An infernal cross‐talk between oncogenic β‐catenin and c‐Met in hepatocellular carcinoma: Evidence from mouse modeling
Authors: Rosa M. Pascale, Francesco Feo, Diego F. Calvisi
Journal: Hepatology (2016)

Human hepatocellular carcinoma (HCC) is the fifth-most common tumor and the second cause of cancer-related deaths worldwide.1 HCC is a deadly disease: Only few patients are diagnosed at early tumor stage, when potentially curative treatments, including partial liver resection and liver transplantation, can be successfully applied.1 Conventional therapies are instead ineffective and the multi-tyrosine kinase inhibitor, sorafenib, the only approved drug for HCC, provides only limited benefits to patients with advanced HCC in terms of survival.1 In order to significantly improve the prognosis of HCC patients, a better understanding of the molecular pathogenesis of liver cancer is mandatory. In particular, the development of animal models recapitulating the molecular events occurring in specific subsets of HCC is highly needed to address the biology as well as to test targeted therapies for specific tumor subtypes. Among the signaling cascades that are strongly implicated in hepatocarcinogenesis is the Wnt/β-catenin pathway.2, 3 β-catenin, a main component of the submembranous plaque of adherens junctions and desmosomes, is physiologically involved in two pivotal functions: cell-cell adhesion and transmission of the proliferative signal of the Wnt pathway.4 β-catenin levels are regulated by phosphorylation of its NH2-terminal region by glycogen synthase kinase 3 beta (GSK-3β), comprising of adenomatous polyposis coli (APC), Axin1/2, and GSK-3β proteins.4 Following phosphorylation, β-catenin undergoes degradation through the ubiquitin-proteasome pathway. Mutations of APC, Axin1/2, or β-catenin itself lead to elevated free β-catenin pools in the cytoplasm, which translocate into the nucleus and interact with the T-cell factor (Tcf) transcription factors. Subsequently, β-catenin/Tcf complexes activate a plethora of target genes promoting cell growth and resistance to apoptosis.4 Another important pathway often activated in HCC is hepatocyte growth factor (HGF)/c-Met signaling.5, 6 C-Met encodes the receptor tyrosine kinase for HGF. In the canonical HGF/c-Met pathway, binding of HGF to c-Met triggers homodimerization and autophosphorylation of c-Met itself, with consequent activation of the mitogen-activated protein kinase (MAPK) and phosphoinositide-3 kinase (PI3K) pathways.5, 6 Activation of HGF/c-Met has been shown to be involved in numerous cellular processes in liver cancer, including proliferation, survival, and metastasis.5, 6 In the present issue of Hepatology,7 through a number of elegant experiments, Tao et al. investigated whether the Wnt/β-catenin and HGF/c-Met pathways functionally interact in HCC. First, the investigators assessed the frequency of β-catenin mutations in HCC specimens from The Cancer Genome Atlas (TGCA), and found that ∼26.3% of these samples exhibited mutant β-catenin forms, mainly of the missense type.7 Of note, gene expression comparison between human HCC specimens harboring different β-catenin exon 3 mutants and normal liver showed that the downstream effectors activated by the latter mutations do not significantly differ. Thus, the biological effects of β-catenin mutations in the cancerous liver are highly similar, irrespective of the amino acid substitution. Subsequently, the investigators determined the eventual simultaneous presence of β-catenin mutations and HGF/c-Met signature in the same TGCA collection as well as in a second, independent cohort. In both collections, ∼9%-15% of samples showed concomitant β-catenin mutations and elevated c-Met activation/overexpression, thus demonstrating the existence of a subset of human liver tumors displaying the activation of the two signaling cascades.7 To unravel the significance of the latter observations in patients, Tao et al. overexpressed c-Met, either alone or in combination with the S45Y or S33Y mutant form of β-catenin, in mouse liver through hydrodynamic gene delivery, a well-established method for stable overexpression of given genes in hepatocytes.8 Whereas overexpression of the three genes alone did not result in any sign of morbidity by 22 weeks posthydrodynamic injection, coexpression of c-Met with β-catenin oncogenic forms triggered the development of multiple liver tumors, almost exclusively of hepatocellular nature, by 9-13 weeks postinjection.7 As expected, liver tumors developed in β-catenin/c-Met doubly transfected mice exhibited activation of the Wnt/β-catenin and HGF/c-Met pathways. In addition, β-catenin/c-Met tumors displayed activation of the MAPK and PI3K/mammalian target of rapamycin signaling cascades.7 Subsequently, the transcriptomic profiles of β-catenin-S45Y/c-Met mouse tumors were compared with those from β-catenin-S33Y/c-Met mice. Once again, the molecular features of the two models were highly similar, regardless of the β-catenin oncogenic form transfected. Finally, Tao et al. evaluated whether the molecular features of mouse β-catenin/c-Met liver lesions recapitulate those from the human HCC subset characterized by concomitant activation of the two oncogenes.7 Of note, the gene signatures of mouse and human HCC displaying simultaneous activation of β-catenin and c-Met were highly homologous, thus indicating that β-catenin/c-Met mouse models are a valuable tool for the study of the human HCC subset with activated β-catenin and c-Met.7 The significant study by Tao et al. provides novel insights of high relevance to better understand the molecular pathogenesis of human HCC. In particular, the study clearly demonstrates that β-catenin and c-Met functionally cooperate to rapidly induce hepatocarcinogenesis in the mouse through molecular mechanisms that are also involved in human liver tumor development and progression driven by the two oncogenes. In addition, because of the pathogenic role of deregulated β-catenin and c-Met signaling in various tumors, the present data might have a broader impact not limited to this cancer type. Furthermore, the present study has identified a large number of β-catenin and c-Met target genes, whose in-depth investigation might provide additional information on the molecular mechanisms responsible for hepatocarcinogenesis as well as for designing new therapeutic strategies against this HCC subset. Also, some of the identified targets of the two oncogenes might be reliable biomarkers of the activation of the β-catenin and c-Met pathways as well as predictors of the effectiveness of therapeutic approaches aimed at suppressing the two signaling cascades. Although the study by Tao et al. has considerably improved our knowledge on the functional role of β-catenin and c-Met in liver cancer, further investigation is required on this topic. In particular, establishment of the β-catenin/c-Met model strongly supports the testing of β-catenin and c-Met inhibitors in these mouse models as a preclinical step to ascertain their effectiveness in treatment of β-catenin-/c-Met-positive human HCC subsets. Nonetheless, it cannot be excluded that human HCCs with a β-catenin/c-Met-signature are presumably characterized by heterogeneous molecular features, which might provide at least partial resistance to the antitumors effects of β-catenin and c-Met inhibition through compensatory activation of alternative oncogenic pathways. Finally, the β-catenin/c-Met mouse models should be used to evaluate the effectiveness of treatments in which β-catenin and c-Met inhibition is coupled to more-conventional therapeutic approaches (chemotherapy, radiofrequency ablation, etc.).