title: High-anxious individuals show increased chronic stress burden, decreased protective immunity, and increased cancer progression in a mouse model of squamous cell carcinoma.
abstract: In spite of widespread anecdotal and scientific evidence much remains to be understood about the long-suspected connection between psychological factors and susceptibility to cancer. The skin is the most common site of cancer, accounting for nearly half of all cancers in the US, with approximately 2-3 million cases of non-melanoma cancers occurring each year worldwide. We hypothesized that a high-anxious, stress-prone behavioral phenotype would result in a higher chronic stress burden, lower protective-immunity, and increased progression of the immuno-responsive skin cancer, squamous cell carcinoma. SKH1 mice were phenotyped as high- or low-anxious at baseline, and subsequently exposed to ultraviolet-B light (1 minimal erythemal dose (MED), 3 times/week, 10-weeks). The significant strengths of this cancer model are that it uses a normal, immunocompetent, outbred strain, without surgery/injection of exogenous tumor cells/cell lines, and produces lesions that resemble human tumors. Tumors were counted weekly (primary outcome), and tissues collected during early and late phases of tumor development. Chemokine/cytokine gene-expression was quantified by PCR, tumor-infiltrating helper (Th), cytolytic (CTL), and regulatory (Treg) T cells by immunohistochemistry, lymph node T and B cells by flow cytometry, adrenal and plasma corticosterone and tissue vascular-endothelial-growth-factor (VEGF) by ELISA. High-anxious mice showed a higher tumor burden during all phases of tumor development. They also showed: higher corticosterone levels (indicating greater chronic stress burden), increased CCL22 expression and Treg infiltration (increased tumor-recruited immuno-suppression), lower CTACK/CCL27, IL-12, and IFN-γ gene-expression and lower numbers of tumor infiltrating Th and CTLs (suppressed protective immunity), and higher VEGF concentrations (increased tumor angiogenesis/invasion/metastasis). 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.
authors.affiliation: Department of Psychiatry & Behavioral Sciences, Stanford University, Stanford, California, United States of America. dhabhar@gmail.com
authors.forename: Firdaus S
authors.initials: FS
authors.lastname: Dhabhar
authors.forename: Alison N
authors.initials: AN
authors.lastname: Saul
authors.forename: Tyson H
authors.initials: TH
authors.lastname: Holmes
authors.forename: Christine
authors.initials: C
authors.lastname: Daugherty
authors.forename: Eric
authors.initials: E
authors.lastname: Neri
authors.forename: Jean M
authors.initials: JM
authors.lastname: Tillie
authors.forename: Donna
authors.initials: D
authors.lastname: Kusewitt
authors.forename: Tatiana M
authors.initials: TM
authors.lastname: Oberyszyn
mesh_terms: D000818:Animals; D001007:Anxiety / Q000150:complications* / Q000276:immunology; D002294:Carcinoma, Squamous Cell / Q000209:etiology* / Q000523:psychology*; D018925:Chemokines / Q000378:metabolism; D003345:Corticosterone / Q000097:blood; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000276:immunology; D007150:Immunohistochemistry; D051379:Mice; D016133:Polymerase Chain Reaction; D012878:Skin Neoplasms / Q000209:etiology* / Q000523:psychology*; D013315:Stress, Psychological / Q000150:complications* / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D014466:Ultraviolet Rays; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
chemical_list: D018925:Chemokines; D042461:Vascular Endothelial Growth Factor A; D003345:Corticosterone