Trp53R172H and KraSG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice
Trp53R172H and KraSG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice
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DOI：
10.1016/j.ccr.2005.04.023
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发表时间：
2005-05-01
期刊：
影响因子：
50.3
通讯作者：
Tuveson, DA
中科院分区：
文献类型：
--
作者：
Hingorani, SR;Wang, LF;Tuveson, DA
为了确定胰腺导管腺癌（PDA）的遗传要求，我们将Trp53（R172 H）和Kras（G12 D）的内源性表达靶向小鼠胰腺，揭示了与人类疾病相似的侵袭性和广泛转移性癌的协同发展。原发癌和转移癌表现出高度的基因组不稳定性，表现为非相互易位，没有明显的端粒侵蚀人类癌的标志，通常在小鼠中观察不到。在其他主要的抑癌基因通路中未发现突变，这与以前的结果一起表明PDA具有不同的生物学行为的不同遗传通路。这些发现对于理解疾病的发病机制以及检测和靶向治疗策略的发展具有明确的意义。
To define the genetic requirements for pancreatic ductal adenocarcinoma (PDA), we have targeted concomitant endogenous expression of Trp53(R172H) and Kras(G12D) to the mouse pancreas, revealing the cooperative development of invasive and widely metastatic carcinoma that recapitulates the human disease. The primary carcinomas and metastases demonstrate a high degree of genomic instability manifested by nonreciprocal translocations without obvious telomere erosion hallmarks of human carcinomas not typically observed in mice. No mutations were discovered in other cardinal tumor suppressor gene pathways, which, together with previous results, suggests that there are distinct genetic pathways to PDA with different biological behaviors. These findings have clear implications for understanding mechanisms of disease pathogenesis, and for the development of detection and targeted treatment strategies.