The effects of black raspberry extract on UVB-induced inflammation and carcinogenesis.

摘要

Non-melanoma skin cancers (NMSCs), especially squamous cell carcinoma (SCC), are a significant problem in the general population, and a deadly one among immunosuppressed populations. Nearly a third of transplant patients die from aggressive SCCs, and the risk for development increases as the length of time under immunosuppression increases. It is not yet fully understood how immunosuppression impacts UVB-induced inflammation and carcinogenesis. In Chapter 2, we determine the impact of different immunosuppressive drugs on UVB-induced inflammation and carcinogenesis. We found that cyclosporine (CsA) exacerbates all markers of inflammation and carcinogenesis, including angiogenesis. Mycophenolate mofetil (MMF), when co-administered with CsA reduced the markers of inflammation and carcinogenesis to near vehicle levels. Choice of immunosuppression, therefore, plays a role in the development of SCC in transplant patients.;The changes wrought in keratinocytes by the change from normal cell to malignant cell are poorly understood. Understanding the changes in cytokine and chemokine expression, as well as the changes in programmed cell death pathways would give new avenues for treatment and prevention. To expand the knowledge of these changes, we used an in vitro system of normal (JB6) and pre-malignant (308) keratinocytes in the presence and absence of UVB (Chapter 3). We found that 308 cells produce more inflammatory cytokines than JB6 cells, and 308 cells have an altered expression of autophagy proteins. These changes may illustrate the steps necessary for malignant transformation.;Preventing the transformation of normal cells would be a life saver to the general population. The use of a treatment that would not interfere with immunosuppressive medications would be a boon to transplant patients. To address both of these we developed a post-UVB-exposure treatment derived from black raspberries (BRE). In Chapter 4, we explore the efficacy of BRE in the prevention of UVB-induced inflammation and carcinogenesis. BRE is able to reduce all markers of inflammation, with the exception of neutrophil infiltration. BRE is also able to reduce carcinogenesis, possibly through a reduction in tumor-infiltrating regulatory T cells.;In Chapter 5, we further explored the mechanisms behind the extract's ability to reduce the effects of UVB exposure. We again used the in vitro system of JB6 and 308 cells in the absence or presence of UVB. BRE was able to alter the cytokine and chemokine production of both cells lines whether UVB was used or not, but the results did not always match in vivo results. BRE also was able to return the expression of autophagy proteins in 308 cells more to a pattern resembling JB6 cells. We also used acutely exposed dorsal skin and UVB-induced tumors in attempt to confirm the in vitro findings. The in vitro and in vivo data correlated well.