Early impact of social isolation and breast tumor progression in mice

Abstract

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 stress-induced 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 tumor-promoting 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.

Housing temperature-induced stress drives therapeutic resistance in murine tumour models through β2-adrenergic receptor activation

“…Although, we have not specifically examined the effect of housing temperature on innate immune cells such as neutrophils, macrophages or natural killer cells, it is possible that they could also influence the response of tumours to therapies at different ambient temperatures. In addition, work by Madden et al 69 have shown that in a model of social isolation, increased NE levels were associated with an accumulation of suppressive immune cells. Nevertheless, the in vitro studies reported here support the conclusion that NE has significant direct effects on tumour cells and their therapeutic resistance.…”

Restraint and Social Isolation Stressors Differentially Regulate Adaptive Immunity and Tumor Angiogenesis in a Breast Cancer Mouse Model

“…Using the 4T1 cells to model aggressive, triple negative breast cancer, we show that SI significantly increased disease progression resulting in an early sacrifice of the mice. SI has previously been associated with increased mammary tumor growth and tumor invasiveness in SV40 T-antigen FVB/N (TAg) mice, and in mouse and rat xenografts with MDA-MB-231 cells (Hermes et al, 2009; Madden et al, 2013; Williams et al, 2009). However, the effects of stress on tumor size were thought to have a short term impact and were dependent on when mice were subjected to SI (i.e.…”

“…However, the effects of stress on tumor size were thought to have a short term impact and were dependent on when mice were subjected to SI (i.e. before or after palpable tumor formation) (Madden et al, 2013). We did not observe significant effects of SI on the primary tumor size at the time of death which raises the possibility that SI modulates the ability to adapt to growing tumors, presumably through the immune system, rather than affecting the ability to control tumor growth.…”

Role of social factors on cell death, cerebral plasticity and recovery after stroke

“…House, et al, 1988 reviewed findings from clinical studies (House et al , 1988) which generated significant interest in understanding the physiological underpinnings of the detrimental effects of SI in the scientific community and encouraged researchers to develop animal models to study the effects of isolation. This has led to significant advancements in our understanding of SI effects in both disease and non-disease conditions over the past two decades (Liu & Wang, 2005; Stranahan et al , 2006; Karelina et al , 2009b; Cacioppo et al , 2011; Karelina et al , 2011; Liu et al , 2012; Stuller et al , 2012; Madden et al , 2013). Animal studies using models of Alzheimer’s disease, schizophrenia, depression, stroke and epilepsy to note a few ( see Table.…”