Cancer cell dormancy in novel mouse models for reversible pancreatic cancer: a lingering challenge in the development of targeted therapies.
Cancer cell dormancy in novel mouse models for reversible pancreatic cancer: a lingering challenge in the development of targeted therapies.
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DOI：
10.1158/0008-5472.can-13-3437
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发表时间：
2014-04-15
期刊：
影响因子：
11.2
通讯作者：
Wagner KU
中科院分区：
文献类型：
--
作者：
Lin WC;Rajbhandari N;Wagner KU
在胰腺导管腺癌(PDAC)的发生和发展中起关键作用的关键分子通路的识别已经取得了重大进展。在常见的遗传和表观遗传学改变中，Kras癌基因突变和c-Myc癌基因上调是PDAC中常见的事件。利用基因定义的活体模型，最近的几项研究表明，突变的Kras和c-Myc的表达在胰腺癌的发生和维持中同样重要。单个癌基因的定向下调导致原发和转移部位的癌细胞死亡。这些发现非常令人鼓舞，并为开发针对这些致癌驱动因素的靶向治疗提供了强有力的理由。尽管对癌基因的切除似乎有完全的反应，但仍有一些处于休眠状态的癌细胞存在，而且已经证明，它们是癌基因重新激活后胰腺癌迅速复发的细胞储存库。本文综述了肿瘤休眠的基本原理和可逆转移PDAC的新的遗传模型在阐明肿瘤干细胞的作用以及调节休眠肿瘤细胞存活的生物学和分子机制方面的适用性。
Significant advances have been made in the identification of key molecular pathways that play pivotal roles in the initiation and progression of pancreatic ductal adenocarcinoma (PDAC). Among the common genetic and epigenetic changes, oncogenic mutations in Kras and upregulation of the c-Myc oncogene are frequent events in PDAC. Using genetically defined in vivo models, several studies have recently demonstrated that expression of mutant Kras and c-Myc are equally important for the initiation and maintenance of pancreatic cancer. The targeted downregulation of a single oncogene resulted in cancer cell death at primary and metastatic sites. These findings are very encouraging and provide a strong rationale for the development of targeted therapies against these oncogenic drivers. Despite what appeared to be a complete response to the ablation of the oncogene, a few dormant cancer cells remained present, and it was demonstrated that they are a cellular reservoir for a swift relapse of pancreatic cancer following oncogene reactivation. This review summarizes the basic principles of cancer dormancy and the applicability of the novel genetic models for reversible metastatic PDAC to elucidate the role of cancer stem cells as well as biological and molecular mechanisms that mediate the survival of dormant tumor cells.