Cyclooxygenase-dependent signaling is causally linked to non-melanoma skin carcinogenesis: pharmacological, genetic, and clinical evidence

Abstract

Cyclooxygenase (COX)-derived prostaglandins (PGs) exhibit manifold functions in acute and chronic skin inflammation induced by a number of physical (ultraviolet (UV) light, wounding) and chemical (12-O-tetradecanoylphorbol 13-acetate (TPA), arachidonic acid) noxious stimuli. Depending on the challenge and the context, constitutively expressed COX-1 or the transiently induced COX-2 isoform are of relevance. Moreover, squamous cell carcinoma (SCC) of skin is a prominent example of epithelial neoplasia that consistently overexpresses COX-2 in the parenchyme and the mesenchyme of premalignant and malignant lesions, while COX-1 expression remains unaltered. Pharmacological, clinical, and experimental animal studies as well as a few epidemiological studies document the importance of PG signaling in non-melanoma skin cancer including SCC and basal cell carcinoma (BCC) in humans and mice. Increased levels of PGE(2) and PGF(2α) in premalignant and/or malignant epithelial skin cancers are due to the constitutive upregulation of enzymes involved in PG biosynthesis, such as COX-2, and downregulation of the tumor suppressor gene 15-hydroxy-prostaglandin dehydrogenase (15-PGDH), which is involved in the inactivation of PG, thus counteracting the activities of COX. Most remarkably, genetic studies show that mice which are deficient in COX-2 or COX-1 are protected from the development of SCC when applying the multi-stage chemical carcinogenesis protocol. Conversely, the forced overexpression of COX-2 in the proliferative basal compartment of the stratified skin epidermis results in spontaneous hyperplasia and dysplasia in transgenic mice and furthermore a sensitization for cancer development by conferring an auto-promoted skin phenotype. In multi-stage carcinogenesis, it also becomes clear that aberrant COX-2 overexpression and activity are causally involved in tumor promotion and tumor progression rather than initiation. In contrast, using as inducer of carcinogenesis the complete carcinogen UV B light, depletion of COX-2 but not of COX-1 makes mouse skin resistant for SCC, indicating that here, only COX-2 is essential. Depending on the type of challenge, COX-2-dependent signaling contributes to the pre-invasive growth of the skin epidermis by a delayed onset of terminal differentiation, or stimulation of hyperproliferation and survival. With respect to BCC, the genetic ablation of COX-2 but also of COX-1 leads to a strongly reduced tumor burden in the skin of Patched (Ptch)1(+/-) mice, which due to the deletion of a Ptch1 allele, spontaneously develop BCC resembling human familial basal cell nevus syndrome and sporadic BCC. Nonsteroidal anti-inflammatory drugs and the COX-2-selective inhibitors (COXibs) exhibit impressive efficacy inhibiting tumor burden in various mouse models of SCC and BCC. Most importantly, in humans the interruption of COX-2 signaling is an effective strategy to treat and chemo-prevent non-melanoma skin cancer in individuals who are at high risk for the disease. However, any potential beneficial effect of...

Preventive Effect of Hydrazinocurcumin on Carcinogenesis of Diethylnitrosamine-induced Hepatocarcinoma in Male SD Rats

“…COX-2 signaling influence the carcinogenesis through inflammation suppression, immune response suppression, apoptosis inhibition, angiogenesis regulation and tumor cell invasion (Müller-Decker et al, 2011), which are all crucial in the development and progression of cancer . Cellular expression of COX-2 is increased in the earliest stage of carcinogenesis through tumor development and invasive tumor growth (Yildirim et al, 2008).…”

Differential modulation of inflammatory markers in plasma and skin after single exposures to UVA or UVB radiation in vivo

“…No significant effect was detected following a single UVB exposure. It is not so surprising because COX-2 is understood to be mainly a marker of pro-inflammatory conditions and cancerogenesis that is linked to repeated UVB exposures 35 . Nevertheless in human keratinocytes, Buckman et al found a moderate COX-2 protein increase at 6 h and strong one at 24 h after UVB (290-320 nm, 30 mJ/cm 2 ) exposure 36 .…”

Cell-type-specific roles for COX-2 in UVB-induced skin cancer

“…Prostaglandins play a major role in modulating the inflammatory properties observed in UVB-irradiated skin and in UVB-induced experimental tumors (2). Two cyclooxygenase isoforms, COX-1 and COX-2, are responsible for production of prostaglandin H2 (PGH2), the common precursor to a wide range of prostanoids (3).…”

“…In mouse skin, UVB irradiation induces extensive Cox-2 gene activation and COX-2 protein accumulation (5,6). Both COX-1 and COX-2 are present in non-melanoma skin cancers from patients and in UVB radiation-induced SKH-1 mouse premalignant skin papillomas and squamous cell carcinomas (SCCs) (2). COX-dependent prostaglandins are, consequently, postulated to be drivers of UVB-induced skin cancer promotion and progression (7).…”

“…A second approach to determine the roles of COX-1 and COX-2 in biological phenomena has been the use of mice with global Cox-1 and Cox-2 gene deletions (2). The use of these genetically altered mice eliminates questions of off-target NSAID and coxib effects but introduces potential problems of altered developmental and physiological mechanisms in the mutant mice to compensate for absence of the COX enzymes.…”