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Molecular and Cellular Mechanisms of Photocarcinogenesis

Authors


  • This paper is dedicated to Professor Margaret L. Kripke on the occasion of her retirement from the University of Texas, MD Anderson Cancer Center.

*email: beisser@uni-muenster.de (Stefan Beissert)

Abstract

Skin cancer constitutes one of the most frequent types of malignancies in humans with rapidly increasing incidences almost worldwide. UVR is an essential risk factor for the development of premalignant as well as malignant skin lesions. In this context UVR can function as a complete carcinogen by inducing “UV signature” DNA mutations and by suppressing protective cellular antitumoral immune responses. UV-induced DNA damage can result in impaired cutaneous cell cycle control if cell cycle regulators, such as the p53 gene, are affected. Besides interfering with cell cycle control genes, UV-induced DNA damage can result in the release of interleukin-10, a cytokine with known immunosuppressive effects on T-helper(h)-1 cells. For the development of antitumoral immune responses antigen-specific activation of effector T cells by antigen-presenting cells (APC) is required. It was demonstrated that UVR can inhibit antigen presentation both directly and indirectly via the induction of suppressive cytokines. In addition, subsets of T cells are induced upon UVR, which can actively suppress major histocompatibility complex class I/II-restricted immune responses. These UV-induced regulatory T cells appear to belong to the CD4+CD25+ T cell lineage and can express the characteristic transcription factor Foxp3, which programs for suppressor function. In mice UV-induced regulatory T cells can control the development of UV-induced skin cancer. Peripheral regulatory T cells are maintained by the expression of B7 molecules and can be expanded by APC of the skin. Recently, epidermal expression of CD254 (RANKL) has been shown to connect UVR with the expansion of regulatory CD4+CD25+ T cells. In the following, new molecular and cellular mechanisms of UV-induced skin tumor development will be described and discussed.

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