Republic.
authors.forename: Michaela
authors.initials: M
authors.lastname: Sochorová
authors.affiliation: Institute for Pharmacy, Freie Universität Berlin, Königin-Luise-Str. 2+4, 14195 Berlin, Germany.
authors.forename: Christopher
authors.initials: C
authors.lastname: Wolff
authors.affiliation: Faculty of Pharmacy, Charles University in Prague, Akademika Heyrovského 1203, 50005 Hradec Králové, Czech Republic.
authors.forename: Kateřina
authors.initials: K
authors.lastname: Vávrová
authors.affiliation: Institute of Biomaterial Science, Department of Biocompatibility, Helmholtz Centre for Materials and Coastal Research, Kantstr. 55, 14153 Teltow, Germany.
authors.forename: Nan
authors.initials: N
authors.lastname: Ma
authors.affiliation: Department of Dermatology, Venereology and Allergology, Skin Cancer Center Charité, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Claas
authors.initials: C
authors.lastname: Ulrich
authors.affiliation: Department of Dermatology and Venereology, University Hospital Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany.
authors.forename: Johanna M
authors.initials: JM
authors.lastname: Brandner
authors.affiliation: Institute for Pharmacy, Freie Universität Berlin, Königin-Luise-Str. 2+4, 14195 Berlin, Germany. Electronic address: monika.schaefer-korting@fu-berlin.de.
authors.forename: Monika
authors.initials: M
authors.lastname: Schäfer-Korting
mesh_terms: D002110:Caffeine / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018920:Coculture Techniques; D004224:Diterpenes / Q000494:pharmacology; D004950:Esterases / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism; D050356:Lipid Metabolism; D008297:Male; D012867:Skin / Q000187:drug effects / Q000378:metabolism*; D012878:Skin Neoplasms / Q000378:metabolism*; D062725:Tight Junction Proteins / Q000378:metabolism
chemical_list: C486592:3-ingenyl angelate; D004224:Diterpenes; D062725:Tight Junction Proteins; D002110:Caffeine; D004950:Esterases
keywords: Ceramides; Ingenol mebutate; Non-melanoma skin cancer; Reflectance confocal microscopy; Skin absorption; Tight junctions