A complete carcinogen, Ultraviolet B radiation (290-320 nm; UVB), is the major cause of skin cancer. UVB-induced systemic immunosuppression that contributes to photocarcinogenesis is due to the glycerophosphocholine-derived lipid mediator Platelet-activating factor. A major question in photobiology is how UVB radiation, which only absorbs appreciably in the epidermal layers of skin, can generate systemic effects. UVB exposure and PAF Receptor (PAFR) activation in keratinocytes induce large amounts of microvesicle particle (extracellular vesicles 100-1000nm; MVP) release. MVPs released from skin keratinocytes in vitro in response to UVB (UVB-MVP) are dependent upon the keratinocyte PAFR. The present studies used both pharmacologic and genetic approaches in cells and mice to determine that both the PAFR and enzyme acid sphingomyelinase (aSMase) were necessary for UVB-MVP generation. Discovery that the calcium-sensing receptor is a keratinocyte-selective MVP marker allowed us to determine that UVB-MVP leaving the keratinocyte can be found systemically in mice and in human subjects following UVB. Moreover, UVB-MVP contain bioactive contents including PAFR agonists which allow them to serve as effectors for UVB downstream effects, in particular UVB-mediated systemic immunosuppression.

Recent studies have implicated subcellular microvesicle particles (MVP) in the ability of ultraviolet B radiation to exert both local and systemic effects. Indeed, UVB generates MVP (UVB-MVP) in human skin and systemically following phototherapy. The current studies were designed to test the hypothesis that the ability of UVB to generate MVP was dependent upon reactive oxygen species (ROS). To that end, we tested urine samples from subjects undergoing UVB phototherapy for the presence of isoprostanes as well as the oxidized guanosine derivative 8OHdG. We also conducted a clinical study in which volar forearms of subjects were treated with localized UVB and erythema/MVP measured. The same cohort was then treated with 7 days of vitamin C (2 g day À1 ) and vitamin E (1000 IU day À1 ), and UVBinduced MVPs tested on the contralateral forearm. Urine specimens from subjects undergoing phototherapy were found to have increased levels of isoprostanes and 8OHdG, with maximal levels noted 8-16 h post-treatment. Treatment with antioxidant vitamins resulted in diminished UVBgenerated skin MVP to baseline levels. These studies suggest that whole-body UVB generates a systemic pro-oxidative response, and that antioxidants can attenuate localized skin UVB-MVPs.

Actinic keratoses (AK), also known as solar keratoses, are precancerous hyperkeratotic papules caused by long-term exposure to ultraviolet radiation. Management of AK prior to progression to cutaneous malignancy represents an important window of intervention. This is important on a population level, given the high incidence, morbidity, financial costs, and the low but measurable risk of mortality from cutaneous neoplasia. Treatments for AK have been refined for many years with significant progress over the past decade. Those recent advancements lead to questions about current treatment paradigms and the role of harnessing the immune system in field therapies. Recent studies suggest a key interplay between vitamin D and cancer immunity; in particular, the systemic and/or topical vitamin D analogs can augment field therapies used for severe actinic damage. In this review, we will examine the literature supporting the use of vitamin D-directed therapies to improve field therapy approaches. An enhanced understanding of these recent concepts with a focus on mechanisms is important in the optimized management of AK. These mechanisms will be critical in guiding whether selected populations, including those with immunosuppression, heritable cancer syndromes, and other risk factors for skin cancer, can benefit from these new concepts with vitamin D analogs and whether the approaches will be as effective in these populations as in immunocompetent patients.