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Toxicologic Pathology
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*Compound via MeSH
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*12-O-TETRADECANOYLPHORBOL-13-ACETATE
*7,12-DIMETHYLBENZ(A)ANTHRACENE
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*Skin Cancer
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Articles

Differential Tumor Biology Effects of Double-Initiation in a Mouse Skin Chemical Carcinogenesis Model Comparing Wild Type versus Protein Kinase Cepsilon Overexpression Mice

Yafan Li1
Deric L. Wheeler2
Honnavara N. Ananthaswamy3
Ajit K. Verma2
Terry D. Oberley4,5

1 Program in Toxicology & Pharmacology, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM
2 Department of Human Oncology, School of Medicine and Public Health, University of Wisconsin-Madison
3 Department of Immunology, The University of Texas M.D. Anderson Cancer Center
4 Pathology and Laboratory Medicine Service, VA Hospital, Madison, WI, USA
5 Department of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin-Madison

Correspondence: Address correspondence to: Terry D. Oberley (M.D., Ph.D), Department of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin, and William S. Middleton Memorial Veterans Administration Hospital, Room A35, 2500 Overlook Terrace, Madison, WI 53705; e-mail:toberley{at}wisc.edu

Our previous studies showed that protein kinase Cepsilon (PKC{varepsilon}) verexpression in mouse skin resulted in metastatic squamous cell carcinoma (SCC) elicited by single 7,12-dimethylbenz(a)anthracene (DMBA)-initiation and 12-O-tetradecanoylphorbol-13-acetate (TPA)-promotion in the absence of preceding papilloma formation as is typically observed in wild type mice. The present study demonstrates that double-DMBA initiation modulates tumor incidence, multiplicity, and latency period in both wild type and PKC{varepsilon}overexpression transgenic (PKC{varepsilon}-Tg) mice. After 17 weeks (wks) of tumor promotion, a reduction in papilloma multiplicity was observed in double- versus single-DMBA initiated wild type mice. Papilloma multiplicity was inversely correlated with cell death indices of interfollicular keratinocytes, indicating decreased papilloma formation was caused by increased cell death and suggesting the origin of papillomas is in interfollicular epidermis. Double-initiated PKC{varepsilon}-Tg mice had accelerated carcinoma formation and cancer incidence in comparison to single-initiated PKC{varepsilon}-Tg mice. Morphologic analysis of mouse skin following double initiation and tumor promotion showed a similar if not identical series of events to those previously observed following single initiation and tumor promotion: putative preneoplastic cells were observed arising from hyperplastic hair follicles (HFs) with subsequent cancer cell infiltration into the dermis. Single-initiated PKC{varepsilon}-Tg mice exhibited increased mitosis in epidermal cells of HFs during tumor promotion.

Key Words: protein kinase Cepsilon • cell death • papilloma • squamous cell carcinoma

Abbreviations: DAG, diacylglycerol • DMBA, 7, 12-dimethylbenz[a]anthracene • H&E, hematoxylin and eosin • HF, hair follicle • PBS, phosphate-buffered saline • PCR, polymerase chain reaction • PKC{varepsilon}, protein kinase Cepsilon • PKC{varepsilon}-Tg, protein kinase Cepsilon overexpressing transgenic mice • RT, room temperature • SCC, squamous cell carcinoma • TPA, 12-O-tetradecanoylphorbol-13-acetate • wk, week

Toxicologic Pathology, Vol. 35, No. 7, 942-951 (2007)
DOI: 10.1080/01926230701748164
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