Velazquez-Torres Guermarie, Fuentes-Mattei Enrique, Choi Hyun Ho, Yeung Sai-Ching J, Meng Xiangqi, Lee Mong-Hong
Department of Molecular and Cellular Oncology, Division of Basic Science Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Guangdong Provincial Key laboratory of Colorectal and Pelvic Floor Disease, Sun Yat-sen University, Guangzhou, P. R. China.
Gastroenterol Rep (Oxf). 2020 May 27;8(4):261-276. doi: 10.1093/gastro/goaa018. eCollection 2020 Aug.
Diabetes mellitus type 2 (DM2) is a modifiable risk factor associated with pancreatic carcinogenesis and tumor progression on the basis of epidemiology studies, but the biological mechanisms are not completely understood. The purpose of this study is to demonstrate direct evidence for the mechanisms mediating these epidemiologic phenomena. Our hypothesis is that DM2 accelerates pancreatic cancer growth and that metformin treatment has a beneficial impact.
To determine the effect of glucose and insulin in pancreatic cancer proliferation, we used conditioned media to mimic DM2 conditions. Also, we studied the effect of anti-diabetic drugs, particularly metformin and rosiglitazone on pancreatic cancer growth. We established orthotopic/syngeneic ( ) mouse cancer models to evaluate the effect of diabetes on pancreatic tumor growth and aggressiveness.
Our results showed that diabetes promotes pancreatic tumor growth. Furthermore, enhanced tumor growth and aggressiveness (e.g. epithelial-mesenchymal transition) can be explained by functional transcriptomic and metabolomic changes in the mice with diabetes, namely via activation of the AKT/mTOR pathway. Metformin treatment suppressed the diabetes-induced AKT/mTOR pathway activation and tumor growth. The metabolic profile determined by mass spectrum showed important changes of metabolites in the pancreatic cancer derived from diabetic mice treated with metformin.
Diabetes mellitus type 2 has critical effects that promote pancreatic cancer progression via transcriptomic and metabolomic changes. Our animal models provide strong evidence for the causal relationship between diabetes and accelerated pancreatic cancers. This study sheds a new insight into the effects of metformin and its potential as part of therapeutic interventions for pancreatic cancer in diabetic patients.
基于流行病学研究，2型糖尿病（DM2）是一种与胰腺癌发生及肿瘤进展相关的可改变风险因素，但其生物学机制尚未完全明确。本研究旨在为介导这些流行病学现象的机制提供直接证据。我们的假设是DM2会加速胰腺癌的生长，而二甲双胍治疗具有有益作用。
为了确定葡萄糖和胰岛素对胰腺癌增殖的影响，我们使用条件培养基模拟DM2条件。此外，我们研究了抗糖尿病药物，特别是二甲双胍和罗格列酮对胰腺癌生长的影响。我们建立了原位/同基因小鼠癌症模型，以评估糖尿病对胰腺肿瘤生长和侵袭性的影响。
我们的结果表明，糖尿病促进胰腺肿瘤生长。此外，糖尿病小鼠的功能性转录组学和代谢组学变化，即通过激活AKT/mTOR途径，可以解释肿瘤生长和侵袭性增强（如上皮-间质转化）。二甲双胍治疗可抑制糖尿病诱导的AKT/mTOR途径激活和肿瘤生长。质谱测定的代谢谱显示，用二甲双胍治疗的糖尿病小鼠来源的胰腺癌中代谢物有重要变化。
2型糖尿病通过转录组学和代谢组学变化对促进胰腺癌进展具有关键作用。我们的动物模型为糖尿病与加速胰腺癌之间的因果关系提供了有力证据。本研究为二甲双胍的作用及其作为糖尿病患者胰腺癌治疗干预措施一部分的潜力提供了新的见解。
