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Carcinogenesis |
Department of Carcinogenesis, University of Texas M. D. Anderson Cancer Center, Smithville, Texas 78957 [J. D., D. K. B., E. W., L. B., S. C., S. M., K. K.], and Department of Cell and Molecular Biology, Ciemat Instituto, 28040 Madrid, Spain [A. R., J. J.]
Transgenic mice overexpressing insulin-like growth factor-1 (IGF-1) in
the basal layer of skin epidermis were generated using the bovine
keratin 5 promoter (BK5). Neonatal transgenic mice were slightly
smaller at birth and exhibited early ear unfolding, wrinkled and
thickened skin, and slightly enlarged ears compared with nontransgenic
littermates. Morphological evaluation of the skin revealed that
persistent overexpression of IGF-1 in the basal layer of the epidermis
resulted in epidermal hyperplasia, hyperkeratosis, and an increased
labeling index that persisted in adult mice. Phenotypic changes
observed in skin were associated with transgene expression in the basal
layer of the epidermis and activation of the IGF-1 receptor. Squamous
papillomas (some of which converted to carcinomas) developed in a
significant proportion (
50%) of older BK5.IGF-1 mice. Treatment of
BK5.IGF-1 transgenic mice with multiple topical applications of the
phorbol ester, 12-O-tetradecanoylphorbol-13-acetate, in
the absence of tumor initiation led to the development of additional
skin papillomas. Furthermore, treatment of BK5.IGF-1 transgenic mice
with an initiating dose of
7,12-dimethylbenz[a]anthracene only led to the
formation of additional papillomas in the absence of promotion. In
two-stage carcinogenesis experiments, BK5.IGF-1 transgenic mice
developed 7-fold more papillomas than nontransgenic littermates.
Phosphatidylinositol-3-kinase and protein kinase B (Akt) activities
were elevated (3–4-fold), and mitogen-activated protein kinase
activity was elevated 1.7-fold in the epidermis of transgenic mice
compared with nontransgenic mice. In addition, UV light-induced
epidermal apoptosis was significantly suppressed in BK5.IGF-1
transgenic mice. These data suggest that persistent activation of IGF-1
receptor signaling pathways in basal epithelial cells leads to
spontaneous tumor promotion and that up-regulation of both mitogenic
and cell survival signaling pathways may play an important role in the
action of IGF-1 in this model system.
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