Do Stress Responses Promote Leukemia Progression? An Animal Study Suggesting a Role for Epinephrine and Prostaglandin-E2 through Reduced NK Activity

Abstract

In leukemia patients, stress and anxiety were suggested to predict poorer prognosis. Oncological patients experience ample physiological and psychological stress, potentially leading to increased secretion of stress factors, including epinephrine, corticosteroids, and prostaglandins. Here we tested whether environmental stress and these stress factors impact survival of leukemia-challenged rats, and studied mediating mechanisms. F344 rats were administered with a miniscule dose of 60 CRNK-16 leukemia cells, and were subjected to intermittent forced swim stress or to administration of physiologically relevant doses of epinephrine, prostaglandin-E2 or corticosterone. Stress and each stress factor, and/or their combinations, doubled mortality rates when acutely applied simultaneously with, or two or six days after tumor challenge. Acute administration of the β-adrenergic blocker nadolol diminished the effects of environmental stress, without affecting baseline survival rates. Prolonged β-adrenergic blockade or COX inhibition (using etodolac) also increased baseline survival rates, possibly by blocking tumor-related or normal levels of catecholamines and prostaglandins. Searching for mediating mechanisms, we found that each of the stress factors transiently suppressed NK activity against CRNK-16 and YAC-1 lines on a per NK basis. In contrast, the direct effects of stress factors on CRNK-16 proliferation, vitality, and VEGF secretion could not explain or even contradicted the in vivo survival findings. Overall, it seems that environmental stress, epinephrine, and prostaglandins promote leukemia progression in rats, potentially through suppressing cell mediated immunity. Thus, patients with hematological malignancies, which often exhibit diminished NK activity, may benefit from extended β-blockade and COX inhibition.

Propranolol Attenuates Surgical Stress–Induced Elevation of the Regulatory T Cell Response in Patients Undergoing Radical Mastectomy

“…This finding differs from earlier animal studies demonstrating that only the combined use of propranolol and etodolac had a significant effect on postoperative immunosuppression and the recurrence-free survival rate (14)(15)(16)(17)(18). We hypothesize that two main reasons may account for this discrepancy.…”

“…Recent data have demonstrated that CAs and PGs may be key factors that mediate the suppressive effects on antimetastatic CMI perioperatively (14)(15)(16)(17)(18). Both hormones have been repeatedly demonstrated to suppress most aspects of CMI as well as promote the Treg response in vitro (19)(20)(21)(22).…”

Natural killer cells responsiveness to physical exercise: A brief review

“…Translating all the above considerations on possible interactions among NK cells, physical exercise and tumour proliferation/inhibition, a recent and very important study by Inbar et al [86] on rats, to which a dose of CRNK-16 leukemia cells was administered, showed that when they were subjected to intermittent forced swim stress mortality rates were increased. However, prolonged β-adrenergic blockade increased baseline survival rates possibly by blocking tumour-related levels of catecholamines and prostaglandins.…”

“…However, more knowledge about the effects of exercise on immune function in these patients is needed. A systemic review was recently carried out by Kruijsen-Jaarsma et al [86] and they found that various immune parameters improved after exercise. However, knowledge of the effects of exercise on immune function in cancer patients is still limited.…”

Reducing the Risk of Post-Surgical Cancer Recurrence: A Perioperative Anti-Inflammatory Anti-Stress Approach

“…Indeed, pre-clinical in vitro and in vivo studies have indicated that β-adrenergic blockade and/or PGs synthesis inhibition can reduce the immune-suppressive and pro-metastatic effects of stress and surgery in several tumor lines and models (e.g., [10][11][12]). Specifically, the perioperative use of the β-adrenergic blocker, propranolol and the COX2 inhibitor, etodolac, was shown to be safe at the perioperative setting, and reduced post-operative metastases and mortality rates (reviewed in [2]).…”