Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse
Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse
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DOI：
10.1016/s1535-6108(03)00309-x
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发表时间：
2003-12-01
期刊：
影响因子：
50.3
通讯作者：
Tuveson, DA
中科院分区：
文献类型：
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作者：
Hingorani, SR;Petricoin, EF;Tuveson, DA
为了评估致癌性RAS突变在胰腺肿瘤发生中的作用，我们将KRAS（G12D）的内源性表达引向小鼠胰腺的祖细胞。我们发现，KRAS（G12D）的生理水平诱导导管病变，这些病变概括了人类胰腺上皮内肿瘤（PANINS）（PANINS），假定的前体为侵入性胰腺癌。 Panins具有高度增殖，显示了组织学进展的证据，并激活了导管上皮中通常静止的信号传导途径，这表明对同源人类状况的潜在治疗和化学预防靶标。在低频率下，这些病变也自发地发展为浸润性和转移性腺癌，将Panins确立为侵入性疾病的确定性前体。最后，带有Panins的小鼠具有可识别的血清蛋白质组学特征，这表明一种检测患者侵入性状态的方法。
To evaluate the role of oncogenic RAS mutations in pancreatic tumorigenesis, we directed endogenous expression of KRAS(G12D) to progenitor cells of the mouse pancreas. We find that physiological levels of Kras(G12D) induce ductal lesions that recapitulate the full spectrum of human pancreatic intraepithelial neoplasias (PanINs), putative precursors to invasive pancreatic cancer. The PanINs are highly proliferative, show evidence of histological progression, and activate signaling pathways normally quiescent in ductal epithelium, suggesting potential therapeutic and chemopreventive targets for the cognate human condition. At low frequency, these lesions also progress spontaneously to invasive and metastatic adenocarcinomas, establishing PanINs as definitive precursors to the invasive disease. Finally, mice with PanINs have an identifiable serum proteomic signature, suggesting a means of detecting the preinvasive state in patients.