All ETDs from UAB

Advisory Committee Chair

Laura Timares

Advisory Committee Members

Craig A Elmets

Mohammad Athar

Chander Raman

Zdenek Hel

Document Type

Dissertation

Date of Award

2014

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

The incidence of new cases of skin cancer, which includes non-melanoma epithelial tumors and melanoma, has increased dramatically over the last few decades. Approximately 75% of all skin cancer-related deaths is due to melanoma, which is one of the most aggressive and difficult cancers to treat. The initiating events and mechanisms that influence melanoma development are not fully known, due in part to a paucity of animal models amenable to identifying new oncogenic mutations, and investigating mechanisms of immunosurveillance. Transgenic mouse models often harbor an activating mutation in a known oncogene in all somatic cells, and its widespread expression from birth induces immune tolerance. We have established that exposure to a chemical carcinogen can sensitize the immune system to recognize an induced single point mutation in expressed genes that is presented as a neo-epitope on initiated, early transformed epithelial skin cells. Further, such neo-epitopes can be used to prevent the formation of carcinogen-induced squamous cell carcinoma. To determine if similar mechanisms are involved in melanocyte transformation into melanoma, we developed a new mouse carcinogenesis model using C3H/HeN mice. The role of the yellow pigment, pheomelanin, in contributing to the known increased risk of melanoma in human populations with red or light-colored hair, and in mice with light colored fur, such C3H/HeN mice, is reviewed. We present data that establishes that carcinogen-induced nevi in C3H/HeN mice contain gene alterations similar to those found in human melanoma and develop a tumor-specific microenvironment that promotes melanocytic cell transformation. The skin, where melanocytes reside, is an important source of immune mediators IL-12 and IL-23, which are reported to play important roles in non-melanoma skin cancer development and autoimmune skin diseases. Using panels of cytokine-deficient gene-knockout mice, we show that IL-23 plays a key role in nevus initiation and progression, altering melanocyte biology through direct and indirect mechanisms. Further, we determine epidermal Langerhans cells (LCs), which are required to protect against melanoma development, are the main source of these cytokines. Our work highlights that care should be taken while employing anti-IL-23-based therapeutics due to their serious side effects such as susceptibility to melanoma development.

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