Abstract 5235: Surgical stress promotes the development of cancer metastases by coagulation dependent inhibition of natural-killer cell mediated tumor cell clearance
Authors: Seth Rashmi , Tai Lee-Hwa , Kus Agnieszka , Falls Theresa , Bell John , Carrier Marc , Atkins Harold , Boushey Robin , Auer Rebecca 
Published: June 2012

Background: Surgery precipitates a hypercoagulable state and has been shown to increase the development of cancer metastases in animal models. Coagulation facilitates the formation of microthrombi around tumor cell emboli (TCE) in the microvasculature thereby inhibiting Natural-Killer (NK) cell mediated destruction. We hypothesize that the pro-metastatic effect of surgery may be secondary to the postoperative hypercoagulable state.

Objective: The aim of the study was to determine if surgical stress promotes the development of cancer metastases by increased formation of TCE associated microthrombi resulting in decreased NK cell mediated destruction and to evaluate the ability of low-molecular-weight heparin (LMWH) to inhibit the pro-metastatic effect of surgery.

Methods: Surgical stress was induced in BalbC mice by laparotomy and partial left hepatectomy, preceded by tail vein injection of colon cancer (CT26LacZ) cells to establish pulmonary metastases with or without perioperative anticoagulation with subcutaneous tinzaparin. Mice were euthanized at various time points and TCE were quantified. Fibrinogen and platelets were fluorescently labeled prior to surgical stress to evaluate TCE associated fibrin and platelet clots. Involvement of NK cells in tumor cell clearance was examined by depletion of NK cells using anti-asialo antibody.

Results: Surgery resulted in a two- to four-fold increase in metastases while anticoagulation with LMWH completely abrogated this effect. Significant difference in metastatic foci was seen at 12h and 3d post surgery but not at earlier time points (10 min and 4h) suggesting that surgical stress facilitates metastases by enhancing sustained adherence and survival of individual TCE in the vasculature while anticoagulation with LMWH prevents this effect. Fibrin and platelet clots were associated with TCE significantly more frequently in mice that underwent surgery, as compared to mice with no surgery or pretreatment with LMWH. Platelet depletion led to attenuation of metastatic deposits in surgically stressed mice. NK depletion increased metastases in control animals; surgical stress did not further increase metastases and treatment with LMWH did not decrease metastases in animals depleted of NK cells.

Conclusions: Surgery promotes the formation of fibrin and platelet clots around TCE thereby inhibiting NK cell mediated tumor cell clearance and this appears to be the mechanism for the increase in metastases seen following surgery. Anticoagulation with LMWH appears to completely abrogate this pro-metastatic 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.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5235. doi:10.1158/1538-7445.AM2011-5235