Marginating pulmonary-NK activity and resistance to experimental tumor metastasis: suppression by surgery and the prophylactic use of a β-adrenergic antagonist and a prostaglandin synthesis inhibitor

Abstract

Surgery is imperative for cancer treatment, but was suggested to suppress immunity and facilitate metastasis. Here we study the involvement of catecholamines and prostaglandins (PG) in such outcomes, and the role played by marginating-pulmonary (MP)-NK cells in controlling MADB106 metastasis. Non-operated and laparotomized F344 rats were injected postoperatively with a PG synthesis inhibitor (indomethacin, 4 mg/kg i.p.), a β-blocker (nadolol, 0.6 mg/kg s.c.), both drugs, or vehicle. Rats were then inoculated intravenously with non-immunogenic syngeneic MADB106 cells, and 24 h later lung tumor retention was assessed, or 3 weeks later lung metastases were counted. Additionally, 12 h after surgery we harvested MP-NK cells and circulating-NK cells and compared their numbers and cytotoxicity against MADB106 cells and standard YAC-1 target cells. Surgery significantly increased MADB106 metastasis. Nadolol and indomethacin reduced this effect by approximately 50% when used alone, and significantly more (75%) when used together. Only MP-leukocytes exhibited NK cytotoxicity against MADB106 cells. Surgery markedly suppressed it, and nadolol and indomethacin additively restored it. Similar effects were observed assessing MP-NK and circulating-NK cytotoxicity against YAC-1 target cells. Alterations in the numbers of NK cells were partly associated with alterations in total MP-NK activity, but not with circulating-NK activity. Last, administrating naı¨ve rats with physiologically relevant doses of a β-adrenergic agonist (metaproterenol), and/or with PGE 2, additively and independently of each other promoted MADB106 metastasis, simulating the effects of surgery. These findings point at potential prophylactic measures in cancer patients undergoing surgery, and suggest a role for MP-NK cells in resisting metastasis of apparently insensitive tumors.