Cancer Control Research5R01CA107498-06
Dhabhar, Firdaus S.
STRESS & UV-INDUCED SQUAMOUS CELL CARCINOMA
DESCRIPTION (provided by applicant): The primary goal of the studies proposed here is to examine the effects of acute (skin immunoenhancing) versus chronic (skin immunosuppressive) stress on the emergence, progression or regression of skin cancer. We will use a murine model of ultraviolet B radiation (UVB) induced squamous cell carcinoma (SCC). SCCs afflict over 200,000 Americans per year and cause approximately 2,000 deaths per year. An examination of the effects of stress on SCC is warranted given the rising incidence of skin cancer and the ubiquitous nature of psychological stress. However, no study has examined the relationship between stress and SCC. Five key findings support such an examination: First, acute stress has been shown to enhance skin cell mediated immunity (CMI). A stress-induced trafficking of leukocytes to the skin, and increased pro-inflammatory and Th1 cytokines mediate this immunoenhancement. Second, in contrast to acute stress, chronic stress significantly suppresses skin CMI by decreasing leukocyte mobilization and T cell numbers. Importantly. SCCs are antigenic tumors that are eliminated by anti-tumor T cell immunity and hence may be affected by stressors that modulate CMI. Third, preliminary results suggest that acute stress suppresses the emergence of UVB induced SCC. Acute stress induced trafficking of T cells to skin may mediate this effect. Fourth, preliminary data show that chronic stress increases the emergence & progression of UVB induced SCC. Suppression of IFN-y production and inhibition of tumor infiltration by T cells may mediate susceptibility. Fifth, preliminary data show that baseline anxiety status predicts susceptibility to SCC. In light of these findings, we propose experiments that will accomplish the following specific aims: Aim 1: Elucidate mechanisms by which acute or chronic stress affect tumor emergence, progression or regression following repeated UVB exposure. Aim 2: Elucidate the effects of acute vs. chronic stress on DNA damage & inflammation following single UVB exposure. Aim 3: Determine whether specific phases of UV induced pathology are accompanied by dysregulation of the circadian corticosterone rhythm (such dysregulation increases mortality in cancer patients) and identify potential cytokine mediators of dysregulation. Aim 4: Determine whether differences in anxiety-related behavior can predict susceptibility to SCC and identify potential biological mediators. Our overarching hypothesis is that acute stress may enhance resistance to SCC through increased Th1 cyotkine action & leukocyte infiltration into SCC and sentinel lymph nodes, while chronic stress will increase susceptibility by suppressing leukocyte infiltration and altering the Th2-Th2 balance in favor of Th2 cytokines within and around SCC and in sentinel lymph nodes. These findings are likely to be generalizable to other cancers that are naturally antigenic or induced to be antigenic via tumor immunotherapy. The knowledge gained from these studies may lead to development of clinical treatments using behavioral and/or pharmacological manipulations to enhance endogenous anti-tumor responses or counter factors that favor tumor progression. These studies are important in light of increasing morbidity and mortality associated with skin cancer, the ubiquitous nature of stress, and our preliminary findings on the effects of stress on SCC.