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Transgenic cyclooxygenase-2 overexpression sensitizes mouse skin for carcinogenesis
Karin Muller-Decker1, Gitta Neufang, Irina Berger
1Research Program Tumor Cell Regulation, Deutsches Krebsforschungszentrum, and Department of Pathology, Ruprecht-Karls-University, 69120 Heidelberg, Germany. K.Mueller-Decker@DKFZ-Heidelberg.de
Abstract:
Genetic and pharmacological evidence suggests that overexpression of cyclooxygenase-2 (COX-2) is critical for epithelial carcinogenesis and provides a major target for cancer chemoprevention by nonsteroidal antiinflammatory drugs. Transgenic mouse lines with keratin 5 promoter-driven COX-2 overexpression in basal epidermal cells exhibit a preneoplastic skin phenotype. As shown here, this phenotype depends on the level of COX-2 expression and COX-2-mediated prostaglandin accumulation. The transgenics did not develop skin tumors spontaneously but did so after a single application of an initiating dose of the carcinogen 7,12-dimethylbenz[a]anthracene (DMBA). Long-term treatment with the tumor promoter phorbol 12-myristate 13-acetate, as required for tumorigenesis in wild-type mice, was not necessary for transgenics. The ratios of squamous cell carcinomas to papillomas and of sebaceous gland adenomas to papillomas plus squamous cell carcinomas were increased markedly in transgenic mice treated with DMBA alone compared with DMBA/phorbol 12-myristate 13-acetate-treated transgenic and wild-type mice. Thus, COX-2 overexpression, which leads to high levels of epidermal prostaglandin E(2), prostaglandin F(2alpha), and 15-deoxy(delta12,14)-PGJ(2), is insufficient for tumor induction but transforms epidermis into an "autopromoted" state, i.e., dramatically sensitizes the tissue for genotoxic carcinogens.
Insights
Overexpression of cyclooxygenase-2 (COX-2) in skin sensitizes it to carcinogens, creating an "autopromoted" state. This COX-2 activity accelerates tumor development without needing additional promoters.
Area of Science:
- Oncology
- Molecular Biology
- Dermatology
Background:
- Cyclooxygenase-2 (COX-2) overexpression is implicated in epithelial carcinogenesis.
- Nonsteroidal anti-inflammatory drugs targeting COX-2 are explored for cancer chemoprevention.
- Keratin 5 promoter-driven COX-2 overexpression in mice creates a preneoplastic skin phenotype.
Purpose of the Study:
- To investigate the role of COX-2 overexpression in skin carcinogenesis.
- To determine if COX-2 overexpression alone is sufficient for tumor induction.
- To assess the impact of COX-2 mediated prostaglandin accumulation on skin tumor development.
Main Methods:
- Generation of transgenic mouse lines with keratin 5 promoter-driven COX-2 overexpression in basal epidermal cells.
- Administration of the carcinogen 7,12-dimethylbenz[a]anthracene (DMBA) to transgenic and wild-type mice.
- Treatment with the tumor promoter phorbol 12-myristate 13-acetate (PMA) in some groups.
- Analysis of tumor types (papillomas, squamous cell carcinomas, sebaceous gland adenomas) and ratios.
Main Results:
- Transgenic mice with COX-2 overexpression did not develop spontaneous tumors.
- A single dose of DMBA induced tumors in COX-2 overexpressing transgenics, unlike wild-type mice requiring long-term PMA treatment.
- COX-2 overexpression led to increased levels of epidermal prostaglandins (PGE2, PGF2α, 15-deoxy(Δ12,14)-PGJ2).
- Tumor profiles shifted towards squamous cell carcinomas and sebaceous gland adenomas in DMBA-treated transgenics.
Conclusions:
- COX-2 overexpression is insufficient for tumor induction but creates an "autopromoted" epidermal state.
- This "autopromoted" state dramatically sensitizes the skin to genotoxic carcinogens like DMBA.
- COX-2 mediated prostaglandin accumulation plays a key role in this sensitization process.