糖尿病对促进乳腺癌生长的影响

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。

Impact of diabetes on promoting the growth of breast cancer

Background:Type Ⅱ diabetes mellitus(DM2)is a significant risk factor for cancers,including breast cancer.However,a proper diabetic breast cancer mouse model is notwell-established for treatment strategy design.Additionally,the precise diabetic signaling pathways that regulate cancer growth remain unresolved.In the present study,we established a suitable mouse model and demonstrated the pathogenic role of diabetes on breast cancer progression.Methods: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)mice.Themousemodelswere administrated with antidiabetic drugs to assess the impacts of controlling DM2 in affecting tumor growth.Magnetic resonance spectroscopic imaging was employed to analyze the tumor metabolism.Results: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 progression.Anti-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 reaction.The 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 production.Metformin decreased the expression of Myc and pyruvate kinase isozyme 2(PKM2),leading to metabolism reprogramming.Moreover,metformin attenuated the mTOR/AKT signaling pathway and altered adipokine profiles.Conclusions:MMTV-ErbB2/Lepr^(db/db) mouse model was able to recapitulate diabetic HER2^(+) human breast cancer.Additionally,our results defined the signaling pathways deregulated in HER2^(+) breast cancer under diabetic condition,which can be intervened by anti-insulin resistance therapy.

2型糖尿病通过驱动代谢重编程促进胰腺癌生长

背景:流行病学研究显示,2型糖尿病(DM2)是胰腺癌发生和进展的危险因素,但其生物学机制尚不明了。本项研究旨在为阐明这一机制提供直接证据。本研究假设是DM2促进胰腺癌的进展,而二甲双胍则具有一定的治疗效果。方法:我们应用条件培养基模拟DM2来研究葡萄糖和胰岛素对胰腺癌细胞增殖的影响。同时,我们还研究了降糖药二甲双胍和罗格列酮对胰腺癌的作用。利用原位和同种异体移植小鼠模型(Leprdb/Leprdb)研究糖尿病对胰腺癌细胞生长和侵袭的影响。结果:我们发现,糖尿病可促进胰腺癌细胞生长。进一步研究发现,糖尿病小鼠胰腺癌细胞增殖能力和侵袭力(如上皮间质转化)的增强是由功能转录组学和代谢组学的变化所引起的,也就是说是激活了AKT/mTOR信号通路。二甲双胍可抑制由糖尿病引起的AKT/mTOR通路的激活进而抑制肿瘤生长。质谱分析结果显示,糖尿病小鼠经二甲双胍治疗后,其代谢谱发生了改变。结论:DM2通过改变胰腺癌细胞的转录组学和代谢组学,增强其增殖和侵袭能力,从而促进胰腺癌进展。我们的动物模型为糖尿病与胰腺癌进展之间的因果关系提供了有力的证据,并为二甲双胍的作用及其对于胰腺癌合并糖尿病患者的潜在治疗价值提供了新的认知。