Distinct pathways of genomic progression to benign and malignant tumors of the liver

Abstract

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 in both instances arose from cooperation between MET and constitutively active versions of ␤-catenin. In contrast, adenomas were produced by cooperation between MET and defective signaling through the transcription factor HNF1␣. Prompted by these findings, we uncovered a coincidence between activation of the protein-tyrosine kinase encoded by MET and activating mutations of ␤-catenin in a subset of human hepatocellular carcinomas. Inactivation of MET transgenes led to regression of hepatocellular carcinomas despite the persistence of activated ␤-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 ␤-catenin in lieu of MET. These results offer insight into hepatic tumorigenesis, provide mouse models that should be useful in the further study of hepatic tumorigenesis and for preclinical testing, and identify a subset of human hepatocellular carcinomas that may be susceptible to combination therapy directed against Met and the Wnt signaling pathway.␤-catenin ͉ hepatocyte nuclear factor 1␣ ͉ liver cancer ͉ MET ͉ mouse ͉ hepatocellular carcinoma

Induction of hepatocellular carcinoma by in vivo gene targeting

“…A recent report showed that c-Met overexpression in transgenic mice can also induce Afp + HCCs that express Dlk1 and a subset (23 of 42) of the Rian-Mirg microRNAs (18). However, in this model additional secondary mutations are required for HCC formation (39), and c-Met was not overexpressed in the mouse tumors we produced by gene targeting (Table S3).…”

Inhibition of insulin‐like growth factor 1 receptor enhances the efficacy of sorafenib in inhibiting hepatocellular carcinoma cell growth and survival

“…Co‐activation of MET and β‐catenin often occurs in HCC 22. Codelivery of both MET and CAT (ΔN90‐β‐catenin, exon 3 deleted), but neither MET nor CAT alone, into mouse livers using the sleeping beauty transposon system efficiently induces HCC within several weeks 22, 23, 24. Therefore, this model (referred to here as MET/CAT) is useful for studying the functions of genes in hepatocarcinogenesis because of its clinical relevance and efficiency of HCC induction.…”

“…For the c‐met (MET)/constitutively active β‐catenin (CAT)‐driven HCC model,19, 22, 23, 24 55 μg of total plasmids, encoding the sleeping beauty transposase (HSB2) and transposons with oncogenes MET/CAT and gaussia luciferase (Gluc) (22.5 μg pT3‐EF1a‐c‐MET [human], 22.5 μg pT3‐EF1a‐DN90‐β‐catenin [human], 5 μg pT3‐Gluc1, and 5 μg HSB2) were injected hydrodynamically into age‐ and sex‐matched mice. Six weeks after MET/CAT injection, mice were treated with vehicle (30% captisol), ceritinib (25 mg/kg), sorafenib (25 mg/kg), or a combination of ceritinib and sorafenib by oral gavage daily for 4 weeks prior to being sacrificed.…”

Prognostic significance of c-Met, β-catenin and FAK in patients with hepatocellular carcinoma following surgery

“…Activation of c-Met signaling and β-catenin mutations are frequent genetic occurrences observed in liver cancer initiation (9)(10)(11). Previous studies have reported that c-Met and β-catenin are coactivated in HCC, and possess a possible correlation with hepatic carcinogenesis (12,13).…”

“…Following the review of previous studies on FAK, c-Met and β-catenin oncoproteins, their correlation with HCC has been identified in a variety of studies (12,13,(18)(19)(20)(21)(22). However, the intercorrelation among them requires further investigation.…”