Wang Guangfu, Gao Hao, Dai Shangnan, Li Mingna, Gao Yong, Yin Lingdi, Zhang Kai, Zhang Jingjing, Jiang Kuirong, Miao Yi, Lu Zipeng
Pancreas Center, First Affiliated Hospital of Nanjing Medical University, Nanjing, 210000, China; Pancreas Institute, Nanjing Medical University, Nanjing, 210000, China.
Department of Pathology, First Affiliated Hospital of Nanjing Medical University, Nanjing, 210000, China.
Cancer Lett. 2023 May 28;562:216155. doi: 10.1016/j.canlet.2023.216155. Epub 2023 Apr 6.
Obesity has been linked to a higher risk of pancreatic cancer. However, the mechanism by which obesity promote pancreatic carcinogenesis is still unclear. We investigated the effect of obesity on pancreatic carcinogenesis in Pdx1-Cre; LSL-Kras (KC) mice. Metformin was administrated to rescue the effects of obesity and NETs. The pro-tumorigenic effects of neutrophil extracellular traps (NETs) were further evaluated in vivo and vitro. We found that obesity significantly promoted the progression of murine pancreatic ductal intraepithelial neoplasia (mPanIN). The proliferation rate and epithelial-mesenchymal transition (EMT) of mPanIN ductal cells were increased in obese mice. More visceral adipocytes, PD-L1 neutrophil infiltration and NETs formation were found in the pancreas of obese mice and visceral adipocytes could recruit neutrophils and promote NETs formation. The latter could induce an inflammatory response in ductal cells via TLR4-dependent pathways both in vivo and vitro, as demonstrated by upregulation of IL-1β. Metformin and DNase I significantly reversed the pro-tumorigenic effects of obesity and NETs in vivo and in vitro. Our study provides causal evidence for the contribution of obesity in promoting pancreatic carcinogenesis in genetic model and reveals the mechanism by NETs to regulate mPanIN progression.
肥胖与胰腺癌风险升高有关。然而，肥胖促进胰腺癌发生的机制仍不清楚。我们研究了肥胖对Pdx1-Cre; LSL-Kras（KC）小鼠胰腺癌发生的影响。给予二甲双胍以挽救肥胖和中性粒细胞胞外陷阱（NETs）的影响。在体内和体外进一步评估了中性粒细胞胞外陷阱（NETs）的促肿瘤作用。我们发现肥胖显著促进了小鼠胰腺导管上皮内瘤变（mPanIN）的进展。肥胖小鼠中mPanIN导管细胞的增殖率和上皮-间质转化（EMT）增加。在肥胖小鼠的胰腺中发现更多的内脏脂肪细胞、PD-L1中性粒细胞浸润和NETs形成，并且内脏脂肪细胞可以募集中性粒细胞并促进NETs形成。后者可通过TLR4依赖性途径在体内和体外诱导导管细胞发生炎症反应，如IL-1β的上调所示。二甲双胍和脱氧核糖核酸酶I在体内和体外均显著逆转了肥胖和NETs的促肿瘤作用。我们的研究为肥胖在遗传模型中促进胰腺癌发生的作用提供了因果证据，并揭示了NETs调节mPanIN进展的机制。
