Enhancement of susceptibility to diverse skin tumor promoters by activation of the insulin-like growth factor-1 receptor in the epidermis of transgenic mice.
Insulin-like growth factor-1 (IGF-1) and its receptor are believed to play an important role in mitogenesis and neoplastic transformation. The purpose of this study was to further examine the role of IGF-1 during tumor promotion in mouse skin. HK1.IGF1 transgenic mice, which overexpress IGF-1 in epidermis via the human keratin 1 promoter, were previously shown to be hypersensitive to skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate (TPA). We examined these mice for their sensitivity to diverse classes of tumor-promoting agents. HK1.IGF-1 transgenic mice initiated with 7,12-dimethylbenz[a]anthracene were more sensitive to treatment with a wide variety of tumor promoters, including chrysarobin, okadaic acid, and benzoyl peroxide, which resulted in more rapid development of tumors and a dramatic increase in the number of tumors per mouse compared with corresponding non-transgenic mice treated with the same compounds. Histological analyses of skin from HK1.IGF-1 mice treated with various tumor promoters revealed that these mice were also more sensitive to the induction of epidermal hyperplasia and cell proliferation. Analysis of the IGF-1 receptor (IGF-1r) and epidermal growth factor (EGFr) in the epidermis of TPA-treated HK1.IGF-1 transgenic and non-transgenic mice revealed that both receptors were activated (hyperphosphorylated on tyrosine residues), and the level of activation was higher in transgenic mice. The mechanism for the increased sensitivity of HK1.IGF-1 mice to tumor promoters may involve cooperation between the IGF-1r and EGFr signaling pathways. Our data suggest that IGF-1r signaling may play an important role in the process of tumor promotion by diverse classes of tumor promoters.
Wilker
E
E
Department of Carcinogenesis, The University of Texas M.D. Anderson Cancer Center, Smithville 78957, USA.
Bol
D
D
Kiguchi
K
K
Rupp
T
T
Beltrán
L
L
DiGiovanni
J
J
D000818:Animals; D000873:Anthracenes / Q000633:toxicity; D001585:Benzoyl Peroxide / Q000633:toxicity; D002273:Carcinogens / Q000633:toxicity*; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D019319:Okadaic Acid / Q000633:toxicity; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000139:chemically induced*; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity; D019076:Transgenes
D000873:Anthracenes; D002273:Carcinogens; D019319:Okadaic Acid; C013883:chrysarobin; D066246:ErbB Receptors; D017526:Receptor, IGF Type 1; D013755:Tetradecanoylphorbol Acetate; D001585:Benzoyl Peroxide