title: Surgical stress promotes the development of cancer metastases by a coagulation-dependent mechanism involving natural killer cells in a murine model.
abstract: OBJECTIVE
  To determine whether the postoperative hypercoagulable state is responsible for the increase in metastases observed after surgery.
  
  
  BACKGROUND
  Surgery precipitates a hypercoagulable state and increases the formation of cancer metastases in animal models. Coagulation promotes metastases by facilitating the formation of microthrombi around tumor cell emboli (TCE), thereby inhibiting natural killer (NK) cell-mediated destruction.
  
  
  METHODS
  Mice underwent surgery preceded by tumor cell inoculation to establish pulmonary metastases in the presence or absence of various perioperative anticoagulants. Pulmonary TCE were quantified and characterized using fluorescently labeled fibrinogen and platelets. The role of NK cells was evaluated by repeating these experiments after antibody depletion in a genetically deficient strain and by adoptively transferring NK cells into NK-deficient mice.
  
  
  RESULTS
  Surgery resulted in a consistent and significant increase in metastases while a number of different anticoagulants and platelet depletion attenuated this effect. Impaired clearance of TCE from the lungs associated with an increase in peritumoral fibrin and platelet clot formation was observed in surgically stressed mice, but not in control mice or mice that received perioperative anticoagulation. The increase in TCE survival conferred by surgery and inhibited by perioperative anticoagulation was eliminated by the immunological or genetic depletion of NK cells. Adoptive transfer experiment confirms that surgery impairs NK cell function.
  
  
  CONCLUSIONS
  Surgery promotes the formation of fibrin and platelet clots around TCE, thereby impairing NK cell-mediated tumor cell clearance, whereas perioperative anticoagulation attenuates this effect. Therapeutic interventions aimed at reducing peritumoral clot formation and enhancing NK cell function in the perioperative period will have important clinical implications in attenuating metastatic disease after cancer surgery.
authors.affiliation: Department of Surgery, Division of General Surgery, University of Ottawa, Ottawa, Canada.
authors.forename: Rashmi
authors.initials: R
authors.lastname: Seth
authors.forename: Lee-Hwa
authors.initials: LH
authors.lastname: Tai
authors.forename: Theresa
authors.initials: T
authors.lastname: Falls
authors.forename: Christiano T
authors.initials: CT
authors.lastname: de Souza
authors.forename: John C
authors.initials: JC
authors.lastname: Bell
authors.forename: Marc
authors.initials: M
authors.lastname: Carrier
authors.forename: Harold
authors.initials: H
authors.lastname: Atkins
authors.forename: Robin
authors.initials: R
authors.lastname: Boushey
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Auer
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology; D001777:Blood Coagulation; D001780:Blood Coagulation Tests; D004195:Disease Models, Animal; D005260:Female; D007694:Killer Cells, Natural / Q000276:immunology*; D008175:Lung Neoplasms / Q000276:immunology* / Q000556:secondary*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis / Q000276:immunology*; D009374:Neoplasms, Experimental / Q000276:immunology*; D009360:Neoplastic Cells, Circulating / Q000276:immunology*; D019007:P-Selectin / Q000097:blood; D013312:Stress, Physiological / Q000276:immunology*; D013514:Surgical Procedures, Operative / Q000009:adverse effects*
chemical_list: D000925:Anticoagulants; D019007:P-Selectin