Abstract SY31-01: Stress, anxiety, and susceptibility to squamous cell carcinoma: Role of immune mediators
Authors: Dhabhar Firdaus S. 
Published: August 2012

Approximately 2-3 million cases of non-melanoma cancers occur each year worldwide, and the skin is the most common site of cancer accounting for nearly half of all cancers in the US. Importantly, cancer patients across diverse cultures consistently rank stress as a major contributing factor to their disease which highlights the importance of investigating the effects of stress on cancer. Given that stress is an almost ubiquitous fact of life for most people, it is important and reassuring to recognize that although widely known for its negative effects on health, stress is not always or necessarily harmful. In fact, short-term or acute stress, as seen in the fight-or-flight stress response, is nature's fundamental survival system. Studies have shown that while chronic stress is known to suppress/dysregulate immune function, under certain conditions an acute/short-term stress response experienced during immune activation can enhance primary/innate and secondary/adaptive immunity (for review see: Dhabhar, NeuroImmunoModulation).

It is important to investigate the negative effects of stress in order to ameliorate or eliminate these effects. However, it also important to investigate the positive effects of stress that until recently have been largely ignored, because understanding the mechanisms by which short-term stress activates survival-promoting physiological systems may enable us to clinically harness the body's natural defenses to enhance immune responses, and promote healing and health during vaccination, surgery or cancer. Therefore, recent studies have examined the negative versus positive effects of stress on cancer using a naturalistic model of skin cancer (ultraviolet light (UV) induced squamous cell carcinoma (SCC)). The significant strengths of this cancer model are that it uses a normal, immuno-competent, outbred strain, without surgery/injection of exogenous tumor cells/cell lines, and induces precancerous lesions and tumors that closely resemble human tumors. It provides a naturalistic, non-invasive system for studying tumor emergence, regression, and progression.

In the first series of studies, mice were exposed to chronic stress during weeks 4-6 of a 10-week UV-exposure protocol (minimum-erythemal-dose, 3-times/week). Chronic stress suppressed CTACK, IL-12 and IFN-gamma gene expression, decreased CD4+ and CD8+ T cell infiltration, and significantly increased tumor burden. Interestingly, chronic stress also increased numbers of tumor-infiltrating and circulating regulatory/suppressor T cells, which represents a novel immuno-suppressive mechanism mobilized by chronic stress (Saul et al., J. National Cancer Institute). In the second series of studies mice were exposed to acute stress during weeks 4-6 of the 10-week UV-exposure protocol. These studies showed that in contrast to chronic stress, acute stress enhanced CTACK, IL-12, and IFN-gamma gene expression, increased CD4+ and CD8+ T cell infiltration, and decreased tumor burden during the early phase of tumor development (Dhabhar, et al., Brain Behavior, & Immunity).

Since high-anxious individuals may be more likely to perceive and experience stress resulting in a greater chronic stress burden, in a third series of studies we examined the effects of trait anxiety on susceptibility to SCC. Mice were phenotyped as “high-anxious” or “low-anxious” based on ethological tests. Importantly, behavioral phenotyping was performed at baseline weeks before tumor induction. High-anxious mice showed higher corticosterone levels (indicating higher chronic stress burden) and decreased anti-tumor immunity. Interestingly, high-anxious mice showed a higher tumor burden than low-anxious mice during all phases of tumor development. These results suggest that the deleterious effects of high trait-anxiety could be: exacerbated by life-stressors, accentuated by the stress of cancer diagnosis/treatment, and mediate increased tumor progression and/or metastasis. Therefore, it may be beneficial to investigate the use of chemotherapy-compatible anxiolytic treatments immediately following cancer diagnosis, and during cancer treatment/survivorship.

Taken together, these studies show that activation of chronic or acute stress physiology during UV exposure can respectively suppress or enhance anti-tumor immunity and correspondingly increase or decrease susceptibility to skin cancer. These studies add to a growing understanding of how stress affects tumor development, and may provide a means for optimizing a patient's response to cancer treatment.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY31-01. doi:1538-7445.AM2012-SY31-01