Chronic stress and susceptibility to skin cancer.
BACKGROUND
Studies have shown that chronic stress or UV radiation independently suppress immunity. Given their increasing prevalence, it is important to understand whether and how chronic stress and UV radiation 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/m2 of UVB radiation three times a week for 10 weeks. Half of the UVB-exposed mice were left nonstressed (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 interleukin (IL)-12p40, interferon (IFN)-gamma, IL-4, IL-10, CD3epsilon, 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 to 3.3 weeks; P = .03) and reached 50% incidence earlier than controls (15 weeks versus 21 weeks). Stressed mice also had lower IFN-gamma ( 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 = 8.1 to 74.4; P = .03), and CD3epsilon (mean = 0.18 versus mean = 0.36, difference = 0.18, 95% CI = 0.06 to 0.30; P = .007) gene expression and lower numbers of infiltrating CD4+ cells (mean = 9.40 versus mean = 13.7, difference = 4.3, 95% CI = 2.36 to 6.32; P = .008) than nonstressed mice. In addition, stressed mice had more regulatory/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 nonstressed 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.
Saul
Alison N
AN
Colleges of Medicine and Public Health, The Ohio State University, Columbus, OH, USA.
Oberyszyn
Tatiana M
TM
Daugherty
Christine
C
Kusewitt
Donna
D
Jones
Susie
S
Jewell
Scott
S
Malarkey
William B
WB
Lehman
Amy
A
Lemeshow
Stanley
S
Dhabhar
Firdaus S
FS
D000818:Animals; D017252:CD3 Complex / Q000097:blood; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002294:Carcinoma, Squamous Cell / Q000209:etiology* / Q000276:immunology; D054425:Chemokine CCL27; D019742:Chemokines, CC / Q000032:analysis; D002908:Chronic Disease; D016207:Cytokines / Q000097:blood*; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000097:blood; D016753:Interleukin-10 / Q000097:blood; D015847:Interleukin-4 / Q000097:blood; D007958:Leukocyte Count; D051379:Mice; D008815:Mice, Inbred Strains; D009365:Neoplasm Regression, Spontaneous; D015375:Receptors, Interleukin-2 / Q000276:immunology; D012867:Skin / Q000737:chemistry; D012878:Skin Neoplasms / Q000209:etiology* / Q000276:immunology; D013315:Stress, Psychological / Q000150:complications* / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D013997:Time Factors; D014466:Ultraviolet Rays / Q000009:adverse effects*
D017252:CD3 Complex; C119538:Ccl27a protein, mouse; C485468:Cd3e protein, mouse; D054425:Chemokine CCL27; D019742:Chemokines, CC; D016207:Cytokines; D015375:Receptors, Interleukin-2; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma