Evaluating the Role of mtDNA Mutations in the Development of Non-melanoma Skin Cancer

Skin cancer continues to be the most common type of cancer in the U.S. The skin functions as a critical protective barrier to the outside world, but the skin tissue is vulnerable to the external environmental insults as well as to the damage of aging. Photo damage in the skin, in addition to other effects, causes neoplastic changes in keratinocytes which may progress to non-melanoma skin cancer.

Atypical keratinocyte growth is often associated with unprotected exposure to UV-radiation and is the result of an accumulation of somatic mutations and an increase of levels of reactive oxygen species. Although the genetic mechanism by which neoplastic changes occur is not fully established yet, it is thought that accumulation of multiple mutations is required prior to transformation into a malignant phenotype. Mitochondria play a central role in production of ATP through the process of oxidative phosphorylation. Reactive oxygen species (ROS), natural byproducts of this pathway, can damage lipids, proteins and DNA and contribute to the development of malignant tumors.

There is increasing awareness of a role of mtDNA alterations in the development of cancer since mtDNA point mutations are found at high frequency in a variety of human tumors as well as photo-aged human skin. However, the functional significance of mtDNA mutations in this complex process is not fully understood yet. Accumulation of mtDNA changes andoxidative damage generated by UV radiation may increase the levels of ROS to the point where the cells start hyper-proliferate and other carcinogenic phenotypes such migration and invasiveness can be triggered.

While high levels of ROS are known to be toxic to cells, low levels of ROS have been proposed as possible mitogenic signals for cells and their role as specific second messengers in signaling cascades involved in cell proliferation, differentiation and migration can be supported.

This proposal seeks to elucidate the mechanisms by which acquired mtDNA mutations contribute to the generation of skin cancer by producing higher levels of ROS, using cybrid model system. Cybrids are cells created by introducing mtDNAs of interest into ρ0 cells depleted of endogenous mtDNAs. In this way, the nuclear genetic complement is held constant and observed tumorigenic changes can be linked to the introduced mtDNA. Thus, this model is useful tool for studying the contributions of mtDNA mutations to the neoplastic phenotype since a role for mtDNA mutations in the development of cancer has been suggested.