Department of Surgery, Technische Universität München (TUM), Munich, Germany.
Department of Gastroenterology, Nanjing Drum Tower Hospital, Nanjing University, Nanjing, China.
Gut. 2018 Jan;67(1):146-156. doi: 10.1136/gutjnl-2015-310913. Epub 2016 Sep 19.
The initial steps of pancreatic regeneration versus carcinogenesis are insufficiently understood. Although a combination of oncogenic Kras and inflammation has been shown to induce malignancy, molecular networks of early carcinogenesis remain poorly defined.
We compared early events during inflammation, regeneration and carcinogenesis on histological and transcriptional levels with a high temporal resolution using a well-established mouse model of pancreatitis and of inflammation-accelerated Kras-driven pancreatic ductal adenocarcinoma. Quantitative expression data were analysed and extensively modelled in silico.
We defined three distinctive phases-termed inflammation, regeneration and refinement-following induction of moderate acute pancreatitis in wild-type mice. These corresponded to different waves of proliferation of mesenchymal, progenitor-like and acinar cells. Pancreas regeneration required a coordinated transition of proliferation between progenitor-like and acinar cells. In mice harbouring an oncogenic Kras mutation and challenged with pancreatitis, there was an extended inflammatory phase and a parallel, continuous proliferation of mesenchymal, progenitor-like and acinar cells. Analysis of high-resolution transcriptional data from wild-type animals revealed that organ regeneration relied on a complex interaction of a gene network that normally governs acinar cell homeostasis, exocrine specification and intercellular signalling. In mice with oncogenic Kras, a specific carcinogenic signature was found, which was preserved in full-blown mouse pancreas cancer.
These data define a transcriptional signature of early pancreatic carcinogenesis and a molecular network driving formation of preneoplastic lesions, which allows for more targeted biomarker development in order to detect cancer earlier in patients with pancreatitis.
胰腺再生与癌变的初始步骤尚未得到充分理解。虽然致癌 Kras 和炎症的结合已被证明会诱发恶性肿瘤，但早期癌变的分子网络仍未得到明确界定。
我们使用一种已建立的胰腺炎和炎症加速 Kras 驱动的胰腺导管腺癌小鼠模型，在组织学和转录水平上，以高时间分辨率比较了炎症、再生和癌变的早期事件。对定量表达数据进行了分析，并在计算机中进行了广泛的建模。
我们在野生型小鼠中诱导中度急性胰腺炎后，定义了三个不同的阶段——炎症、再生和细化。这些阶段对应于间充质、祖细胞样和腺泡细胞不同的增殖波。胰腺再生需要祖细胞样和腺泡细胞之间增殖的协调转变。在携带致癌 Kras 突变并接受胰腺炎挑战的小鼠中，存在延长的炎症期和间充质、祖细胞样和腺泡细胞的平行连续增殖。对野生型动物的高分辨率转录数据进行分析表明，器官再生依赖于一个正常控制腺泡细胞内稳态、外分泌指定和细胞间信号的基因网络的复杂相互作用。在携带致癌 Kras 的小鼠中，发现了一个特定的致癌特征，在完全成熟的小鼠胰腺癌中也得到了保留。
这些数据定义了早期胰腺癌变的转录特征和驱动前瘤病变形成的分子网络，这使得能够更有针对性地开发生物标志物，以便在胰腺炎患者中更早地发现癌症。
