Correspondence to (Present Address): Firdaus S. Dhabhar, 259 Campus Drive, MC5135, Stanford University School of Medicine, Stanford, CA 94305 moc.liamg@rahbahd

Abstract

Background

Studies have shown that chronic stress or UV radiation (UVR) independently suppress immunity. Given their increasing prevalence, it is important to understand whether and how chronic stress and UVR may act together to increase susceptibility to disease. Therefore, we investigated potential mediators of a stress-induced increase in emergence and progression of UV-induced squamous cell carcinoma.

Methods

SKH1 mice susceptible to UV-induced tumors were unexposed (naïve, n = 4) or exposed (n=16) to 2240 J/m^{of UVB three times a week for 10 weeks. Half of the UVB-exposed mice were left non-stressed (i.e., they remained in their home cages) and the other half were chronically stressed (i.e., restrained during weeks 4–6). UV-induced tumors were measured weekly from week 11 through week 34, blood was collected at week 34, and tissues were collected at week 35. mRNA expression of IL-12p40, IFN-γ IL-4, IL-10, CD3ε and CCL27/CTACK, the skin T cell-homing chemokine, in dorsal skin was quantified using real-time polymerase chain reaction. CD4+, CD8+, and CD25+ leukocytes were counted using immunohistochemistry and flow cytometry. All statistical tests were two-sided.}

Results

Stressed mice had a shorter median time to first tumor (15 versus 16.5 weeks, difference = 1.5 weeks, 95% confidence interval [CI] =−3.0 weeks to 3.3 weeks; P=.03) and reached 50% incidence earlier than controls (15 weeks versus 21 weeks). Stressed mice also had lower IFN-γ (mean = 0.03 versus mean = 0.07, difference = 0.04, 95% CI = 0.004 to 0.073; P=.02), CCL27/CTACK (mean=101 versus mean = 142, difference = 41, 95% CI =8.10 to 74.36; P=.03), and CD3ε (mean=0.18 versus mean = 0.36, difference = 0.18, 95% CI = 0.06 to 0.30; P=.007) gene expression and lower CD4+ (mean = 9.40 versus mean = 13.7, difference = 4.3, 95% CI = 2.36 to 6.32; P=.008) than non-stressed mice. In addition, stressed mice had moreregulatory/suppressor CD25+ cells infiltrating tumors and more CD4+CD25+ cells in circulation (mean=0.36 versus mean = 0.17, difference = 0.19, 95% CI = 0.005 to 0.38; P=.03) than non-stressed mice.

Conclusions

Chronic stress increased susceptibility to UV-induced squamous cell carcinoma in this mouse model by suppressing Type 1 cytokines and protective T cells and increasing regulatory/suppressor T cell numbers.

Keywords: UVB radiation, Chronic stress, CD25+ suppressor/regulatory T cell, non melanoma skin cancer, diurnal rhythm

Abstract

Stress and sunlight and are two factors that affect many people’s daily lives. Both can be beneficial in moderation, but long-term exposure to either can be detrimental in that both may contribute to the development and/or exacerbation of disease. It is estimated that over 2–3 million new cases of non-melanoma skin cancer occur each year (1). Due to a host of psycho-socio-political factors, stress has become an increasing and inevitable part of people’s lives. Chronic stress has been shown to dysregulate immune function (2) and is thought to play a role in the etiology of many diseases. Given the increasing prevalence of exposure to chronic stress and UV and their ability to independently induce pathologic effects, it becomes important to understand whether and how these factors may act together to increase susceptibility to disease.

Stress is defined as a constellation of events—a stimulus (stressor) that precipitates a reaction in the brain (stress perception) and activates physiologic fight/flight systems in the body (stress response) (3,4). Chronic stress, defined as stress that persists for several hours a day for weeks, months, or years (3,4), has been shown to have immunosuppressive effects (2) that include suppression of skin cell mediated immunity (3).

The ultraviolet B (UVB) component of sunlight is a complete carcinogen and is responsible for most non-melanoma skin cancers (5). Immediate effects of UVB radiation include DNA damage, epidermal hyperplasia and inflammation (6). UVB also suppresses lymphocyte trafficking, T cell, natural killer (NK) cell function (7), and immune responses that are directed against squamous cell carcinoma (8,9).

Here we test the hypothesis that chronic stress accelerates the emergence and progression of UVB induced squamous cell carcinoma and inhibits its regression. We examined the effects of moderate chronic stress on the emergence, progression, and regression of squamous cell carcinoma induced by low level (minimal erythemal dose [MED], i.e., without blistering) exposure to UVB radiation in a mouse model. Our goal was to identify potential molecular and cellular immunologic mediators of the exacerbating effects of chronic stress on the emergence and progression of squamous cell carcinoma. Because both squamous cell carcinoma and basal cell carcinoma are immunogenic non-melanoma skin cancers, our findings may also be applicable to basal cell carcinoma, which is the most common form of skin cancer in the United States (10).

Abbreviations

UVB	Ultraviolet-B
UVBR	Ultraviolet-B radiation
SCC	squamous cell carcinoma
IL-12	Interleukin-12
IFNγ	Interferon gamma
NK	Natural Killer
CCL27 / CTACK	Cutaneous T-cell Attracting Chemokine
IL-10	Interleukin 10
IL-4	Interleukin 4
PCR	Polymerase Chain Reaction
GAPDH	Glyceraldehyde-3-phosphate dehydrogenase
NS	no stress
ChrSTR	chronic stress

Abbreviations

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