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Early Epidermal Destruction with Subsequent Epidermal Hyperplasia Is a Unique Feature of the Papilloma-Independent Squamous Cell Carcinoma Phenotype in PKC Overexpressing Transgenic Mice

¹ Molecular and Environmental Toxicology Center, University of Wisconsin, Madison, Wisconsin, USA
² Fred Hutchinson Cancer Research Center, Division of Basic Sciences, Seattle, Washington, USA
³ Department of Pathology and Laboratory Medicine, University of Wisconsin, Medical School, Madison, Wisconsin, USA
⁴ Department of Human Oncology, Medical School, Madison, Wisconsin, USA
⁵ Pathology and Laboratory Medicine Service, VA Hospital, Madison, Wisconsin, USA

Correspondence: Address correspondence to: Terry D. Oberley, Department of Pathology and Laboratory Medicine, University of Wisconsin Medical School, and William S. Middleton Memorial Veterans Administration Hospital, Room A35, 2500 Overlook Terrace, Madison, WI 53705, USA; e-mail:toberley{at}wisc.edu or Ajit K. Verma, Department of Human Oncology, University of Wisconsin, Room K4/532, Clinical Sciences Center, 600 Highland Ave., Madison, WI 53792, USA; e-mail:akverma{at}wisc.edu

Protein kinase C epsilon (PKC) overexpressing transgenic (PKCTg) mice develop papilloma-independent squamous cell carcinomas (SCC) elicited by 7,12-dimethylbenz[a]anthracene (DMBA) tumor initiation and 12-O-tetradecanoylphorbol-13-acetate (TPA) tumor promotion. We examined whether epidermal cell turnover kinetics was altered during the development of SCC in PKC Tg mice. Dorsal skin samples were fixed for histological examination. A single application of TPA resulted in extensive infiltration of polymorphonuclear neutrophils (PMNs) into the epidermis at 24 h after TPA treatment in PKC Tg mice while wild-type (WT) mouse skin showed focal infiltration by PMNs. Complete epidermal necrosis was observed at 48 h in PKC Tg mice only; at 72 h, epidermal cell regeneration beginning from hair follicles was observed in PKC Tg mice. Since the first TPA treatment to DMBA-initiated PKC Tg mouse skin led to epidermal destruction analogous to skin abrasion, we propose the papilloma-independent phenotype may be explained by death of initiated interfollicular cells originally destined to become papillomas. Epidermal destruction did not occur after multiple doses of TPA, presumably reflecting adaptation of epidermis to chronic TPA treatment. Prolonged hyperplasia in the hair follicle may result in the early neoplastic lesions originally described by Jansen et al. (2001) by expanding initiated cells in the hair follicles resulting in the subsequent development of SCC.

Key Words: Cell death • hyperplasia • protein kinase C epsilon • transgenic mice • polymorphonuclear neutrophils • skin

Abbreviations: DAB, 3,3'-diaminobenzidine tetra-hydrochloride • DAG, diacylglycerol • DMBA, 7,12-dimethylbenz[a]anthracene • EM, electron microscopy • IHC, immunohistochemistry • K10, Keratin 10 • mSCC, metastatic squamous cell carcinoma • MPO, myeloperoxidase • PCNA, proliferating cell nuclear antigen • PKC, protein kinase C epsilon • PKC Tg, protein kinase C epsilon overexpressing transgene • PMNs, polymorphonuclear neutrophils • PS, phosphatidylserine • RT, room temperature • TBS, Tris buffered saline • TPA, 12-O-tetradecanoylphorbol-13-acetate • WT, wild-type

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