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首页> 外文期刊>Neoplasia: an international journal for oncology research >Constitutively Active Akt1 Cooperates with KRasG12D to Accelerate In Vivo Pancreatic Tumor Onset and Progression
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Constitutively Active Akt1 Cooperates with KRasG12D to Accelerate In Vivo Pancreatic Tumor Onset and Progression

机译：组成型活性Akt1与Krasg12d合作，以加速体内胰腺肿瘤发作和进展

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BACKGROUND AND AIMS: Pancreatic adenocarcinoma is a deadly disease characterized by metastatic progression and resistance to conventional therapeutics. Mutation of KRAS is the most frequent early event in pancreatic tumor progression. AKT isoforms are frequently activated in pancreatic cancer, and reports have implicated hyperactivation of AKT1, as well as AKT2, in pancreatic tumor formation. The objective here is to delineate the role of AKT in facilitating in vivo pancreatic tumor progression in the context of KRAS mutation and predisposition to pancreatic cancer. METHODS: Mice with Akt1 and KRas mutant alleles expressed using the pancreas Pdx promoter were mated to characterize the incidence and frequency of histologic and genetic alterations known to occur commonly in human pancreatic ductal adenocarcinoma. RESULTS: Active Akt1 (Akt1Myr, containing a myristoylation sequence) cooperated with active mutant KRasG12D to accelerate pancreatic carcinoma onset and progression and increase phosphorylation of downstream effectors in the Akt pathway. Mucin and smooth muscle actin expression was found in and around pancreatic intraepithelial neoplasms (PanINs), and accelerated time to metastasis was found in Akt1Myr/KRasG12D mice. CONCLUSIONS: In contrast to prior reports of pancreatic KRas mutant mice mated with mice deficient for various tumor suppressor genes, which resulted in aggressive disease within a few months of age, Akt1Myr/KRasG12D mice enabled the study of PanINs and spontaneous pancreatic transformation more characteristic of human pancreatic progression in elderly individuals. The Akt1Myr/KRasG12D model holds promise for delineating the tumor biology and biomarkers critical for understanding their cooperation in cancer oncogenesis and future targeting in therapeutic strategies.
机译：背景和目的：胰腺腺癌是一种致命的疾病，其特征在于转移性进展和对常规治疗症的抵抗力。 KRA的突变是胰腺肿瘤进展中最常见的早期事件。 Akt同种型经常在胰腺癌中激活，报告在胰腺肿瘤形成中具有含有Akt1的αkt1的多动激活，以及Akt2。这里的目的是描绘AKT在KRAS突变和胰腺癌的易感性的情况下促进体内胰腺肿瘤进展的作用。方法：使用胰腺PDX启动子表达的AKT1和KRAS突变等位基因的小鼠进行交配，以表征已知在人胰腺导管腺癌中通常发生的组织学和遗传改变的发病率和频率。结果：活性AKT1（AKT1MYR，含有肌中福利序列），其与活性突变KRASG12D配合，加速胰腺癌发作和进展，并增加AKT途径中下游效应的磷酸化。在Akt1myr / Krasg12d小鼠中发现粘膜上皮内肿瘤（胰腺上皮内肿瘤（胰岛上皮内肿瘤（胰蛋白）中发现了粘蛋白和平滑肌肌动蛋白表达，并在Akt1myr / krasg12d小鼠中发现了加速时间。结论：与对各种肿瘤抑制基因缺乏的小鼠进行胰腺KRAS突变小鼠的先前报道，导致几个月内的侵袭性疾病，AKT1MYR / KRASG12D小鼠使胰腺和自发性胰腺转化的研究更具特征老年人的人类胰腺进展。 AKT1MYR / KRASG12D模型占据划清肿瘤生物学和生物标志物的承担承担令人担忧，以了解他们在癌症的癌症中的合作和治疗策略中的未来靶向。

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