Psychosocial stressors and mammary tumor growth (original) (raw)
Related papers
Interactive Effects of Psychosocial Stressors and Gender on Mouse Mammary Tumor Growth
Physiology & Behavior, 1999
Interactive effects of psychosocial stressors and gender on mouse mammary tumor growth. PHYSIOL BEHAV 66 (2) 277-284, 1999.-We have previously demonstrated that social housing condition significantly affects the growth rate of the androgen-responsive Shionogi mouse mammary carcinoma (AR SC115) in male mice. The present study examined the effects of social housing condition and acute daily exposure to a novel environment on the growth rate of an androgen-independent variant of the AR SC115 carcinoma, designated SC115V, in male and female mice. Immediately following tumor cell injection, male and female mice that were reared as individuals (I) or in groups (G) of the same sex were rehoused either from individual to same-sex groups (IG) or from group to individual (GI), or remained in their group housing condition (GG). Approximately half the mice in each housing condition were subjected to acute daily exposure to novel environments (novelty stress), a treatment shown previously to increase the significant difference in tumor growth rates between male mice in the IG and GI housing conditions. The remaining mice were left undisturbed (no novelty stress). In the presence of acute daily novelty stress, the growth rate of the SC115V tumor was significantly increased in GI compared to IG males. However, no significant differences in SC115V tumor growth rates among nonstressed GI, IG, or GG males were observed. For females, in contrast to males, acute daily novelty stress significantly decreased tumor growth in GI compared to IG mice, whereas under nonstressed conditions, tumor growth rate was significantly increased in GI compared to IG females. Neither housing condition nor novelty stress altered estrous cyclicity, nor did the stage of the estrous cycle at the time of tumor cell injection influence tumor growth rates. These findings suggest that social housing condition and novelty stress may interact to produce differential effects on the growth rate of the SC115V tumor in male and female mice.
Proceedings of the National Academy of Sciences, 2009
In a life span study, we examined how the social environment regulates naturally occurring tumor development and malignancy in genetically prone Sprague-Dawley rats. We randomly assigned this gregarious species to live either alone or in groups of five female rats. Mammary tumor burden among social isolates increased to 84 times that of age-matched controls, as did malignancy, specifically a 3.3 relative risk for ductal carcinoma in situ and invasive ductal carcinoma, the most common early breast cancers in women. Importantly, isolation did not extend ovarian function in late middle age; in fact, isolated animals were exposed to lower levels of estrogen and progesterone in the middle-age period of mammary tumor growth, with unchanged tumor estrogen and progesterone receptor status. Isolates, however, did develop significant dysregulation of corticosterone responses to everyday stressors manifest in young adulthood, months before tumor development, and persisting into old age. Among isolates, corticosterone response to an acute stressor was enhanced and recovery was markedly delayed, each associated with increased mammary tumor progression. In addition to being stressed and tumor prone, an array of behavioral measures demonstrated that socially isolated females possessed an anxious, fearful, and vigilant phenotype. Our model provides a framework for studying the interaction of social neglect with genetic risk to identify mechanisms whereby psychosocial stressors increase growth and malignancy of breast cancer.
Cancer Prevention Research, 2009
Clinical studies have revealed that social support improves the outcome of cancer patients, whereas epidemiologic studies suggest that social isolation increases the risk of death associated with several chronic diseases. However, the precise molecular consequences of an unfavorable social environment have not been defined. To do so, robust, reproducible preclinical models are needed to study the mechanisms whereby an adverse environment affects gene expression and cancer biology. Because random assignment of inbred laboratory mice to well-defined social environments allows accurate and repeated measurements of behavioral and endocrine parameters, transgenic mice provide a preclinical framework with which to begin to determine gene-environment mechanisms. In this study, we found that female C3(1)/SV40 T-antigen mice deprived of social interaction from weaning exhibited increased expression of genes encoding key metabolic pathway enzymes in the premalignant mammary gland. Chronic social isolation was associated with up-regulated lipid synthesis and glycolytic pathway gene expression-both pathways are known to contribute to increased breast cancer growth. Consistent with the expression of metabolic genes in premalignant mammary tissue, isolated mice subsequently developed a significantly larger mammary gland tumors burden compared with group-housed mice. Endocrine evaluation confirmed that isolated mice developed a heightened corticosterone stress response compared with group-housed mice. Together, these transdisciplinary studies show for the first time that an adverse social environment is associated with altered mammary gland gene expression and tumor growth. Moreover, the identification of specific alterations in metabolic pathways gene expression favoring tumor growth suggests potential molecular biomarkers and/or targets (e.g., fatty acid synthesis) for preventive intervention in breast cancer. The epidemiologic association between social environment, stress, and a variety of human pathologies, including cardiovascular disease and cancer, is well established (1-3). The underlying molecular mechanisms, however, are largely unknown. Because of the genetic and environmental variation in human populations, studying these underlying mechanisms is highly complex. Therefore, preclinical models are required to guide and refine hypothesis-driven clinical research questions. The recent discovery that mediators of neuroendocrine physiology [e.g., the β-adrenergic receptors 1 and 2 and glucocorticoid receptor (GR)] are expressed in breast (4, 5), ovarian (6), and prostate (7) cancer epithelium, as well as in diverse cell types of the surrounding stroma, provides evidence of potential physiologic connections between the (a) social environment, (b) neuroendocrine stress response, and (c) tumor gene expression and phenotype. An in vivo model to examine gene-environment interactions of such complexity requires a transdisciplinary approach that combines biobehavioral, endocrine, and tumor biology expertise. In turn, clinical and translational research might then examine the hypotheses suggested by preclinical animal data (8). Despite the intriguing evidence supporting a connection between chronic social stressors and the natural history of human cancer, previous animal models have not combined biobehavioral, endocrine, and tumor biology expertise in a Authors' Affiliations: Departments of 1 Medicine and 2 Pathology,
Role of natural killer cells in psychosocial stressor-induced changes in mouse mammary tumor growth
Cancer research, 1995
We have shown that social housing conditions affect the growth rate of the androgen-responsive Shionogi mouse mammary tumor (SC115) and differentially stimulate splenic natural killer (NK) cell activity. Mice reared in a social group and then singly housed (GI) following tumor cell injection have increased tumor growth rates and increased NK cell activity, whereas mice reared individually and then group housed following tumor cell injection have decreased tumor growth rates and decreased NK cell activity compared to that in mice remaining in their rearing group. The present study was undertaken to determine whether NK cells are involved in mediating the effects of social housing conditions on SC115 tumor growth rates. We demonstrate that the presence of the SC115 tumor significantly stimulates the activity of NK cells at the tumor site in the first 7 days after tumor cell injection, and that, consistent with the data on splenic NK cells, mice of the GI group (largest tumors) have si...
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.
Impact of stress and levels of corticosterone on the development of breast cancer in rats
Psychology Research and Behavior Management, 2016
Stress is experienced during cancer, and impairs the immune system's ability to protect the body. Our aim was to investigate if isolation stress has an impact on the development of tumors in rats, and to measure the size and number of tumors and the levels of corticosterone. Breast cancer was induced in two groups of female rats (N=20) by administration of a single dose of N-methyl-N-nitrosourea 50 mg/kg. Rats in the control group (cancer induction condition) were allowed to remain together in a large cage, whereas in the second group, rats were also exposed to a stressful condition, that is, isolation (cancer induction and isolation condition, CIIC). The CIIC group displayed anxious behavior after 10 weeks of isolation. In the CIIC group, 16 tumors developed, compared with only eleven tumors in the control cancer induction condition group. In addition, compared with the control group, the volume of tumors in the CIIC group was greater, and more rats had more than one tumor and cells showed greater morphological damage. Levels of corticosterone were also significantly different between the two groups. This study supports the hypothesis that stress can influence the development of cancer, but that stress itself is not a sufficient factor for the development of cancer in rats. The study also provides new information for development of experimental studies and controlled environments.
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 .
Psicothema, 2008
We examined the influence of individual psychological profile and social behavior on tumor development in dominant male mice. Male OF1 mice were subjected to an open field test (OFT) to observe their motor activity and latency. Subsequently, the animals were divided into three groups: Stress-Non-Inoculated (SNI), Stress-Inoculated (SI) and Control-Inoculated (CI). The SI and CI groups were inoculated with tumor cells and the SNI group with vehicle. SNI and SI were exposed to social stress with an anosmic intruder six (T1) and twenty one (T2) days after inoculation and their behavior was analyzed. After T2, subjects were put down and the pulmonary metastatic foci counted. SI developed greater pulmonary metastasis than CI, indicating an effect of stress despite the animal's dominant status. Active animals developed less pulmonary metastasis than their passive counterparts. No differences were found in social behavior at T1. Differences were found, however, in some behavioral categ...
Stress Exposure in Significant Relationships Is Associated with Lymph Node Status in Breast Cancer
PLOS ONE, 2016
Objective Life stress exposure may impact on health and disease. Previous literature showed that stressful life events are associated with cancer incidence, survival and mortality. In animal models, patterns of maternal care have been shown to critically affect stress sensitivity and immunity trajectories later in life, by modifying DNA methylation during critical periods early in life. However, the role of parental care in breast cancer progression and survival has only limitedly been explored. Here, we investigated whether these factors may be linked to biological prognostic variables. Methods One hundred twenty-three women hospitalized for surgery of primary breast cancer completed a questionnaire assessing parental bonding. Stressful events throughout the life span were also assessed. Results We found that the absence of optimal parental relationships is significantly associated with an increased risk of lymph node involvement, adjusting for confounders, while cumulative stress in the area of sentimental relationships is borderline significantly associated with the same prognostic factor. Conclusions Our results suggest that parental bonding and sentimental relations may have a role in breast cancer progression. These variables represent an important evolutionary aspect which may modulate cancer progression through psycho-physiological stress pathways and influence the immune system.
Behavioural Brain Research, 2009
It has been found that acute social stress in male OF1 mice produced a general immunosuppression and increased B16F10 tumor development. This study examined the effects of blocking either the hypothalamic-pituitary-adrenocortical (HPA) axis or the sympathetic adrenomedullary (SAM) system on the impact of such stress on tumor development. Naive male OF1 mice were individually housed for 12 days before being inoculated with tumor cells or vehicle. Six days later, tumor-bearing mice were inoculated with antalarmin (a corticotropin-releasing factor receptor antagonist), nadolol (a beta-adrenergic antagonist) or vehicle. All these mice were subjected to social stress by pairing them for 24 h with counterparts selected for their high and homogeneous levels of aggressiveness. The pairs were only in physical contact for three 5-min periods, being in sensory contact for the rest of this period. One hour after social stress, serum corticosterone and IFN-gamma levels were analyzed in each experimental group. Fifteen days later, lungs were removed to determine the number of metastatic foci with their areas, and blood samples were taken to assess serum titers of corticosterone and IFN-gamma. Both antalarmin and nadolol-treated mice developed significantly fewer metastatic foci with smaller areas than vehicletreated subjects although only the group treated with antalarmin had reduced corticosterone levels. This study confirms that social stress has complex effects on immune system and tumor development that are not simply linked to corticosterone titers.