Enhancement of susceptibility to diverse skin tumor promoters by activation of the insulin-like growth factor-1 receptor in the epidermis of transgenic mice

Abstract

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.

Reduced Susceptibility to Two-Stage Skin Carcinogenesis in Mice with Low Circulating Insulin-Like Growth Factor I Levels

“…5 and 6, topical treatment of both wild-type mice and LID mice with either 3.4 or 6.8 nmol of TPA led to rapid activation (i.e., phosphorylation) of the EGFR, IGF-IR/IR, IRS-1, Akt, mTOR, and downstream effectors of mTOR (e.g., p70S6K, p-eIF4B, p-4E-BP1, and p-S6-ribosomal protein). These data are consistent with previously published data from our laboratory (16,17,24,25). Notably, the level of activation as assessed by phosphorylation of all signaling molecules examined was reduced in LID mice following TPA treatment compared with wild-type littermates (Figs.…”

“…The reduction in epidermal proliferation observed in LID mice following TPA treatment may explain, in part, the significant inhibition of skin tumorigenesis seen in LID mice. As noted in the Introduction, previous work from our laboratory using transgenic mice in which IGF-I expression was elevated at the tissue level through targeted overexpression in skin keratinocytes showed that these mice have an increased susceptibility to two-stage skin carcinogenesis (10,25,26). The current results clearly show that levels of circulating IGF-I can also directly affect the susceptibility to skin tumor promotion and two-stage skin carcinogenesis.…”

“…These data suggest that reduced circulating IGF-I levels influenced signaling through both the EGFR and IGF-IR following TPA treatment. In support of this idea, we previously reported the development of HKI.IGF-I transgenic mice in which expression of IGF-I was targeted to the epidermis using the human keratin 1 (HK1) promoter (25,26). Following treatment with TPA, there was a significant increase in EGFR activation in the epidermis of HKI.IGF-I transgenic mice compared with wild-type mice.…”

“…Previous studies from our laboratory have shown that activation of EGFR and erbB2 is an early event in mouse keratinocytes following exposure to tumor promoters, including TPA, either in vivo or in vitro (16,24,25,29). Activation of the EGFR and erbB2 seems to be due to increased availability of EGFR ligands through a combination of ectodomain shedding and increased synthesis (16,(30)(31)(32).…”

Expression and effects of inhibition of type I insulin-like growth factor receptor tyrosine kinase in mantle cell lymphoma

“…10,11 These effects have been extensively investigated in a variety of solid tumors including breast, prostate, lung, ovary, skin, and soft tissue cancers. [12][13][14][15][16] It is not surprising, therefore, that inhibitors of IGF-IR are currently being evaluated in several clinical trials enrolling patients with some of the most aggressive and resistant types of solid cancers, and some of these inhibitors have shown promising effects. 17,18 It is of note that, in contrast to the widely studied solid tumors, not so many studies have been performed to systematically explore a role of IGF-IR in hematologic neoplasms.…”