Prevention of pancreatic acinar cell carcinoma by Roux-en-Y Gastric Bypass Surgery

Yue Yin,Jing Zhao,Weizhen Zhang,Rui He,Wenzhen Yin,Yin Li

doi:10.1038/s41467-018-06571-w

Abstract

Roux-en-Y Gastric Bypass Surgery (RYGB) prevents the occurrence of pancreatic cell acinar carcinoma (ACC) in male and female Ngn3-Tsc1−/− mice. Ngn3 directed Cre deletion of Tsc1 gene induced the development of pancreatic ACC. The transgenic mice with sham surgery demonstrated a cancer incidence of 96.7 ± 3.35% and survival rate of 67.0 ± 1.4% at the age of 300 days. Metastasis to liver and kidney was observed in 69.7 ± 9.7% and 44.3 ± 8.01% of these animals, respectively. All animals with RYGB performed at the age of 16 weeks survived free of pancreatic ACC up to the age of 300 days. RYGB significantly attenuated the activation of mTORC1 signaling and inhibition of tumor suppressor genes: p21, p27, and p53 in pancreatic ACC. Our studies demonstrate that bariatric surgery may limit the occurrence and growth of pancreatic ACC through the suppression of mTORC1 signaling in pancreas. RYGB shows promise for intervention of both metabolic dysfunction and organ cancer.

Highlights

Roux-en-Y Gastric Bypass Surgery (RYGB) prevents the occurrence of pancreatic cell acinar carcinoma (ACC) in male and female neurogenin 3 (Ngn3)-tuberous sclerosis complex 1 (Tsc1)−/− mice
Using a mouse model of pancreatic acinar carcinoma[7]: Ngn3Tsc1−/− transgenic mice in which tuberous sclerosis complex 1 (Tsc1) gene is deleted and mTOR complex 1 (mTORC1) signaling activated in neurogenin 3 (Ngn-3) positive cells, we here report that RYGB surgery blocks the spontaneous development of pancreatic cell acinar carcinomas (ACC)
In the sham surgery group of Ngn3-Tsc1−/− male transgenic mice (Fig. 1a) in which Tsc[1] gene is deleted and mTORC1 signaling activated (Fig. 1b) in Ngn-3 positive cells, spontaneous development of pancreatic ACC steadily increased over the time from 19.2 ± 5.9% to 45 ± 5.0% and 96.7 ± 3.5% at age of 150, 200, and 300 days, respectively (Fig. 1c)

Summary

Introduction

Roux-en-Y Gastric Bypass Surgery (RYGB) prevents the occurrence of pancreatic cell acinar carcinoma (ACC) in male and female Ngn3-Tsc1−/− mice. Previous studies have demonstrated a close association of pancreatic neoplasia with hyper-activation of mTORC1 in both human beings and animals[8,9] These observations suggest that mTORC1 is critical for the carcinogenesis of pancreatic cancers. A retrospective analysis of patients at a large tertiary bariatric surgery center has demonstrated a significantly lower organ cancer risk associated with greater weight loss after RYGB surgery[14] Despite of this finding, there is currently no direct evidence supporting that RYGB surgery can effectively prevent the occurrence of cancers. Using a mouse model of pancreatic acinar carcinoma[7]: Ngn3Tsc1−/− transgenic mice in which tuberous sclerosis complex 1 (Tsc1) gene is deleted and mTORC1 signaling activated in neurogenin 3 (Ngn-3) positive cells, we here report that RYGB surgery blocks the spontaneous development of pancreatic cell acinar carcinomas (ACC)

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Results

Conclusion