Transgenic cyclooxygenase-2 overexpression sensitizes mouse skin for carcinogenesis

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 DMBA͞phorbol 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 F2␣, and 15-deoxy ⌬12,14 -PGJ2, is insufficient for tumor induction but transforms epidermis into an ''autopromoted'' state, i.e., dramatically sensitizes the tissue for genotoxic carcinogens.

Eryngium foetidum Suppresses Inflammatory Mediators Produced by Macrophages

“…Many studies have demonstrated that transgenic mice that overexpressed COX-2 in mammary glands, skin, and stomach are prone to develop tumours in these organs (Neufang et al, 2001;Muller-Decker et al, 2002;Oshima et al, 2004). In contrast, COX-2 knock-out mice are more resistant to tumorigenesis in various organs (Oshima et al, 1996;Tiano et al, 2002;Howe et al, 2005).…”

15-Deoxy-Δ12,14-prostaglandin J2 stabilizes, but functionally inactivates p53 by binding to the cysteine 277 residue

“…Inappropriately elevated COX-2 upregulation could contribute to promotion of cell proliferation, metastasis and angiogenesis, and resistance to apoptosis (Tsujii et al, 1998;Fischer, 2002;Muller-Decker et al, 2002;Tiano et al, 2002;Furstenberger et al, 2003). One of the terminal products of the COX-2-mediated arachidonic acid pathway is 15d-PGJ 2 , which is formed by dehydration and isomerization of PGD 2 .…”

Potential Role of Microsomal Prostaglandin E Synthase-1 in Tumorigenesis

“…In addition to colorectal cancer, transgenic overexpression of COX-2 in mouse mammary gland results in spontaneous development of mammary tumor (10). Similarly, transgenic mice with keratin 5 promoter-driven COX-2 overexpression in basal epidermal cells exhibit a preneoplastic skin phenotype (39). PGE 2 regulates COX-2-dependent, CD44-and matrix metalloproteinase-2-mediated invasion in non-small cell lung cancer in an autocrine/ paracrine manner via EP4 receptor signaling (40).…”