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-beta1 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-beta receptor type 11 expression was strongly downregulated in most tumours, indicating that impairment of TGF-beta1-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 identification of prognostic markers of transformation.

Synergy between truncated c-Met (cyto-Met) and c-Myc in liver oncogenesis: Importance of TGF-beta signalling in the control of liver homeostasis and transformation / Amicone, Laura; Terradillos, O.; Calvo, L.; Costabile, B.; Cicchini, Carla; DELLA ROCCA, Carlo; Lozupone, F.; Piacentini, M.; Buendia, M. A.; Tripodi, Marco. - In: ONCOGENE. - ISSN 0950-9232. - STAMPA. - 21:(2002), pp. 1335-1345. [10.1038/sj/onc/1205199]

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

AMICONE, Laura;CICCHINI, Carla;DELLA ROCCA, Carlo;TRIPODI, Marco
2002

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-beta1 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-beta receptor type 11 expression was strongly downregulated in most tumours, indicating that impairment of TGF-beta1-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 identification of prognostic markers of transformation.
2002
01 Pubblicazione su rivista::01a Articolo in rivista
Synergy between truncated c-Met (cyto-Met) and c-Myc in liver oncogenesis: Importance of TGF-beta signalling in the control of liver homeostasis and transformation / Amicone, Laura; Terradillos, O.; Calvo, L.; Costabile, B.; Cicchini, Carla; DELLA ROCCA, Carlo; Lozupone, F.; Piacentini, M.; Buendia, M. A.; Tripodi, Marco. - In: ONCOGENE. - ISSN 0950-9232. - STAMPA. - 21:(2002), pp. 1335-1345. [10.1038/sj/onc/1205199]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/248920
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