Synergy between truncated c-Met (cyto-Met) and c-Myc in liver oncogenesis: importance of TGF-β signalling in the control of liver homeostasis and transformation

Abstract

The c-Met tyrosine kinase receptor and its ligand, Hepatocyte Growth Factor/ Scatter Factor, have been implicated in human cancer. We have previously described that the transgenic expression of a truncated form of human c-Met (cyto-Met) in the liver confers resistance to several apoptotic stimuli. Here we show the impact of cyto-Met expression on liver proliferation and transformation. Despite a sixfold increase of hepatocyte proliferation, adult transgenic livers displayed normal size and architecture. We present evidence showing that activation of TGF-b1 signalling controls the liver mass in cyto-Met mice. The oncogenic potential of cyto-Met was further assessed in the context of c-Myc-induced hepatocarcinogenesis, using WHV/c-Myc transgenic mice. Co-expression of cyto-Met and c-Myc further enhanced hepatocyte proliferation and caused a dramatic acceleration of the Myc-induced tumorigenesis, leading to the emergence of hepatocarcinomas in 3 ± 4-month-old animals. Importantly, the TGF-b receptor type II expression was strongly downregulated in most tumours, indicating that impairment of TGF-b1-mediated growth inhibition plays a major role in accelerated neoplastic development. The strong potential of cyto-Met for oncogenic cooperation without direct transforming activity designates cyto-Met mice as an ideal tool for studying the early steps of multistage hepatocarcinogenesis and for identi®cation of prognostic markers of transformation.

TGFbeta Induces Binucleation/Polyploidization in Hepatocytes through a Src-Dependent Cytokinesis Failure

“…Observations made inhibiting the TGFbeta pathway in animals are of particular relevance since they permitted to highlight the role played by the cytokine in the healthy growing liver. So far, indeed, the role of TGFbeta in the liver had been widely explored in pathological conditions (cancer, fibrosis, compensatory regeneration and control of liver mass under mitogenic stimulus) [46–49], while data on its contribution to physiological processes are quite poor. Regarding the physiological postnatal liver polyplodization, TGFbeta can act in parallel with (or integrating) other signals, already described in the hepatic ploidy control.…”

Breast cancer expression of CD163, a macrophage scavenger receptor, is related to early distant recurrence and reduced patient survival

“…Polyclonal antibodies against IL‐10 (sc‐7888) and TGF‐β (sc‐146) were obtained from SDS Bioscience (Santa Cruz Biotechnology, CA). These antibodies are well characterized and used in many previous studies 22–30…”

Targeting the HGF/c-MET Pathway in Hepatocellular Carcinoma

“…Liver-specific overexpression of c-MET in mice led to HCC formation in a ligand-independent fashion, and withdrawal of c-MET overexpression promoted marked tumor regression, suggesting a continued role of c-MET in tumor maintenance in vivo (10). Moreover, overexpression of c-MET cooperated with other oncogenes characteristic of HCC — c-myc or mutant beta-catenin — to generate HCC with shorter latency and survival in mice (46, 47). These data support the role of c-MET in HCC tumor progression and maintenance, providing a rationale for the clinical development of c-MET inhibitors for HCC.…”