Photocarcinogenesis

There is a strong association between exposure to reactive oxygen species generating sunlight and human nonmelanoma skin cancer. The relation between UV induction and melanoma is less clear and still controversially discussed in the scientific community. However, recent epidemiological studies and results from animal studies30-36 support the concept that recreational UV-exposure and sunburns with subsequent influx of ROS- generating inflammatory cells into the skin may play an important role in the etiology of cutaneous malignant melanoma. In a recent paper, the long-term combined application of the photosensitizing agent 8-methoxypsoralen and UVA irradiation, widely used for the treatment of psoriasis and other dermatological diseases, resulted in an increased incidence in melanoma development.37

Most likely similar to nonmelanoma skin cancer, melanoma undergoes a multistage development towards the fully malignant phenotype. Operationally, this process can be subdivided into three stages, termed initiation, promotion, and progression. Initiation is thought to involve permanent genetic alterations in protooncogenes and tumor suppressor genes that make epidermal cells resistant to signals for terminal differentiation. Tumor progression appears to involve clonal expansion of initiated cells in response to tumor promoters, finally giving rise to benign papillomas. The tumor promoting agents were shown to transiently induce the expression of genes related to hyperproliferation and tissue invasion, like the matrix-metalloproteinases and distinct members of the serine protease family. Whereas benign papillomas constitutively express genes associated with hyperproliferation but not with tissue invasion, the latter property is a characteristic for the conversion of papillomas to squamous cell carcinomas during tumor progression. It was shown that these protease genes are transcriptionally regulated by the transcription factor complex AP-1, which transactivates the promoter of different matrix-degrading metalloproteinases. Constitutive AP-1 activity was observed in malignant squamous cell carcinomas, but not in benign pap-illoma producing cell lines.6

ROS generated by UVA/UVB irradiation have been shown to be involved in all three stages of (photo) carcinogenesis.1, 38 Currently both UVA and UVB are considered to be complete carcinogens. For many of the tumors studied, progression from benign hyperproliferation through dysplasia to invasion and metastasis is accompanied by changes in cell-matrix interactions (i.e. localized proteolysis of the basement membrane allowing migration of the tumor cells into the connective tissue of the dermis or of distant organs due to MMP activity). The family of matrix-metalloproteinases (MMPs) is growing and comprises at least 19 members.39, 40 While MMP-1 (collagenase) cleaves collagen type I, MMP-2 is able to degrade basement membrane compounds, including collagen type IV and type VII. MMP-3 reveals the broadest substrate specificity for proteins such as collagen type IV, proteoglycans, fibronectin, and laminin.41-44 As to their proteolytic activity, UV-induced MMPs may contribute to the dissolution of the basement membrane and der mal structural proteins. This process directly leads to tumor invasion and metastasis at distant body sites.45,46 Furthermore, MMP-1 appears also to be involved in the initiation of carcinogenesis.47 Beside UV generation of ROS, there is now evidence that tumor cells may constitutionally overproduce reactive oxygen species.48 An overproduction of a reactive oxygen species may stimulate the synthesis and activation of matrix-metalloproteinases in the peritumoral connective tissue, enhancing the invasion and spreading of tumor cells. In fact, there is evidence from in situ hybridization experiments that specific mRNAs of MMPs are synthesized in fibroblasts adjacent to basal cell carcinomas (Mauch and Krieg, unpublished observation). The activity of all MMPs is inhibited by a special class of tissue inhibitors of metalloproteinases (TIMPs). Like MMPs, TIMPs are synthesized by ordinarily resident fibroblasts. Interestingly, ROS are able to inactivate TIMPs by a direct oxidative attack, thus contributing to tumor progression and photoaging.49

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