www.elsevier.com/locate/jhep

Journal of Hepatology 48 (2008) 884–886

Journal ClubSpecial Section Editors: Peter R. Galle, Peter L.M. Jansen, Francesco Negro

Human and mouse hepatocellular adenoma and carcinomadisplay similar tumorigenesis pathway alterations q

Jessica Zucman-Rossi*

Inserm, U674, Genomique fonctionnelle des tumeurs solides, Paris F-75010, France

Universite Paris Diderot – Paris 7, Institut Universitaire d’Hematologie, Paris F-75010, France

Distinct pathways of genomic progression to benign and insight into hepatic tumorigenesis, provide mouse models

malignant tumors of the liver. Tward AD, Jones KD,

Yant S, Cheung ST, Fan ST, Chen X, Kay MA, WangR, Bishop JM.

We used several of the genetic lesions commonly

associated with human liver tumors to reconstruct genetic

progression to hepatocellular carcinoma and adenoma in

mouse models. We initiated tumorigenesis with a

transgene of the protooncogene MET or by hydrodynamic

transfection of MET in combination with other genes into

the livers of adult animals. Hepatocellular carcinoma inboth instances arose from cooperation between MET

and constitutively active versions of b-catenin. In contrast,

adenomas were produced by cooperation between MET

and defective signaling through the transcription factor

HNF1a. Prompted by these findings, we uncovered a

coincidence between activation of the protein–tyrosine

kinase encoded by MET and activating mutations of

b-catenin in a subset of human hepatocellular carcinomas.Inactivation of MET transgenes led to regression of

hepatocellular carcinomas despite the persistence of acti-

vated b-catenin. The tumors eventually recurred in the

absence of MET expression, however, presumably after

the occurrence of one or more events that cooperated with

activated b-catenin in lieu of MET. These results offer

0168-8278/$34.00 � 2008 European Association for the Study of Liver. Pub

doi:10.1016/j.jhep.2008.02.001

Abbreviations: HBV, hepatitis B virus; HCV, hepatitis C virus;HGF, hepatocyte growth factor; HCC, hepatocellular carcinoma;HCA, hepatocellular adenoma; HNF1a, hepatocyte nuclear factor 1alpha.

q The author declares that she does not have anything to discloseregarding funding from industries or conflict of interest with respect tothis manuscript.

* Tel.: +33 1 53 72 51 66; fax: +33 1 53 72 51 58.E-mail address: zucman@cephb.fr

that should be useful in the further study of hepatic

tumorigenesis and for pre-clinical testing, and identify asubset of human hepatocellular carcinomas that may be

susceptible to combination therapy directed against Met

and the Wnt signaling pathway.

[Abstract reproduced by permission of Proc Natl Acad

Sci USA 2007;104:14771–14776]

Hepatocellular carcinoma (HCC) and hepatocellularadenoma (HCA) occur in distinct populations. HCC isthe most frequent liver malignancy, occurring preferen-tially in males following exposure to well-known risk fac-tors, including HBV and HCV viral infections, chronicalcohol abuse, or consumption of aflatoxin. HCC aremalignant tumors which are usually observed in cirrhoticliver and cirrhotic nodules, particularly those exhibitingsmall cell dysplasia that are true pre-neoplastic lesions[1]. As is often observed in solid tumors, a large numberof genetic alterations accumulate during HCC carcino-genesis [2]. Some of these genetic alterations are specificto aetiological factors, particularly HBV infections thatcan induce chromosome instability and insertional muta-genesis. Other genetic alterations in HCC are unrelatedto risk factors; for example, the most frequently dysreg-ulated pathway results in Wnt/wingless activation,usually through CTNNB1 mutations that activateb-catenin [3]. On the other hand, HCA are rare benignliver tumors, usually observed in women following oralcontraceptive use for more than two years. HCA tumorshave been divided into 3 subtypes, depending on themolecular alteration detected within the tumors: HNF1ainactivation (40–45%), b-catenin activation (15–19%),and/or an acute inflammatory response (30–35% of the

lished by Elsevier B.V. All rights reserved.

J. Zucman-Rossi / Journal of Hepatology 48 (2008) 884–886 885

cases). These molecular features correlate closely to clin-ical and pathological features, and the most critical is theb-catenin activation in HCA, which poses a high risk ofmalignant transformation [4,5]. In a recent study, Bishopand collaborators identified carcinogenic pathwaysin a transgenic mouse model that mimic human tumors[6].

MET is a cell surface receptor that possesses a tyrosinekinase activity. MET ligand is the hepatocyte growth fac-tor (HGF). The MET pathway elicits multiple biologicalresponses including proliferation, migration, invasion,and morphogenesis. Bishop’s team previously showedthat liver-specific over-expression of a wild-type humanMET receptor in mice induces a high incidence of HCC(>60%) after 12 months [7]. Interestingly, activation ofthe transgenic MET receptor was independent of mouseHGF ligand expression but was dependent on cell adher-ence. Transgenic mice developed HCC that regressedwhen the transgene was inactivated. These results indi-cated that over-expression of a wild-type MET receptorappeared to play a key role in the genesis and mainte-nance of HCC. The results also suggested that cell adher-ence may be an alternative activation mechanism fortumor development in cancers related to hyperactivationor over-expression of wild-type tyrosine kinase receptors.

In their recent work [6], Tward and co-workerscarefully characterised liver tumors that developed intransgenic mice with inducible MET receptors. Histolog-ically, they found a wide range of liver lesions includinghyperplastic foci, dysplastic lesions, HCC, and HCA;moreover, all these lesions were frequently observed inthe same liver. However, they did not observe a HCCtumor develop within a HCA lesion, reproducing theso-called ‘‘nodule in nodule” described in humans. Look-ing at different oncogenic pathways that are putativelyaltered in mice tumors, they found b-catenin activationin almost all HCCs. This b-catenin activation was relatedto a b-catenin activating mutation identified in 20 out of21 HCC nodules. In contrast, no b-catenin mutationswere found in the 12 HCA. Furthermore, by immuno-staining, no dysplastic nodules or HCAs demonstratedan over-expression of either b-catenin or the target ofb-catenin, glutamine synthetase. In contrast, a HNF1ainactivation was specifically found in all HCAs. Thiswas evident by the finding that a well-known HNF1a tar-get in mice, phenylalanine hydroxylase (PAH), was notexpressed in adenomas but was detected in HCC anddysplastic nodules. However, in contrast to humans [8],no HNF1a mutations were identified in HCA developedin mice. Altogether, these results indicated that in METreceptor transgenic mice, liver tumorigenesis occurredthrough two independent mechanisms: either b-cateninactivation or HNF1a inactivation, and these led toHCC and HCA, respectively.

Interestingly, in MET receptor transgenic mice thatdeveloped tumors, the switching off of MET receptor

expression by administration of doxycycline led to tumorregression and resulted in persistent microscopic foci oftumor cells that over-expressed b-catenin in scar tissues.However, despite the MET receptor shut down, HCCwith b-catenin activation recurred after a few monthsin the absence of MET receptor re-expression or activa-tion. This observation opens new, interesting therapeuticalleys involving the inactivation of the MET receptorpathway.

To better understand the inter-relationship and spec-ificities of the MET, b-catenin, and HNF1a pathways,the authors reconstructed HCC and HCA tumorigenesiswith the use of hydrodynamic transfections. Theyshowed that none of the three pathways alone, b-cateninactivation, MET activation, or HNF1a inactivation,was able to induce HCC or HCA. In contrast, simulta-neous MET and b-catenin activations gave rise to HCCin 74% of the surviving animals. Furthermore, a combi-nation of MET activation with HNF1a inactivation ledto the development of HCA in more than 50% of theanimals. These elegant experiments clearly demon-strated that MET activation was cooperative with eitherb-catenin activation or HNF1a inactivation to induceHCC or HCA, respectively.

Finally, Twang and collaborators studied the expres-sion of phosphorylated MET receptors and b-cateninin a series of 56 human HCC cases. They found a signif-icant association between MET receptor expression andb-catenin activation (P < 0.001). This result contrastsstrikingly with a recent report from the Thorgeirsson lab-oratory [9]. Using a transcriptomic signature derivedfrom mouse hepatocytes, HCCs related to MET receptoractivation in humans were not well differentiated. SinceHCCs related to MET receptor activation clustered with‘‘group A” tumors, they were not expected to be associ-ated with b-catenin activation [10]. Taking into accountthese two contrasting reports and previous data reportedin the literature, the relevance and timing of MET recep-tor activation relative to other carcinogenic pathwaysinvolved in human HCC remain to be clarified.

In conclusion, carcinogenic pathways altered in theMET receptor transgenic mouse model closely resemblethose observed in humans that have HNF1a and b-cate-nin alterations promoting HCA and HCC, respectively(Fig. 1). As expected, the genetic diversity found inhuman HCA and HCC is broader than that found ingenetically modified laboratory mouse strains. However,the MET receptor transgenic mice recapitulated two fre-quent mechanisms of human carcinogenesis, and this isa fundamental point in the development of meaningfulpre-clinical animal models representative of human dis-eases. Given the spectacular tumor regression observedin the mouse model, MET pathway inhibition appearsto be a promising direction for developing new HCCtherapies, especially those directed against b-cateninactivation. However, considering that the HGF/c-Met

Fig. 1. Diagram of the different carcinogenesis pathways altered in MET transgenic mice and in human liver. Benign and malignant tumors are

represented in blue and green, respectively. HCA, hepatocellular adenoma; HCC, hepatocellular carcinoma; HNF1a, hepatocyte nuclear factor 1 alpha.

[This figure appears in colour on the web.]

886 J. Zucman-Rossi / Journal of Hepatology 48 (2008) 884–886

signaling pathway could also suppress tumorigenesis bycontrolling the intracellular redox state [11], the effect ofa MET receptor inhibitor on non-tumor liver tissueshould not be overlooked and remains to be evaluated.

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