Role of natural killer cells in psychosocial stressor-induced changes in mouse mammary tumor growth (original) (raw)
Related papers
Life Sciences, 1993
The present report investigated whether percentages of circulating natural killer (NK) cells and NK cell activity (NKCA) are associated with psychological variables. Subjects (n=95) were selected, based on a combination of low or high scores on questionnaires on daily hassles and selfreported symptoms, to create four extreme groups. NK cell percentages were different between two of the four groups, only when the analysis was not controlled for gender, life style and endocrine parameters. No evidence was found for a relationship between group membership and NKCA. NKCA, however, was found to differ between men and women and to be associated with percentages of NK cells and invacellular levels of cAMP. Furthermore, the hypothesis was tested, that hormone-induced changes in NKCA in vitro are dependent on the individual's current stress proffie. To investigate this issue, NKCA was measured after cells had been incubated with hydrocortisone (10 .6 or 10 -7 M) or the l~-adrenergic agonist isoprenaline (10 .5 or 10 -7 M) in vitro. Changes in NKCA were found to be related to plasma adrenaline levels, but no evidence was found for involvement of psychological variables. It is concluded that, in the current setting, there is no association between the combination of scores on the two psychological questionnaires, and NKCA or hormone-induced changes therein.
Brain, Behavior, and Immunity, 2012
Natural killer (NK) cells are specialized innate lymphocytes important in the early defense against tumor and virus bearing cells. Many factors influence the immune system's effectiveness against pathogens, including stress. Social disruption (SDR) "primes" macrophages/monocytes and dendritic cells thereby enhancing their antimicrobial function. What remains unclear is whether similar responses are evident in NK cells. Current studies investigated the cellular distribution and activation/inhibitory phenotypes of NK cells in the spleen, lung, and blood of C57BL/6 male mice following SDR. Furthermore, cytolytic activity and anti-viral cytokine production of splenic NK cells were determined. Lastly, β-adrenergic receptor (β-AR) signaling was investigated to determine possible mechanisms behind the SDR-induced NK cell alterations. Results indicated NK cells from SDR mice have increased expression of CD16 and CD69 and reduced NKG2a and Ly49a expression on splenic CD3-/DX5+ NK cells indicative of an activated phenotype, both immediately and 14hrs post-SDR. Administration of propranolol (10mg/kg; non-selective βadrenergic receptor antagonist) was shown to block these "priming" effects at the 14hr time-point. In the lung, SDR had similar effects on activation and inhibitory receptors 14hr post-SDR, however no alterations were evident in the blood besides increased NK cells directly after SDR. Additionally, splenic NK cells from SDR mice had increased CD107a surface expression, cytolytic activity, and IFN-γ production was increased upon costimulation with IgG and IL-2 ex vivo. Collectively, these data suggest that social stress "primes" NK cells in the spleen and lung to be more proficient in their cytolytic and antiviral/tumor effecter functions through β-adrenergic receptor dependent signaling.
Social Support, Psychological Distress, and Natural Killer Cell Activity in Ovarian Cancer
Journal of Clinical Oncology, 2005
Purpose Psychosocial stress has been related to impaired immunity in cancer patients. However, the extent to which these relationships exist in immune cells in the tumor microenvironment in humans has not been explored. We examined relationships among distress, social support, and natural killer (NK) cell activity in ovarian cancer patients in peripheral-blood mononuclear cells (PBMC), ascitic fluid, and tumor-infiltrating lymphocytes (TIL). Patients and Methods Patients awaiting surgery for a pelvic mass suspected of being ovarian cancer completed psychological questionnaires and gave a presurgical sample of peripheral blood. Samples of tumor and ascites were taken during surgery, lymphocytes were then isolated, and NK cytotoxicity and percentage were determined. The final sample, which was confirmed by surgical diagnosis, included 42 patients with epithelial ovarian cancer and 23 patients with benign masses. Results Peripheral NK cell activity was significantly lower among ovarian...
Stress Causes Reduced Natural Killer Activity in Mice
Scandinavian Journal of Immunology, 1983
The natural killer (NK) activity of spleen cells from C57B1/10 mice subjected to standardized stress conditions was reduced when compared with that of untreated controls. Both the total number of nucleated spleen cells and their cytotoxic activity against an NK-sensitive target were reduced. The reduction appeared after induction of stress, and the NK activity was reduced throughout an 8-day stress period,
Psychosocial stressors and mammary tumor growth
Neurotoxicology and Teratology, 2000
Stressful life events and the ability to cope with stress may play a role in the progression of breast cancer; however, the complex relationship between stressors and tumor growth is difficult to investigate in humans. Our studies have utilized the androgen-responsive Shionogi mouse mammary carcinoma (AR SC115) in male mice to investigate the effects of social housing condition on tumor growth rates and responses to chemotherapy. We demonstrate that, depending on social housing condition, mammary tumor growth and response to chemotherapy can both increase and decrease. We have examined the possible role(s) of 1) psychosocial variables, 2) testosterone and corticosterone, hormones altered by stress and known to stimulate SC115 cells in vivo and in vitro, 3) NK cells, one of the body's first lines of defense against tumor cells, 4) stress proteins, in mediating the differential tumor growth rates observed in our model. This review discusses the investigations we have undertaken to elucidate the mechanisms through which a psychosocial stressor, social housing condition, can alter tumor growth rate.
Effects of Social Stress on Immunomodulation and Tumor Development
Over the last 30 years, much interesting research has been carried out in the field of psychoneuroimmunology which has shown, with scientific rigor, that psychological states, including those generated by exposure to stress-inducing agents, may alter the immune balance and influence both health and illness. Psychoneuroimmunology is the convergence of various different disciplines (behavioral science, endocrinology, neuroscience and immunology) which studies the immune changes associated with behavioral change and the behavioral changes associated with immunological changes, as well as the mechanisms involved in this relationship. It is based on the reciprocal relationships which exist between the Central Nervous System (CNS) and the Immune System (IS), the two most complex systems involved in the maintenance of homeostasis. Communications between the CNS and the IS are bidirectional and involve neurotransmitters, neurohormones, neuropeptides and cytokines, which together form a complex network that is still being explored today. Four general research areas have found evidence of the existence of afferent and efferent communication channels between the two systems. These areas are: -Studies focusing on lesions to or stimulations of certain regions of the brain which alter the immune response . -Studies which have revealed the extensive presence of sympathetic nervous system fibers, mainly noradrenergic in nature, innervating both the primary and secondary lymphoid organs. These nervous fibers innervate the vascular and parenchymal zones of lymphoid organs, thus providing a close anatomical link between the two systems (D. L. . -Studies focusing on the influence of numerous CNS neurohormones, mainly hypothalamic-pituitary in nature, which have a strong regulatory effect on the IS, as well as on the expression of numerous receptors which the immune cells have for them . -Finally, other studies have shown that products of immune cells, such as cytokines, have a neuroendocrine activity which is capable of influencing diverse brain functions, as well as providing information to the neuroendocrine system, activating inhibitory feedback circuits to ensure their own regulation .
Early impact of social isolation and breast tumor progression in mice
Brain, Behavior, and Immunity, 2013
Evidence from cancer patients and animal models of cancer indicates that exposure to psychosocial stress can promote tumor growth and metastasis, but the pathways underlying stressinduced cancer pathogenesis are not fully understood. Social isolation has been shown to promote tumor progression. We examined the impact of social isolation on breast cancer pathogenesis in adult female severe combined immunodeficiency (SCID) mice using the human breast cancer cell line, MDA-MB-231, a high ß-adrenergic receptor (AR) expressing line. When group-adapted mice were transferred into single housing (social isolation) one week prior to MB-231 tumor cell injection into a mammary fat pad (orthotopic), no alterations in tumor growth or metastasis were detected compared to group-housed mice. When social isolation was delayed until tumors were palpable, tumor growth was transiently increased in singly-housed mice. To determine if sympathetic nervous system activation was associated with increased tumor growth, spleen and tumor norepinephrine (NE) was measured after social isolation, in conjunction with tumorpromoting macrophage populations. Three days after transfer to single housing, spleen weight was transiently increased in tumor-bearing and non-tumor-bearing mice in conjunction with reduced splenic NE concentration and elevated CD11b+Gr-1+ macrophages. At day 10 after social isolation, no changes in spleen CD11b+ populations or NE were detected in singly-housed mice. In the tumors, social isolation increased CD11b+Gr-1+, CD11b+Gr-1-, and F4/80+ macrophage populations, with no change in tumor NE. The results indicate that a psychological stressor, social isolation, elicits dynamic but transient effects on macrophage populations that may facilitate tumor growth. The transiency of the changes in peripheral NE suggest that homeostatic mechanisms may mitigate the impact of social isolation over time. Studies are underway to define the neuroendocrine mechanisms underlying the tumor-promoting effects of social isolation, and to determine the contributions of increased tumor macrophages to tumor pathogenesis.
Biological Psychology, 1998
The present study explored cardiovascular and immune responses to a standardized laboratory challenge (speech task) in 23 breast cancer patients. All patients were diagnosed with positive axilliary lymph nodes and received tamoxifen as an adjuvant treatment throughout the course of the study. As a control group, 15 age-matched healthy women were included. At baseline, there were no differences in blood pressure and heart rate values between breast cancer patients and healthy women. With respect to the lymphocyte subsets at baseline, patients had significantly higher absolute numbers of CD16/56 (NK) cells. We speculate that the increase in circulating NK cells can be either a sign of activation of aspecific natural immunity caused by tumor cells or an immunostimulatory effect of tamoxifen. No differences were found in total lymphocyte count and numbers of CD3, CD4, CD8 or CD19 (B) cells. The pattern of changes induced by the speech task with regard to number and function of peripheral immune cells confirm earlier findings derived from healthy subjects. Overall, marked increases were observed in NK and CD8 cells, whereas smaller changes were observed in numbers of CD4 and CD19 (B) cells in response to the G. 6an der Pompe et al. / Biological Psychology 48 (1998) 21-35 22 speech task. There were no significant differences in the acute stress-induced immune cell changes between breast cancer patients and healthy women. These results seem to implicate that the distribution of immune cells is intact in patients with localized breast disease. With respect to natural killer cell activity (NKCA), our results, as do those of others, show a significant increase in response to the speech task in both healthy women and patients. Compared to the NKCA responses of healthy women, those of breast cancer patients appeared to be delayed. Potential mechanisms behind this difference are discussed.
Correlation of natural killer activity with tumorigenesis of a preneoplastic mouse mammary lesion
Cancer Research, 1989
Tissue infiltrating lymphocytes isolated from the preneoplastic mouse mammary hyperneoplastic alveolar nodule (HAN) tissue line C4 express high levels of natural killer (NK) activity, which gradually wanes as spontaneous tumors develop (W. Z. Wei and G. Heppner. Br. J. Cancer, 55: 589-594, 1987). Experiments were performed to test whether mod ulation of NK cell activity would be associated with altered progression of HAN to tumor. Administration of polyinosinic-polycytidylic acid, which activates NK activity but does not directly affect mammary epithe lial cell growth, to HAN-bearing mice enhanced tumor progression, as measured by a decrease in the latency period and increase in the incidence of mammary adenocarcinomas developing in the HAN implants. Antiasialo GMI, which reduces NK activity, reduced tumor progression. The net effect of indomethacin, which may inhibit mammary epithelial cell growth but enhances NK cell function, was to prolong the latency period of tumor development. However, this effect was reversed by interleukin 2, which activates NK cells. These findings suggest that NK activity mayprovide positive signals for progression of preneoplastic mammary lesions to frank neoplasia.
Brain, Behavior, and Immunity, 1999
In previous studies, we found differences in cellular immune responsiveness in Institute for Cancer Research (ICR) mice selectively bred for high and low levels of aggression. Compared to the high aggressive line, the low aggressive line had low levels of natural killer (NK) and T cell activity and increased susceptibility to tumor development. To dissect further this novel association, experiments were designed to test two competing hypotheses. The first hypothesis was that the phenotypic expression of the line differences in NK cell activity are dependent on and regulated by the expression of high and low levels aggressive behavior in the lines. The alternative hypothesis was that the differences in immune status are independent of the expression of aggression by the lines, suggesting linkage between a subset of genes involved in determining these complex behavioral and immunological traits or pleiotropic gene effects on both traits. In Experiment 1, three conditions of postweaning social experience (mice singly housed, group housed within line, or group housed between lines) were tested in males to determine whether experiential conditions which modify the expression of aggression would in turn modify the line differences in NK cell activity. This experiment revealed that the difference in NK cell activity between high aggressive and low aggressive male mice was attributable to line only. The different postweaning social conditions examined had no effect on modifying the differences in NK activity, and social dominance hierarchy did not correlate with levels of NK cell activity. 175 0889-1591/99 $30.00