Subdiaphragmatic vagotomy promotes tumor growth and reduces survival via TNFα in a murine pancreatic cancer model

Abstract

// Lars Ivo Partecke 1, * , André Käding 1, * , Dung Nguyen Trung 1 , Stephan Diedrich 1 , Matthias Sendler 2 , Frank Weiss 2 , Jens-Peter Kühn 3 , Julia Mayerle 2 , Katharina Beyer 4 , Wolfram von Bernstorff 1 , Claus-Dieter Heidecke 1 , Wolfram Keßler 1 1 Department of General, Visceral, Thoracic and Vascular Surgery, University Medicine, Greifswald, Germany 2 Department of Internal Medicine A, University Medicine, Greifswald, Germany 3 Department of Experimental Radiology, University Medicine, Greifswald, Germany 4 Current address: Department of General, Visceral and Vascular Surgery, Charité–University Medicine, Campus Benjamin Franklin, Berlin, Germany * These authors contributed equally to this work and share first authorship Correspondence to: André Käding, email: andre.kaeding@uni-greifswald.de Keywords: vagus nerve, TNFα, pancreatic cancer, macrophages, murine cancer model Received: September 06, 2016      Accepted: January 23, 2017      Published: February 02, 2017 ABSTRACT This study analyses the effects of vagotomy on tumor growth and survival in a murine, pancreatic cancer model in wild-type and TNFα-knockout (–/–) mice. Throughout many operative procedures in the upper gastrointestinal tract the partial or complete transection of the vagus nerve or its local nerve fibers is unavoidable. Thereby its anti-inflammatory effects in residual tumor tissue may get lost. This effect may be mediated by tumor-associated macrophages (TAM) secreting TNFα. In an orthotopic murine pancreatic cancer model subdiaphragmatic vagotomy versus sham surgery was performed. The impact on tumor growth was monitored in wild type and TNFα –/– mice using MRI. TAMs as well as expression levels of TNFα were analyzed using immunohistochemistry. The role of TNFα on tumor growth and migration was examined in vitro . Vagotomised mice showed increased tumor growth with macroscopic features of invasive growth and had a shorter survival time. The loss of vagal modulation led to significantly increased TNFα levels in tumors and considerably elevated numbers of TAMs. In vitro TNFα significantly stimulated growth ( p < 0.05) and migration ( p < 0.05) of pancreatic cancer cells. TNFα –/– mice survived significantly longer after tumor implantation ( p < 0.05), with vagotomy not affecting the prognosis of these animals ( p > 0.05). Vagotomy can increase tumor growth and worsen survival in a murine pancreatic cancer model mediated through TAMs and TNFα. Hence, the suppression of TAMs and the modulation of TNFα dependent pathways could offer new perspectives in immunotherapies of pancreatic cancer patients especially with remaining vital tumor cells and lost vagal modulation.