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Diabetes mellitus type 2 drives metabolic reprogramming to promote pancreatic cancer growth

Gastroenterology Report 2020年第4期8卷 261-276,I0001页

作者： guermarie velazquez-torres Enrique Fuentes-Mattei Hyun Ho Choi Sai-Ching J.Yeung Xiangqi Meng Mong-Hong Lee Department of Molecular and Cellular Oncology Division of Basic Science ResearchThe University of Texas MD Anderson Cancer CenterHoustonTXUSA Guangdong Provincial Key laboratory of Colorectal and Pelvic Floor Disease Sun Yat-sen UniversityGuangzhouP.R.China Guangdong Research Institute of Gastroenterology The Sixth Affiliated Hospital of Sun Yat-sen UniversityGuangzhouP.R.China Department of Emergency Medicine Division of Internal Medicine The University of Texas MD Anderson Cancer CenterHoustonTXUSA

Background: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 *** purpose of this study is to demonstrate direct evidence for the mechanisms mediating these epidemiologic *** hypothesis is that DM2 accelerates pancreatic cancer growth and that metformin treatment has a beneficial ***:To determine the effect of glucose and insulin in pancreatic cancer proliferation,we used conditioned media to mimic DM2 ***,we studied the effect of anti-diabetic drugs,particularly metformin and rosiglitazone on pancreatic cancer *** established orthotopic/syngeneic(Leprdb/db)mouse cancer models to evaluate the effect of diabetes on pancreatic tumor growth and ***:Our results showed that diabetes promotes pancreatic tumor ***,enhanced tumor growth and aggressiveness(***-mesenchymal transition)can be explained by functional transcriptomic and metabolomic changes in the mice with diabetes,namely via activation of the AKT/mTOR *** treatment suppressed the diabetes-induced AKT/mTOR pathway activation and tumor *** metabolic profile determined by mass spectrum showed important changes of metabolites in the pancreatic cancer derived from diabetic mice treated with ***:Diabetes mellitus type 2 has critical effects that promote pancreatic cancer progression via transcriptomic and metabolomic *** animal models provide strong evidence for the causal relationship between diabetes and accelerated pancreatic *** study sheds a new insight into the effects of metformin and its potential as part of therapeutic interventions for pancreatic cancer in diabetic patients.

关键词： pancreatic cancer type 2 diabetes mellitus cancer metabolism

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Impact of diabetes on promoting the growth of breast cancer

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Cancer Communications 2021年第5期41卷 414-431页

作者： Ping-Chieh Chou Hyun Ho Choi Yizhi Huang Enrique Fuentes-Mattei guermarie velazquez-torres Fanmao Zhang Liem Phan Jaehyuk Lee Yanxia Shi James A.Bankson Yun Wu Huamin Wang Ruiying Zhao Sai-Ching Jim Yeung Mong-Hong Lee Department of Molecular and Cellular Oncology the University of Texas MD Anderson Cancer CenterHoustonTX 77030USA Guangdong Provincial Key laboratory of Colorectal and Pelvic Floor Disease the Sixth Affiliated Hospital of Sun Yat-sen UniversityGuangzhouGuangdong 510020P.R.China Research Institute of Gastroenterology the Sixth Affiliated Hospital of Sun Yat-sen University GuangzhouGuangdong 510020P.R.China Department of Imaging Physics the University of Texas MD Anderson Cancer CenterHoustonTX 77030USA Department of Medical Oncology Sun Yat-sen University Cancer CenterGuangzhouGuangdong 510060P.R.China Department of Pathology the University of Texas MD Anderson Cancer CenterHoustonTX 77030USA Department of Emergency Medicine the University of Texas MD Anderson Cancer CenterHoustonTX 77030USA

Background:Type Ⅱ diabetes mellitus(DM2)is a significant risk factor for cancers,including breast ***,a proper diabetic breast cancer mouse model is notwell-established for treatment strategy ***,the precise diabetic signaling pathways that regulate cancer growth remain *** the present study,we established a suitable mouse model and demonstrated the pathogenic role of diabetes on breast cancer ***:We successfully generated a transgenic mouse model of human epidermal growth factor receptor 2 positive(Her2^(+) or ERBB2)breast cancer with DM2 by crossing leptin receptor mutant(Lepr^(db/+))mice with (MMTV-ErbB2/neu)*** administrated with antidiabetic drugs to assess the impacts of controlling DM2 in affecting tumor *** resonance spectroscopic imaging was employed to analyze the tumor ***:Treatment with metformin/rosiglitazone in MMTV-ErbB2/Lepr^(db/db) mousemodel reduced serum insulin levels,prolonged overall survival,decreased cumulative tumor incidence,and inhibited tumor ***-insulin resistance medications also inhibited glycolytic metabolism in tumors in vivo as indicated by the reduced metabolic flux of hyperpolarized ^(13)C pyruvate-to-lactate *** tumor cells from MMTV-ErbB2/Lepr^(db/db) transgenic mice treated with metformin had reprogrammed metabolism by reducing levels of both oxygen consumption and lactate *** decreased the expression of Myc and pyruvate kinase isozyme 2(PKM2),leading to metabolism ***,metformin attenuated the mTOR/AKT signaling pathway and altered adipokine ***:MMTV-ErbB2/Lepr^(db/db) mouse model was able to recapitulate diabetic HER2^(+) human breast ***,our results defined the signaling pathways deregulated in HER2^(+) breast cancer under diabetic condition,which can be intervened by anti-insulin resistance therapy.

关键词： diabetes human epidermal growth factor receptor 2 breast cancer metformin metabolism

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糖尿病对促进乳腺癌生长的影响

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癌症 2022年第3期41卷 107-124页

作者： Ping-Chieh Chou Hyun Ho Choi Yizhi Huang Enrique Fuentes-Mattei guermarie velazquez-torres Fanmao Zhang Liem Phan Jaehyuk Lee Yanxia Shi James A.Bankson Yun Wu Huamin Wang Ruiying Zhao Sai-Ching Jim Yeung Mong-Hong Lee Department of Molecular and Cellular Oncology the University of Texas MD Anderson Cancer CenterHoustonTX 77030USA 结直肠盆底疾病研究重点实验室中山大学第六附属医院广州广东510020 胃肠病学研究所中山大学第六附属医院广州广东510020 Department of Imaging Physics the University of Texas MD Anderson Cancer CenterHoustonTX 77030USA 中山大学肿瘤防治中心肿瘤内科广州广东510060 Department of Pathology the University of Texas MD Anderson Cancer CenterHoustonTX 77030USA Department of Emergency Medicine the University of Texas MD Anderson Cancer CenterHoustonTX 77030USA

背景与目的2型糖尿病(typeⅡdiabetes mellitus,DM2)是包括乳腺癌在内的多种癌症的危险因素。目前,尚未建立可用于研究的糖尿病乳腺癌小鼠模型。另外,调节癌症生长的糖尿病信号通路也尚未明确。在本研究中,我们建立了一个糖尿病乳腺癌... 详细信息

背景与目的2型糖尿病(typeⅡdiabetes mellitus,DM2)是包括乳腺癌在内的多种癌症的危险因素。目前,尚未建立可用于研究的糖尿病乳腺癌小鼠模型。另外,调节癌症生长的糖尿病信号通路也尚未明确。在本研究中,我们建立了一个糖尿病乳腺癌小鼠模型,并证实了糖尿病在乳腺癌进展中的影响。方法通过将瘦素受体突变(Lepr^(db/+))小鼠和MMTV-ErbB2/neu小鼠杂交,成功构建了人表皮生长因子受体2阳性(human epidermal growth factor receptor 2,Her2^(+)或ERBB2)的乳腺癌转基因小鼠模型。用抗糖尿病药物治疗该小鼠模型来评价治疗DM2对肿瘤生长的影响。用磁共振波谱成像分析肿瘤代谢情况。结果用二甲双胍/罗格列酮治疗MMTV-ErbB2/Lepr^(db/db)小鼠模型可降低血清胰岛素水平,延长生存,降低肿瘤累积发生率,抑制肿瘤进展。超极化^(13)C标记的丙酮酸/乳酸转换代谢流降低,表明抗胰岛素抵抗治疗抑制了体内实验中肿瘤糖酵解。用二甲双胍处理MMTV-ErbB2/Lepr^(db/db)转基因小鼠来源的肿瘤细胞,降低了耗氧量和乳酸产量,使细胞代谢发生了重新编程。二甲双胍可降低Myc和丙酮酸激酶M2型同工酶(pyruvate kinase isozyme 2,PKM2)的表达,引起代谢重编程。另外,二甲双胍可阻断mTOR/AKT信号通路并改变脂肪因子谱。结论MMTV-ErbB2/Lepr^(db/db)转基因小鼠模型可用于糖尿病HER2^(+)人乳腺癌的研究。本研究明确了糖尿病状态下HER2^(+)人乳腺癌中失调的信号通路,该通路可被抗胰岛素抵抗治疗干预。

关键词：糖尿病人表皮生长因子受体2 乳腺癌二甲双胍代谢

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