Metformin suppresses cancer initiation and progression in genetic mouse models of pancreatic cancer.
Metformin suppresses cancer initiation and progression in genetic mouse models of pancreatic cancer.
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二甲双胍抑制胰腺癌基因小鼠模型中的癌症发生和进展
DOI：
10.1186/s12943-017-0701-0
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发表时间：
2017-07-24
期刊：
影响因子：
37.3
通讯作者：
Ma Q
中科院分区：
文献类型：
--
作者：
Chen K;Qian W;Jiang Z;Cheng L;Li J;Sun L;Zhou C;Gao L;Lei M;Yan B;Cao J;Duan W;Ma Q
背景胰腺导管腺癌 (PDAC) 是全球第四大癌症相关死亡原因，总体五年生存率低于 7%。越来越多的证据表明二甲双胍具有癌症预防和治疗作用，二甲双胍是治疗 2 型糖尿病最广泛使用的药物之一。然而，其在胰腺癌中的作用尚未完全阐明。在此，我们旨在进一步研究二甲双胍在基因工程小鼠胰腺癌模型中的预防和治疗作用。建立Pdx1-Cre（KC）小鼠模型，研究二甲双胍抑制胰腺肿瘤发生的作用； LSL-KrasG12D/+；色氨酸53fl/+； Pdx1-Cre (KPC) 小鼠模型用于评估二甲双胍对 PDAC 的治疗效果。通过腹腔注射雨蛙素诱导 KC 小鼠慢性胰腺炎。结果二甲双胍治疗后，KC 小鼠的胰腺腺泡导管化生 (ADM) 和小鼠胰腺上皮内瘤变 (mPanIN) 减少。慢性胰腺炎诱导了富含基质和导管样结构，并增加了 ADM 和 mPanIN 病变的形成，与细胞角蛋白 19 (CK19) 染色区域的增加一致。二甲双胍治疗减少了慢性胰腺炎介导的 ADM 和 mPanIN 的形成。此外，它还减少了 Masson 三色染色的面积百分比，并减少了 Ki67 阳性细胞的数量。在 KPC 小鼠中，二甲双胍抑制肿瘤生长和腹部侵袭的发生。更重要的是，它延长了总生存期。结论二甲双胍可抑制胰腺癌的发生，抑制慢性胰腺炎诱发的肿瘤发生，在PDAC中显示出良好的治疗效果。
BackgroundPancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-associated mortality worldwide with an overall five-year survival rate less than 7%. Accumulating evidence has revealed the cancer preventive and therapeutic effects of metformin, one of the most widely prescribed medications for type 2 diabetes mellitus. However, its role in pancreatic cancer is not fully elucidated. Herein, we aimed to further study the preventive and therapeutic effects of metformin in genetically engineered mouse models of pancreatic cancer.MethodsLSL-KrasG12D/+; Pdx1-Cre (KC) mouse model was established to investigate the effect of metformin in pancreatic tumorigenesis suppression; LSL-KrasG12D/+; Trp53fl/+; Pdx1-Cre (KPC) mouse model was used to evaluate the therapeutic efficiency of metformin in PDAC. Chronic pancreatitis was induced in KC mice by peritoneal injection of cerulein.ResultsFollowing metformin treatment, pancreatic acinar-to-ductal metaplasia (ADM) and mouse pancreatic intraepithelial neoplasia (mPanIN) were decreased in KC mice. Chronic pancreatitis induced a stroma-rich and duct-like structure and increased the formation of ADM and mPanIN lesions, in line with an increased cytokeratin 19 (CK19)-stained area. Metformin treatment diminished chronic pancreatitis-mediated ADM and mPanIN formation. In addition, it alleviated the percent area of Masson’s trichrome staining, and decreased the number of Ki67-positive cells. In KPC mice, metformin inhibited tumor growth and the incidence of abdominal invasion. More importantly, it prolonged the overall survival.ConclusionsMetformin inhibited pancreatic cancer initiation, suppressed chronic pancreatitis-induced tumorigenesis, and showed promising therapeutic effect in PDAC.
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影响因子：
--
作者：
Chae YK;Arya A;Malecek MK;Shin DS;Carneiro B;Chandra S;Kaplan J;Kalyan A;Altman JK;Platanias L;Giles F
通讯作者：
Giles F
DOI：
10.1097/pas.0000000000000533
发表时间：
2015-12
期刊：
The American journal of surgical pathology
影响因子：
--
作者：
Basturk O;Hong SM;Wood LD;Adsay NV;Albores-Saavedra J;Biankin AV;Brosens LA;Fukushima N;Goggins M;Hruban RH;Kato Y;Klimstra DS;Klöppel G;Krasinskas A;Longnecker DS;Matthaei H;Offerhaus GJ;Shimizu M;Takaori K;Terris B;Yachida S;Esposito I;Furukawa T;Baltimore Consensus Meeting
通讯作者：
Baltimore Consensus Meeting
影响因子：
5.7
作者：
Boukalova, Stepana;Stursa, Jan;Neuzil, Jiri
通讯作者：
Neuzil, Jiri
影响因子：
50.3
作者：
Guerra C;Collado M;Navas C;Schuhmacher AJ;Hernández-Porras I;Cañamero M;Rodriguez-Justo M;Serrano M;Barbacid M
通讯作者：
Barbacid M
影响因子：
50.3
作者：
Hingorani, SR;Petricoin, EF;Tuveson, DA
通讯作者：
Tuveson, DA