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.

Individual differences in pre-carcinogen cytokine and corticosterone concentrations and depressive-like behavior predict tumor onset in rats exposed to a carcinogen

“…Thus, models that are characterized by classifying individuals based on natural differences in neophobic or anxiety-like behaviors may come closer to modeling innate differences in emotional disposition. The present results are consistent with studies in which rodents that are selected for reduced exploratory behavior to novelty (apomorphine-unsusceptible Wistar line) or display increased anxiety-like behavior in an elevated plus maze also grow larger tumors and/or more lung metastases (Teunis et al, 2002; Dhabhar et al, 2012). However, in the former study, tumor onset could not be measured and in the latter, potentially related baseline physiological “traits” were not assessed.…”

“…In another neophobic rat model, blunted corticosterone responses earlier in life predict spontaneous mammary tumors (Cavigelli et al, 2006). Finally, mice that are high in anxiety-like behavior using an elevated plus maze exhibit a greater skin tumor burden than those with low anxiety-like behavior (Dhabhar et al, 2012). Although these studies provide categorical links between biobehavioral measures, immune function, and disease progression, the quantitative nature of such relations has not been addressed prospectively.…”

‘As above, so below’ examining the interplay between emotion and the immune system

“…In a number of studies Kiecolt‐Glaser and colleagues have demonstrated that chronically stressful situations such as those experienced by caregivers can weaken the immune response, significantly diminishing antibody production against influenza and pneumococcal pneumonia vaccines and increasing the chance of latent herpes simplex virus flare ups . Further, in a range of clinical and experimental studies Dhabhar and his collaborators have also shown that chronic and acute stress can trigger both a deleterious and a protective T‐cell response in a wide variety of immune‐related disorders including cancer, allergy and post‐operative recovery . As you will see throughout this review, there is little that is clear cut within this developing field.…”

Psychological Stress in Children May Alter the Immune Response

“…This indicates that high-stressed children have a low spontaneous activity of Th2, Tr1, and Th17 cells, which suggests a suppressive immune response. Several studies have shown that stress exposure is associated with impaired cell-mediated acquired immunity (20,(34)(35)(36)(37)(38)(39). In 2010, Freier et al (20) showed that Tregs are downregulated during stress and concluded that this might result in an exacerbation of inflammatory conditions such as an autoimmune condition.…”