title: Reducing liver metastases of colon cancer in the context of extensive and minor surgeries through β-adrenoceptors blockade and COX2 inhibition.
abstract: Liver metastases are a major cause of colorectal cancer death, and the perioperative period is believed to critically affect the metastatic process. Here we tested whether blocking excess release of catecholamines and prostaglandins during surgical procedures of different extent can reduce experimental liver metastasis of the syngeneic CT26 colon cancer in female and male BALB/c mice. Animals were either treated with the beta-blocker, propranolol, the COX-2 inhibitor, etodolac, both drugs, or vehicle. The role of NK cells in controlling CT26 hepatic metastasis and in mediating the effect of the drugs was assessed by in vivo depletion or stimulation of NK cells, using anti-asialo GM1 or CpG-C, respectively. Surgical extent was manipulated by adding laparotomy to small incision, extending surgical duration, and enabling hypothermia. The results indicated that combined administration of propranolol and etodolac, but neither drug alone, significantly improved host resistance to metastasis. These beneficial effects occurred in both minor and extensive surgeries, in both sexes, and in two tumor inoculation approaches. NK cell-mediated anti-CT26 activity is involved in mediating the beneficial effects of the drugs. Specifically, CpG-C treatment, known to profoundly activate mice marginating-hepatic NK cytotoxicity, reduced CT26 hepatic metastases; and NK-depletion increased metastases and prevented the beneficial effects of the drugs. Overall, given prevalent perioperative psychological and physiological stress responses in patients, and ample prostaglandin release by colorectal tumors and injured tissue, propranolol and etodolac could be tested clinically in laparoscopic and open colorectal surgeries, attempting to reduce patients' metastatic disease.
authors.affiliation: Neuroimmunology Research Unit, Sagol School of Neuroscience, and The School of Psychological Sciences, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Liat
authors.initials: L
authors.lastname: Sorski
authors.affiliation: Neuroimmunology Research Unit, Sagol School of Neuroscience, and The School of Psychological Sciences, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Rivka
authors.initials: R
authors.lastname: Melamed
authors.affiliation: Neuroimmunology Research Unit, Sagol School of Neuroscience, and The School of Psychological Sciences, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Pini
authors.initials: P
authors.lastname: Matzner
authors.affiliation: Neuroimmunology Research Unit, Sagol School of Neuroscience, and The School of Psychological Sciences, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Hagar
authors.initials: H
authors.lastname: Lavon
authors.affiliation: Neuroimmunology Research Unit, Sagol School of Neuroscience, and The School of Psychological Sciences, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Lee
authors.initials: L
authors.lastname: Shaashua
authors.affiliation: Neuroimmunology Research Unit, Sagol School of Neuroscience, and The School of Psychological Sciences, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Ella
authors.initials: E
authors.lastname: Rosenne
authors.affiliation: Neuroimmunology Research Unit, Sagol School of Neuroscience, and The School of Psychological Sciences, Tel-Aviv University, Tel-Aviv, Israel. Electronic address: shamgar@post.tau.ac.il.
authors.forename: Shamgar
authors.initials: S
authors.lastname: Ben-Eliyahu
mesh_terms: D000318:Adrenergic beta-Agonists / Q000008:administration & dosage*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000601:surgery*; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage*; D017308:Etodolac / Q000008:administration & dosage*; D005260:Female; D007694:Killer Cells, Natural / Q000378:metabolism; D007813:Laparotomy; D008113:Liver Neoplasms / Q000517:prevention & control* / Q000556:secondary; D008297:Male; D008807:Mice, Inbred BALB C; D013511:Minor Surgical Procedures; D011433:Propranolol / Q000008:administration & dosage*
chemical_list: D000318:Adrenergic beta-Agonists; D000970:Antineoplastic Agents; D052246:Cyclooxygenase 2 Inhibitors; D017308:Etodolac; D011433:Propranolol
keywords: COX-2 inhibition; CT26 colon-cancer; Colorectal cancer; Etodolac; Liver metastasis; Peri-operative period; Propranolol; β-Adrenergic blocker