Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice
Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice
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DOI：
10.1172/jci59227
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发表时间：
2012-02-01
影响因子：
15.9
通讯作者：
di Magliano, Marina Pasca
中科院分区：
文献类型：
--
作者：
Collins, Meredith A.;Bednar, Filip;di Magliano, Marina Pasca
胰腺癌几乎总是与KRAS基因突变相关，最常见的是KRAS（G12 D），导致KRAS GT3的显性活性形式。然而，KRAS突变如何促进胰腺癌发生尚未完全了解，并且尚未确定致癌KRAS是否是维持胰腺癌所必需的。为了解决这些问题，我们产生了两种胰腺肿瘤发生的小鼠模型：诱导型Kras（G12D）转基因小鼠，其允许致癌Kras（G12D）的诱导型、胰腺特异性和可逆表达，有或没有肿瘤抑制基因p53的一个等位基因失活。在这里，我们报告说，在肿瘤发生的早期，致癌Kras（G12D）的诱导可逆地改变正常上皮细胞分化组织损伤后，导致癌前病变。Kras（G12D）在已建立的前体病变中和在向癌症进展期间的失活导致病变消退，表明Kras（G12D）是肿瘤细胞存活所需的。引人注目的是，在癌发生的所有阶段，Kras（G12D）上调Hedgehog信号传导、炎症通路和已知介导上皮细胞与其周围微环境之间的旁分泌相互作用的几种通路，从而促进在胰腺癌中起关键作用的纤维炎性基质的形成和维持。我们的数据证实上皮Kras（G12D）影响多种细胞类型以驱动胰腺肿瘤发生，并且对于肿瘤维持至关重要。他们还强烈支持抑制Kras（G12D）或其下游效应子的观点，可以为胰腺癌的治疗提供一种新的方法。
Pancreatic cancer is almost invariably associated with mutations in the KRAS gene, most commonly KRAS(G12D), that result in a dominant-active form of the KRAS GTPase. However, how KRAS mutations promote pancreatic carcinogenesis is not fully understood, and whether oncogenic KRAS is required for the maintenance of pancreatic cancer has not been established. To address these questions, we generated two mouse models of pancreatic tumorigenesis: mice transgenic for inducible Kras(G12D), which allows for inducible, pancreas-specific, and reversible expression of the oncogenic Kras(G12D), with or without inactivation of one allele of the tumor suppressor gene p53. Here, we report that, early in tumorigenesis, induction of oncogenic Kras(G12D) reversibly altered normal epithelial differentiation following tissue damage, leading to precancerous lesions. Inactivation of Kras(G12D) in established precursor lesions and during progression to cancer led to regression of the lesions, indicating that Kras(G12D) was required for tumor cell survival. Strikingly, during all stages of carcinogenesis, Kras(G12D) upregulated Hedgehog signaling, inflammatory pathways, and several pathways known to mediate paracrine interactions between epithelial cells and their surrounding microenvironment, thus promoting formation and maintenance of the fibroinflammatory stroma that plays a pivotal role in pancreatic cancer. Our data establish that epithelial Kras(G12D) influences multiple cell types to drive pancreatic tumorigenesis and is essential for tumor maintenance. They also strongly support the notion that inhibiting Kras(G12D), or its downstream effectors, could provide a new approach for the treatment of pancreatic cancer.