Suppression of NK Cell Activity and of Resistance to Metastasis by Stress: A Role for Adrenal Catecholamines and β-Adrenoceptors

Abstract

Although acute stress has been reported to suppress natural killer cell activity (NKA) and host resistance to metastasis, it is unclear whether the sympathetic nervous system (SNS) has a role in these effects. The current study in Fischer 344 rats assessed the involvement of adrenal catecholamines and β₁- and β₂-adrenoceptors in mediating these deleterious effects of swim stress. In addition to assessing the number and activity of NK cells following swim stress, we used a tumor model based on the MADB106 mammary adenocarcinoma line: this syngeneic tumor metastasizes only to the lungs, and its lung tumor retention (LTR) and metastatic colonization are highly sensitive to NKA. The findings indicate that stress increased both LTR, assessed 24 h after inoculation, and the number of lung metastases, counted 3 weeks later. These effects were attenuated or completely abolished by the ganglionic blocker chlorisondamine (3 mg/kg i.p.), by adrenal demedullation, by a selective β-adrenergic antagonist (nadolol, 0.4 mg/kg), and additively by a selective β₁- (atenolol, 1–6 mg/kg) and a selective β₂-antagonist (either butoxamine 4–32 mg/kg or ICI-118,551 0.3–8 mg/kg). Stress also suppressed NKA, and adrenal demedullation prevented this suppression. Administration of adrenaline (0.1–1 mg/kg) or of a β-adrenergic agonist (metaproterenol, 0.8 mg/kg), in physiologically relevant doses, suppressed NKA in a dose-dependent manner, and increased LTR to levels characteristic of swim stress. Taken together, these findings suggest that acute stress, by releasing catecholamines from the adrenal glands and activating β₁- and β₂-adrenoceptors, suppresses NKA and consequently compromises resistance to NK-sensitive metastasis.

Does Beta-blocker Therapy Improve the Survival of Patients with Metastatic Non-small Cell Lung Cancer?

“…Beta-adrenergic signaling has an important role in the initiation and progression of cancer, affecting inflammation, angiogenesis, apoptosis, cell migration, DNA damage repair and the epithelial-mesenchymal transition (Cole and Sood, 2012). Another explanation for the association of beta-adrenergic signaling with cancer growth may be related to the immune system (Ben-Eliyahu et al, 2000). Norepinephrine and beta-AR signaling have strong stimulating effects on a number of cancer types, including cancers of the colon (Masur et al, 2001;, prostate (Palm et al, 2006), ovary (Sood et al, 2006;Thaker et al, 2006), breast (Drell et al, 2003) and pancreas .…”

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

“…The perioperative administration of propranolol and other b-blockers have been frequently used to prevent surgery related cardiac complications and mortality (49). We used a nonselective b-antagonist (propranolol), as human leukocytes and human tumor cells express both b-1 and b-2 adrenoceptors (50, 51), and as our previous study indicated that the blockade of both receptor systems was more effective than each alone in preventing stress-induced promotion of metastasis (52). Importantly, in the clinical setting of oncologic surgery, the drug regimen used in this study may be even more efficient if initiated a few days before surgery, because etodolac could reduce PGs release by primary tumors (14); propranolol could reduce anxiety (53) and antagonize the excess release of CAs owing to preoperative physiologic and psychologic stress responses (54,55).…”

Neuroendocrine influences on cancer biology

“…These effects are thought to be mediated in part by the sympathetic nervous system, the HPA axis, and a variety of other hormones and peptides [8,[10][11][12][13]. In both animal and human studies, chronic stress has been shown to decrease cellular immune parameters, such as natural killer (NK) cell cytotoxicity and T-cell responses to mitogen stimulation [14][15][16].…”