title: 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-E(2) 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.
authors.affiliation: Neuroimmunology Research Unit, Department of Psychology, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Shelly
authors.initials: S
authors.lastname: Inbar
authors.forename: Elad
authors.initials: E
authors.lastname: Neeman
authors.forename: Roi
authors.initials: R
authors.lastname: Avraham
authors.forename: Marganit
authors.initials: M
authors.lastname: Benish
authors.forename: Ella
authors.initials: E
authors.lastname: Rosenne
authors.forename: Shamgar
authors.initials: S
authors.lastname: Ben-Eliyahu
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003345:Corticosterone / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D004837:Epinephrine / Q000378:metabolism*; D005260:Female; D007694:Killer Cells, Natural / Q000166:cytology*; D007938:Leukemia / Q000473:pathology*; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D013315:Stress, Psychological; D013550:Swimming; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D015232:Dinoprostone; D003345:Corticosterone; D004837:Epinephrine