文章：

KRAS, Hedgehog, Wnt与胰腺导管腺癌的扭曲发育生物学

KRAS, Hedgehog, Wnt and the twisted developmental biology of pancreatic ductal adenocarcinoma

原文发布日期：2010-09-03

DOI: 10.1038/nrc2899

类型: Review Article

开放获取: 否

要点：

1. Mutations in KRAS are nearly universal in human pancreatic ductal adenocarcinoma (PDAC). Mouse models in which mutant KRAS is targeted to the pancreas reveal that KRAS signalling is sufficient to reprogram pancreatic cells into duct-like lineages capable of progressing through preneoplastic lesions and, ultimately, PDAC in stages that are reminiscent of human disease.
2. The latency, differentiation and type of preneoplastic lesion observed in KRAS-driven PDAC mouse models is sensitive to tumour suppressor loss, suggesting that PDAC evolution is dependent on sequential tuning of signalling pathways.
3. PDAC is characterized by frequent deregulation of embryonic signalling pathways, including Hedgehog (Hh) and Wnt–β-catenin signalling. Recent evidence points to temporal and spatial control of these pathways in PDAC development and maintenance.
4. PDAC cells frequently display aberrant Hh ligand expression. Recent studies suggest that classical ligand-dependent signalling is activated in cells in the tumour microenvironment, supporting tumour maintenance in a paracrine fashion, but not in the tumour epithelium. However, Hh signalling at the level of Gli transcriptional factors is active in the tumour epithelium, dictated by non-canonical regulators of the pathway. Both paracrine ligand activity and epithelial Gli signalling seem to independently support KRAS-driven PDAC evolution in mouse models.
5. Wnt–β-catenin signalling is frequently activated in PDAC and contributes to tumour cell proliferation and biology. Genetic models that allow Wnt–β-catenin deregulation reveal that this pathway can transform pancreatic cells but is insufficient to drive PDAC initiation.
6. Mouse models have revealed that the ability of KRAS to reprogram cells into a duct-like fate that can give rise to PDAC is sensitive to cell differentiation and levels of KRAS signalling. Temporal regulation of embryonic signalling pathways seems to play a part in preneoplastic reprogramming, as shown by a requirement for control of Wnt–β-catenin signalling during KRAS-driven de-differentiation of acinar cells into PDAC precursor lesions.

要点翻译：

1. KRAS基因突变在人类胰腺导管腺癌（PDAC）中几乎普遍存在。通过将突变型KRAS靶向作用于胰腺的小鼠模型研究发现，KRAS信号传导足以将胰腺细胞重编程为导管样谱系，这些细胞能够经历瘤前病变并最终发展为PDAC，其发展阶段与人类疾病进程相似。
2. 在KRAS驱动的PDAC小鼠模型中，观察到的瘤前病变的潜伏期、分化类型及特征对抑癌基因缺失具有敏感性，这表明PDAC的演进依赖于信号通路的顺序性调控。
3. PDAC的特征包括胚胎信号通路（如Hedgehog和Wnt–β-catenin信号）的频繁失调。最新证据表明，这些通路在PDAC的发生和维持过程中存在时空特异性调控。
4. PDAC细胞常出现Hh配体表达异常。近期研究提示，经典的配体依赖性信号在肿瘤微环境中的细胞中被激活，以旁分泌方式支持肿瘤维持，但在肿瘤上皮细胞中未被激活。然而，在转录因子Gli水平上，Hh信号在肿瘤上皮细胞中处于活跃状态，这由该通路的非经典调控因子决定。在小鼠模型中，旁分泌配体活性和上皮细胞Gli信号似乎能独立支持KRAS驱动的PDAC演进。
5. Wnt–β-catenin信号在PDAC中常被激活，并促进肿瘤细胞增殖及生物学行为。允许Wnt–β-catenin失调的遗传模型显示，该通路能转化胰腺细胞，但不足以驱动PDAC的发生。
6. 小鼠模型研究揭示，KRAS将细胞重编程为可导致PDAC的导管样命运的能力，对细胞分化状态和KRAS信号水平敏感。胚胎信号通路的时序性调控在瘤前重编程中发挥作用，这一点在KRAS驱动腺泡细胞去分化为PDAC前体病变过程中对Wnt–β-catenin信号的控制需求中得到证实。

英文摘要：

Pancreatic ductal adenocarcinoma (PDAC) is characterized by near-universal mutations in KRAS and frequent deregulation of crucial embryonic signalling pathways, including the Hedgehog (Hh) and Wnt–β-catenin cascades. The creation of mouse models that closely resemble the human disease has provided a platform to better understand when and in which cell types these pathways are misregulated during PDAC development. Here we examine the central part that KRAS plays in the biology of PDAC, and how the timing and location of Hh and Wnt–β-catenin signalling dictate the specification and oncogenic properties of PDAC.

摘要翻译： 

胰腺导管腺癌（PDAC）的特点是KRAS基因几乎普遍发生突变，以及包括Hedgehog（Hh）和Wnt–β-catenin信号通路在内的关键胚胎信号通路的频繁失调。创建与人类疾病高度相似的小鼠模型，为更好地理解这些通路在PDAC发展过程中何时以及在哪些细胞类型中发生失调提供了一个平台。在此，我们探讨KRAS在PDAC生物学中的核心作用，以及Hh和Wnt–β-catenin信号通路的时机和位置如何决定PDAC的特异性和致癌特性。

原文链接：

KRAS, Hedgehog, Wnt and the twisted developmental biology of pancreatic ductal adenocarcinoma