71. A novel combined psychosocial stress paradigm alters tumor VEGF and circulating exosomes in a spontaneous, metastatic model of breast cancer

Abstract

Metastatic breast cancer carries significant risk of morbidity and mortality with limited treatment options. Psychosocial stress exposure has been linked to tumor growth and metastasis; therefore understanding the underlying neurohormonal mechanisms may yield new therapeutic options and lead to the development of more effective disease interventions. Here we investigated the impact of social isolation combined with acute restraint stress on spontaneous tumor development in MMTV-PyMT mice. Mammary tumor progression in this mouse model of metastatic breast cancer mimics that of invasive ductal carcinoma in humans. Female MMTV-PyMT mice were singly housed at 8 weeks of age during the hyperplastic stage of tumor development. Restraint stress was initiated after 2 weeks of isolation. Control mice remained in their home cages throughout the experiment. Twenty-four hours after the final restraint exposure, stressed mice exhibited elevated circulating corticosterone and splenic normetanephrine (a norepinephrine metabolite), which correlated with increased tumor VEGF and decreased splenic neutrophils. There was no difference in total tumor burden at this early carcinoma stage. Circulating CD63+ exosomes, extracellular vesicles that drive cancer pathogenesis, were decreased. These results demonstrate the dual stressor elicited potent hypothalamic pituitary axis (HPA) and sympathetic nervous system (SNS) activation in conjunction with alterations in the premetastatic tumor that may facilitate progression.