Stress Hormone–Mediated Invasion of Ovarian Cancer Cells

Abstract

Purpose: There is growing evidence that stress and other behavioral factors may affect cancer progression and patient survival.The underlying mechanisms for this association are poorly understood.The purpose of this study is to determine the effects of stress-associated hormones norepinephrine, epinephrine, and cortisol on the invasive potential of ovarian cancer cells. Experimental Design:The ovarian cancer cells EG, SKOV3, and 222 were exposed to increasing levels of either norepinephrine, epinephrine, or cortisol, and the in vitro invasive potential was determined using the membrane invasion culture system. Additionally, the effects of these stress hormones on matrix metalloproteinase-2 (MMP-2) and MMP-9 were determined by ELISA. The effects of the h-adrenergic agonist isoproterenol on in vivo tumor growth were determined using nude mice. Results: Stress levels of norepinephrine increased the in vitro invasiveness of ovarian cancer cells by 89% to 198%. Epinephrine also induced significant increases in invasion in all three cell lines ranging from 64% to 76%. Cortisol did not significantly affect invasiveness of the EG and 222 cell lines but increased invasion in the SKOV3 cell line (P = 0.01). We have previously shown that ovarian cancer cells express h-adrenergic receptors. The h-adrenergic antagonist propanolol (1 Amol/L) completely blocked the norepinephrine-induced increase in invasiveness. Norepinephrine also increased tumor cell expression of MMP-2 (P = 0.02 for both SKOV3 and EG cells) and MMP-9 (P = 0.01and 0.04, respectively), and pharmacologic blockade of MMPs abrogated the effects of norepinephrine on tumor cell invasive potential. Isoproterenol treatment resulted in a significant increase in tumor volume and infiltration in the SKOV3ip1 in vivo model, which was blocked by propranolol. Conclusions: These findings provide direct experimental evidence that stress hormones can enhance the invasive potential of ovarian cancer cells. These effects are most likely mediated by stimulation of MMPs.There is extensive evidence supporting stress-immune relationships in healthy adults (1) and a growing body of literature demonstrating these relationships in cancer patients (2 -4). Meta-analyses and reviews have reported alterations in cellular immunity (decreased T-cell response to mitogen stimulation, decreased natural killer cell cytotoxicity, and altered production of cytokines) in association with chronic stress and/or depressed affect (5, 6). Among cancer patients, behavioral factors may serve as predictors of clinical outcome, such as response to therapy and overall survival (7 -11). These findings suggest that psychosocial stress factors not only affect the immune system adversely but also contribute to poor outcome in cancer patients. However, no study has shown that stressinduced changes in cancer outcomes are mediated by changes in immune system function. Here, we consider the alternative hypothesis that stress hormones directly affect tumor cells to alter their malignant potential.Immune s...

Improving Survival Rates in Two Models of Spontaneous Postoperative Metastasis in Mice by Combined Administration of a β-Adrenergic Antagonist and a Cyclooxygenase-2 Inhibitor

“…Therefore, the beneficial effects of propranolol and etodolac seem not to be mediated by directly affecting B16 or 3LL secretion of VEGF, nor by reducing stresshormone-induced increase in VEGF secretion by these tumor cells. Nevertheless, in vivo tumor responses may differ from the in vitro setting, and Sood et al have also shown that CAs can increase MMP2 and MMP9 secretion by tumor cells and accelerate tumor invasion capacity (20). Therefore, other direct effects of stress hormones on tumor cells, which were not tested herein, could clearly be involved and mediate the beneficial effects evident in this study.…”

“…reported to affect angiogenic-related processes (2,19,20), which can synergistically affect tumor progression. To further estimate the efficacy of the combined drug regimen, we compared it to poly(I:C) and to IL-12 administration, two wellestablished experimental interventions reported to control tumor progression (31).…”

“…Importantly, the aforementioned stress hormones and the cytokine dysregulation seem to suppress additional aspects of CMI, including CTLs, Th cells, and dendritic cells (1). Aside from causing suppression of CMI, CAs and PGs were shown to increase tumor cell invasion capacity, elevate VEGF secretion by malignant cells (2), and enhance tumor microvascular density (19,20). Accordingly, the blockade of CAs and PGs was indeed suggested to reduce cancer progression via multiple mechanisms (2,(20)(21)(22)(23).…”

Sympathectomized tumor-bearing mice survive longer but develop bigger melanomas

“…potentiate the proliferation and migration of the cancer cells, inhibit the tumor cell apoptosis, increase the tumor cell invasiveness and metastatic activity, support the neoangiogenesis in the tumor tissue, or suppress the natural killer cell activity (Godbout and Glaser 2006;Sood et al 2006;Th aker et al 2006;Andersen et al 2007;Sephton et al 2009;Hassan et al 2013;Nagaraja et al 2013). Th ese eff ects are mediated especially by neurotransmitters released by sympathetic nerve endings, particularly by norepinephrine (Yang 2010).…”

Can Regional Anesthesia and Analgesia Prolong Cancer Survival After Orthopaedic Oncologic Surgery?

“…For instance, surgical stress induces the release of catecholamines that act on adrenergic receptors located in the membrane of cancer cells, thus stimulating their proliferation and invasiveness [33,34]. Opioids are the most commonly used analgesics in the perioperative period.…”