Cyclooxygenase-2 Expression in Murine and Human Nonmelanoma Skin Cancers: Implications for Therapeutic Approaches¶

Abstract

Inflammatory stimuli result in the production of cutaneous eicosanoids, which are known to contribute to the process of tumor promotion. Cyclooxygenase (COX), the rate‐limiting enzyme for the production of prostaglandins (PG) from arachidonic acid, exists in at least two isoforms, COX‐1 and COX‐2. COX‐1 is constitutively expressed in most tissues and plays various physiological roles, whereas increased COX‐2 expression is known to occur in several types of epithelial neoplasms. Enhanced PG synthesis is a potential contributing factor in UVB‐induced nonmelanoma skin cancers (NMSC). Increased COX‐2 staining occurs in murine skin neoplasms after chronic exposure to carcinogenic doses of UVB. In this study, immunohistochemical and Western blot analyses were employed to assess longitudinally COX‐2 expression in a standard mouse UVB complete carcinogenesis protocol and in human basal cell carcinomas (BCC) and squamous cell carcinomas (SCC). During UVB irradiation of mice, COX‐2 expression consistently increased in the hyperplastic skin, the benign papillomas and the SCC. COX‐2 expression was also increased in human actinic keratoses, SCC and BCC as well as in murine SCC and BCC. The pattern of COX‐2 expression was quite variable, occurring in a patchy distribution in some lesions with staining confined mainly to suprabasal cell layers. In general, COX‐2 expression progressively became more extensive in benign papillomas and well‐differentiated murine SCC. The staining was predominantly cytoplasmic and perinuclear in some focal areas in tissue stroma around both murine and human tumors. Western blot analysis confirmed negative COX‐2 expression in normal skin, whereas acute UVB exposure resulted in increased enzyme expression, which continued to increase in developing papillomas and SCC. Because of the evidence indicating a pathogenic role for eicosanoids in murine and human skin neoplasms, we performed studies to assess the anti‐inflammatory and anticarcinogenic effects of green tea extracts, which are potent antioxidants. Acute exposure of the human skin to UVB (minimum erythema dose × 4) caused a transient enhancement of the COX‐2 expression, which reverted to baseline within hours; however, in murine skin the expression persisted for several days. Pretreatment with the topically applied green tea extract (1 mg/cm2) largely abrogated the acute COX‐2 response to UVB in mice or humans. In summary, enhanced COX‐2 expression serves as a marker of epidermal UVB exposure for murine and human NMSC. These results suggest that COX‐2 inhibitors could have potent anticarcinogenic effects in UVB‐induced skin cancer.

Chemoprevention of photocarcinogenesis by selected dietary botanicals

“…108 UVB-induced increase in cyclooxygenase-2 expression was abrogated both in murine and human nonmelanoma skin cancer models by topical application of GTPs. 108 Topical treatment of GTPs to mouse skin before UV exposure decreased UV-induced myeloperoxidase activity and number of infiltrating inflammatory leukocytes in the skin. 23, 109 Studies from our laboratory showed that topical application of GTPs before UV irradiation on the backs of human individuals resulted in significantly reduced erythema development as compared to those individuals who did not receive GTPs treatment.…”

The roles of polyphenols in cancer chemoprevention

“…The inhibition of GJIC induced by hydrogen peroxide, but not TPA, is also blocked by treatment with EGCG [42,59]. Green tea extract and EGCG decrease the expression of COX-2 in chemical-or UV-induced carcinogenesis in rodents [2,5,43,54]. Tea polyphenols inhibit COX-dependent arachidonic acid metabolism by microsomes from normal colonic mucosa, with EGCG exhibiting the strongest inhibitory activity [32].…”

“…Tea polyphenols inhibit COX-dependent arachidonic acid metabolism by microsomes from normal colonic mucosa, with EGCG exhibiting the strongest inhibitory activity [32]. A transient elevation of COX-2 in mouse and human skin, on acute exposure to UVB, can be abrogated when the exposed area is pretreated with green tea extract [5]. A recent study showed that EGCG can suppress COX-2 expression induced by TPA in mouse skin in vivo and also in cultured human mammary epithelial cells, possibly by inhibiting the activation of both ERK and NF-κB [54].…”

The dark side of the light: Phototherapy adverse effects

“…48 Considering this, COX-2 inhibitors (Table 2), such as celecoxib, have been used in animal models to prevent UV-induced skin cancers with success. [50][51][52] Epidemiologic evidence suggests that patients taking nonsteroidal anti-inflammatory drugs (NSAIDs) on a regular basis have lower incidence of SCCs. 53 The platelet-activating factor (PAF) and cis-urocanic acid (binding to the receptor 5-HT 2A ) are also mediators of photoimmunosuppression and photocarcinogenesis.…”