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Carcinogenesis |
in Their Epidermis Exhibit Reduced Papilloma Burden but Enhanced Carcinoma Formation after Tumor Promotion1
Department of Human Oncology, Medical School, University of Wisconsin [P. J. R., N. E. D., J. Z., S. E. B., A. K. V.], and Department of Pathology & Laboratory Medicine, Veterans Administration Hospital and Medical School, University of Wisconsin [T. D. O.], Madison, Wisconsin 53792
To determine the role that protein kinase C
(PKC) may play in skin
growth, differentiation, and tumor promotion, transgenic mice were
generated that overexpressed an epitope-tagged protein kinase C
(T7-PKC) in their epidermis using the human keratin 14 promoter.
Three independent mouse lines that overexpressed the T7-PKC in their
epidermis were produced. The three independent lines 206, 224, and 215
exhibited a 3-, 6-, and 18-fold elevation, respectively, in the level
of PKC immunoreactive protein. Line 215 exhibited a 19-fold greater
phosphatidylserine and 12-O-tetradecanoylphorbol-13-acetate
(TPA) stimulated kinase activity than line 224. Line 206 exhibited a
low basal T7-PKC activity, which failed to be stimulated by
phosphatidylserine and TPA. All of the line 215 transgenic mice
(F0 to the F2 generation) displayed phenotypic
changes in the skin. The phenotypic changes progressed gradually,
starting around 4–5 months of age, with mild dryness of the tail
accompanied by hair loss and inflammation at the base of the tail.
Hyperproliferation and ulceration of the affected regions were observed
around 7–8 months of age. The hyperproliferative epidermis from the
affected regions exhibited an expansion of the suprabasal epidermal
cells. Inflammation and/or ulceration were also observed in the dorsal
skin, the ears, and around the eyes. The line 215 mice, which expressed
the highest level of PKC, were evaluated for sensitivity to mouse
skin tumor promotion by TPA. Tumors were elicited by the initiation
(7,12-dimethylbenz[a]anthracene, 100 nmol)-promotion
(TPA, 5 nmol/twice weekly) protocol. The papilloma burden was reduced
by 95–96% for male and female T7-PKC mice compared to wild-type
controls. However, carcinomas developed rapidly in the T7-PKC mice
treated with 7, 12-dimethylbenz[a]anthracene and TPA.
These carcinomas appeared to form independently of prior papilloma
development. These results demonstrate that PKC is an important
regulator of skin tumor development.
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