The epidermal growth factor receptor inhibitor gefitinib prevents the progression of pancreatic lesions to carcinoma in a conditional LSL-KrasG12D/+ transgenic mouse model.
The epidermal growth factor receptor inhibitor gefitinib prevents the progression of pancreatic lesions to carcinoma in a conditional LSL-KrasG12D/+ transgenic mouse model.
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DOI：
10.1158/1940-6207.capr-10-0038
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发表时间：
2010-11
期刊：
影响因子：
--
通讯作者：
Rao CV
中科院分区：
文献类型：
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作者：
Mohammed A;Janakiram NB;Li Q;Madka V;Ely M;Lightfoot S;Crawford H;Steele VE;Rao CV
胰腺导管腺癌（PDAC）是最常见的胰腺恶性肿瘤，预后差。开发预防/延迟胰腺癌的新策略目前受到强烈关注。在条件性LSL-KrasG 12 D/+转基因小鼠中，评价了吉非替尼（一种表皮生长因子受体（EGFR）抑制剂）对胰腺上皮内肿瘤（PanIN）向PDAC进展的化学预防疗效。对LSL-KrasG 12 D/+和p48 Cre/+小鼠进行繁殖，并产生激活的KrasG 12 D/+的后代。对6周龄雄性KrasG 12 D/+（20只/组）和C57 BL/6野生型（12只/组）小鼠饲喂含0、100和200 ppm吉非替尼的（AIN-76 A）饲料35周。在处死时，对胰腺进行PanIN和PDAC的组织病理学评价，并通过IHC、免疫荧光、免疫印迹和/或RT-PCR测量各种生物标志物。与对照饮食相比，100和200 ppm的饮食吉非替尼分别显著抑制PDAC发生率77%和100%（p<0.0001）。重要的是，在用吉非替尼治疗的小鼠中观察到对癌的显著抑制和对PanIN的剂量依赖性抑制（PanIN 1 37 - 62%，p <0.002，PanIN 2 38-41，p<0.001，和PanIN 3 7- 34%，p<0.0141）。此外，100和200 ppm吉非替尼治疗的小鼠显示67.6-77.3%的胰腺无导管病变。此外，吉非替尼降低了胰腺病变/PDAC中的EGFR、PCNA、细胞周期蛋白D1、C2 GNT、RhoA、β-连环蛋白、p38、pERK、小窝蛋白-1和粘蛋白，并增加了细胞周期蛋白B1。总之，这些结果表明，吉非替尼可以防止胰腺癌前病变进展为PDAC在临床前模型。本研究强调了化学预防的前景和EGFR抑制剂在胰腺癌高危人群中的潜在用途。
Pancreatic ductal adenocarcinoma (PDAC) is the most common pancreatic malignancy with a dismal prognosis. Developing novel strategies to prevent/delay pancreatic cancer is currently of intense interest. The chemopreventive efficacy of gefitinib, an epidermal growth factor receptor (EGFR) inhibitor, was evaluated on the progression of pancreatic intraepithelial neoplasms (PanINs) to PDAC in conditional LSL-KrasG12D/+ transgenic mice. LSL-KrasG12D/+ and p48Cre/+ mice were bred and off-spring of activated KrasG12D/+ were generated. Six-week old male KrasG12D/+ (20/group) and C57BL/6 wild-type (12/group) mice were fed (AIN-76A) diets containing 0, 100, and 200 ppm gefitinib for 35 weeks. At termination, pancreases were evaluated histopathologically for PanINs and PDAC, and various biomarkers were measured by IHC, immunofluorescence, immunoblotting and/or RT-PCR. Dietary gefitinib at 100 and 200 ppm significantly suppressed PDAC incidence by 77 and 100%, respectively, (p<0.0001) when compared to control diet. Importantly, significant inhibition of carcinoma and a dose-dependent suppression of PanINs (PanIN1 37 – 62%,p<0.002, PanIN2 38–41,p<0.001, and PanIN3 7–34%, p<0.0141) was observed in mice treated with gefitinib. Furthermore, 100 and 200 ppm gefitinib treated mice exhibited 67.6–77.3% of the pancreas to be free from ductal lesions. Also, gefitinib reduced EGFR, PCNA, Cyclin D1, C2GNT, RhoA, β-catenin, p38, pERK, caveolin-1, and mucin, and increased cyclin B1 in the pancreatic lesions/PDAC. In summary, these results demonstrate that gefitinib can prevent pancreatic cancer precursor lesions progression to PDAC in a preclinical model. The present study highlights the promise of chemoprevention and the potential usefulness of EGFR inhibitors in high-risk individuals for pancreatic cancer.