Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Oncogene. 2010 Feb 4;29(5):674-86. doi: 10.1038/onc.2009.375. Epub 2009 Nov 9.
Mutations of SMAD4/DPC4 are found in about 60% of human invasive pancreatic ductal adenocarcinomas (PDACs); yet, the manner in which SMAD4 deficiency enhances tumorigenesis remains elusive. Using a Cre-LoxP approach, we generated a mutant mouse carrying a targeted deletion of Smad4 in the pancreas. We showed that the absence of Smad4 alone did not trigger pancreas tumor formation; however, it increased the expression of an inactivated form of Pten, suggesting a role of Pten in preventing Smad4-/- cells from undergoing malignancy. To investigate this, we disrupted both Pten and Smad4. We showed that Pten deficiency initiated widespread premalignant lesions, and a low tumor incidence that was significantly accelerated by Smad4-deficiency. The absence of Smad4 in a Pten-mutant background enhanced cell proliferation and triggered transdifferentiation from acinar, centroacinar and islet cells, accompanied by activation of Notch1 signaling. We showed that all tumors developed in the Smad4/Pten-mutant pancreas exhibited high levels of pAKT and mTOR, and that about 50 and 83% of human pancreatic cancers examined showed increased pAKT and pmTOR, respectively. Besides the similarity in gene expression, the pAKT and/or pmTOR-positive human PDACs and mouse pancreatic tumors also shared some histopathological similarities. These observations indicate that Smad4/Pten-mutant mice mimic the tumor progression of human pancreatic cancers that are driven by activation of the AKT-mTOR pathway, and uncovered a synergistic action of Smad4 and Pten in repressing pancreatic tumorigenesis.
SMAD4/DPC4 的突变存在于大约 60%的人浸润性胰腺导管腺癌（PDAC）中；然而，SMAD4 缺陷如何增强肿瘤发生仍然难以捉摸。我们使用 Cre-LoxP 方法，在胰腺中产生了一种靶向缺失 Smad4 的突变小鼠。我们表明，单独缺失 Smad4 本身不会引发胰腺肿瘤形成；然而，它增加了失活形式的 Pten 的表达，表明 Pten 在防止 Smad4-/-细胞发生恶性转化中起作用。为了研究这一点，我们破坏了 Pten 和 Smad4。我们表明，Pten 缺失引发了广泛的癌前病变，并且 Smad4 缺失显著加速了低肿瘤发生率。在 Pten 突变背景下缺失 Smad4 增强了细胞增殖，并引发了从腺泡、中心腺泡和胰岛细胞的转分化，伴随着 Notch1 信号的激活。我们表明，Smad4/Pten 突变胰腺中发育的所有肿瘤都表现出高水平的 pAKT 和 mTOR，并且大约 50%和 83%的人胰腺癌细胞分别显示出增加的 pAKT 和 pmTOR。除了基因表达的相似性之外，pAKT 和/或 pmTOR 阳性的人 PDAC 和小鼠胰腺肿瘤也具有一些组织病理学上的相似性。这些观察表明，Smad4/Pten 突变小鼠模拟了由 AKT-mTOR 通路激活驱动的人类胰腺癌的肿瘤进展，并揭示了 Smad4 和 Pten 在抑制胰腺肿瘤发生中的协同作用。
