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 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.
Department of General, Visceral, Thoracic and Vascular Surgery, University Medicine, Greifswald, Germany.
Lars Ivo
LI
Partecke
Department of General, Visceral, Thoracic and Vascular Surgery, University Medicine, Greifswald, Germany.
André
A
Käding
Department of General, Visceral, Thoracic and Vascular Surgery, University Medicine, Greifswald, Germany.
Dung Nguyen
DN
Trung
Department of General, Visceral, Thoracic and Vascular Surgery, University Medicine, Greifswald, Germany.
Stephan
S
Diedrich
Department of Internal Medicine A, University Medicine, Greifswald, Germany.
Matthias
M
Sendler
Department of Internal Medicine A, University Medicine, Greifswald, Germany.
Frank
F
Weiss
Department of Experimental Radiology, University Medicine, Greifswald, Germany.
Jens-Peter
JP
Kühn
Department of Internal Medicine A, University Medicine, Greifswald, Germany.
Julia
J
Mayerle
Department of General, Visceral and Vascular Surgery, Charité-University Medicine, Campus Benjamin Franklin, Berlin, Germany (current address).
Katharina
K
Beyer
Department of General, Visceral, Thoracic and Vascular Surgery, University Medicine, Greifswald, Germany.
Wolfram
W
von Bernstorff
Department of General, Visceral, Thoracic and Vascular Surgery, University Medicine, Greifswald, Germany.
Claus-Dieter
CD
Heidecke
Department of General, Visceral, Thoracic and Vascular Surgery, University Medicine, Greifswald, Germany.
Wolfram
W
Keßler
D000230:Adenocarcinoma / Q000473:pathology / Q000628:therapy*; D000818:Animals; D063646:Carcinogenesis; D048708:Cell Growth Processes; D045744:Cell Line, Tumor; D003964:Diaphragm / Q000033:anatomy & histology*; D004195:Disease Models, Animal; D006801:Humans; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000473:pathology / Q000628:therapy*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D015167:Vagotomy, Truncal; D014630:Vagus Nerve / Q000473:pathology / Q000601:surgery*; D023041:Xenograft Model Antitumor Assays
D014409:Tumor Necrosis Factor-alpha
TNFα; macrophages; murine cancer model; pancreatic cancer; vagus nerve