Sepsis Increases Perioperative Metastases in a Murine Model

Abstract

ABSTRACTBackgroundCancer surgery can promote tumour metastases and worsen prognosis, but the effects of perioperative complications such as sepsis, blood loss, and hypothermia on subsequent cancer metastases have not been addressed.ObjectiveTo evaluate the effect of common perioperative factors on postoperative tumour metastases in murine models of cancer surgery. We hypothesize that perioperative blood loss, hypothermia, and sepsis facilitate tumour metastases in these murine models.MethodsPrior to surgery, pulmonary metastases were established by intravenous challenge of CT26LacZ colon cancer cells in Balb/c mice or B16LacZ melanoma cells in C57Bl/6 mice. Surgical stress was generated through partial hepatectomy (PH) or left nephrectomy (LN). Sepsis was induced by puncturing the cecum to express stool into the abdomen. Hemorrhagic shock was induced by removal of 30% of total blood volume via saphenous vein. Hypothermia was induced by removing the heating apparatus during surgery and lowering core body temperatures to 30°C. Lung tumour burden was quantified 3 days following surgery.ResultsSurgically stressed mice subjected to Stage 3 hemorrhagic shock or hypothermia did not show an additional increase in lung tumour burden. In contrast, surgically stressed mice subjected to intraoperative sepsis demonstrated an additional 2-fold increase in the number of tumour metastases. Furthermore, natural killer (NK) cell function, as assessed by YAC-1 tumour cell lysis, was significantly attenuated in surgically stressed mice subjected to intraoperative sepsis. Both NK cell-mediated cytotoxic function and lung metastases were improved with perioperative administration of polyI:C, which is a ligand for toll-like receptor (TLR)-3ConclusionsPerioperative sepsis, but not hemorrhagic shock or hypothermia, enhances the prometastatic effect of surgery in murine models of cancer. Identification of the mechanisms underlying perioperative immune suppression will be critical in the development of immunomodulation strategies that aim to attenuate perioperative metastatic disease.