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

This study analyses the effects of vagotomy on tumor growth and survival in a murine, pancreatic cancer model in wild-type and TNF alpha-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 TNF alpha. 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 TNF alpha -/- mice using MRI. TAMs as well as expression levels of TNF alpha were analyzed using immunohistochemistry. The role of TNF alpha 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 TNF alpha levels in tumors and considerably elevated numbers of TAMs. In vitro TNF alpha significantly stimulated growth (p < 0.05) and migration (p < 0.05) of pancreatic cancer cells. TNF alpha -/- 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 TNF alpha. Hence, the suppression of TAMs and the modulation of TNF alpha dependent pathways could offer new perspectives in immunotherapies of pancreatic cancer patients especially with remaining vital tumor cells and lost vagal modulation.