KrasG12D and p53 Mutation Cause Primary Intrahepatic Cholangiocarcinoma

James P. Wilmot Cancer Center, University of Rochester School of Medicine, Rochester, New York 14642, USA.
Cancer Research (Impact Factor: 9.33). 02/2012; 72(6):1557-67. DOI: 10.1158/0008-5472.CAN-11-3596
Source: PubMed


Intrahepatic cholangiocarcinoma (IHCC) is a primary cancer of the liver with an increasing incidence and poor prognosis. Preclinical studies of the etiology and treatment of this disease are hampered by the relatively small number of available IHCC cell lines or genetically faithful animal models. Here we report the development of a genetically engineered mouse model of IHCC that incorporates two of the most common mutations in human IHCC, activating mutations of Kras (Kras(G12D)) and deletion of p53. Tissue-specific activation of Kras(G12D) alone resulted in the development of invasive IHCC with low penetrance and long latency. Latency was shortened by combining Kras(G12D) activation with heterozygous or homozygous deletion of p53 (mean survival of 56 weeks vs. 19 weeks, respectively), which also resulted in widespread local and distant metastasis. Serial analysis showed that the murine models closely recapitulated the multistage histopathologic progression of the human disease, including the development of stroma-rich tumors and the premalignant biliary lesions, intraductal papillary biliary neoplasms (IPBN), and Von Meyenburg complexes (VMC; also known as biliary hamartomas). These findings establish a new genetically and histopathologically faithful model of IHCC and lend experimental support to the hypothesis that IPBN and VMC are precursors to invasive cancers.

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Available from: Christa L Whitney-Miller, May 06, 2014
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    • "Activating mutations of KRAS represent one of the most frequent genetic mutations found in iCCA (5–54%) [58] [60] [65] [66]. KRAS gene has been shown to be a bona fide oncogene inducing iCCA in genetically engineered mouse models [67], and these "

    Journal of Hepatology 06/2014; 60(6). DOI:10.1016/j.jhep.2014.01.021 · 11.34 Impact Factor
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    • "Thus, we find that the cooperative effects of KRAS and p53 drive activation of autophagy rather than either mutation alone. This is consistent with established associations between autophagy dependence and RAS mutant tumor cell lines, many of which harbor p53 mutations (Guo et al., 2011; Lock et al., 2011; O'Dell et al., 2012; Yang et al., 2011). Others have reported conflicting roles of p53 in regulating autophagy (Morselli et al., 2011; Tasdemir et al., 2008), with a recent report showing that in a setting of homozygous p53 deletion during embryonal development loss of autophagy accelerates pancreatic tumor progression (Rosenfeldt et al., 2013). "
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    ABSTRACT: Mutations in p53 and RAS potently cooperate in oncogenic transformation, and correspondingly, these genetic alterations frequently coexist in pancreatic ductal adenocarcinoma (PDA) and other human cancers. Previously, we identified a set of genes synergistically activated by combined RAS and p53 mutations as frequent downstream mediators of tumorigenesis. Here, we show that the synergistically activated gene Plac8 is critical for pancreatic cancer growth. Silencing of Plac8 in cell lines suppresses tumor formation by blocking autophagy, a process essential for maintaining metabolic homeostasis in PDA, and genetic inactivation in an engineered mouse model inhibits PDA progression. We show that Plac8 is a critical regulator of the autophagic machinery, localizing to the lysosomal compartment and facilitating lysosome-autophagosome fusion. Plac8 thus provides a mechanistic link between primary oncogenic mutations and the induction of autophagy, a central mechanism of metabolic reprogramming, during PDA progression.
    Cell Reports 04/2014; 7(4). DOI:10.1016/j.celrep.2014.03.061 · 8.36 Impact Factor
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    • "In addition to the results obtained from human cases, a histological survey of hepatic parenchyma adjacent to ICC, as well as isolated regions of grossly normal livers, in an experimental animal model of ICC, which is characterized by a K-ras mutation and the deletion of p53, revealed several premalignant lesions [30]. Among them, some lesions, frequently found in animals with ICC, were similar to VMCs. "
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    ABSTRACT: Cholangiocarcinoma (CC) is divided into distal, perihilar, and intrahepatic CCs (ICCS), and are further subdivided into large bile duct ICC and peripheral ICC. In distal and perihilar CC and large duct ICC, biliary intraepithelial neoplasm (BilIN) and intraductal papillary neoplasm (IPN) have been proposed as precursor lesions. Peripheral ICC, bile duct adenoma (BDA), biliary adenofibroma (BAF), and von Meyenburg complexes (VMCs) are reportedly followed by development of ICCs. Herein, we surveyed these candidate precursor lesions in the background liver of 37 cases of peripheral ICC and controls (perihilar CC, 34 cases; hepatocellular carcinoma, 34 cases and combined hepatocellular cholangiocarcinoma, 25 cases). In the background liver of peripheral ICC, BDA and BAF were not found, but there were not infrequently foci of BDA-like lesions and atypical bile duct lesions involving small bile ducts (32.4% and 10.8%, resp.). VMCs were equally found in peripheral CCs and also control CCs. In conclusion, BDA, BAF, and VMCs are a possible precursor lesion of a minority of peripheral CCs, and BDA-like lesions and atypical bile duct lesions involving small bile ducts may also be related to the development of peripheral ICC. Further pathologic studies on these lesions are warranted for analysis of development of peripheral ICCs.
    04/2014; 2014:805973. DOI:10.1155/2014/805973
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