Replicative Senescence and Hepatic Tumor Development

Thorgeirsson, Snorri S.

Abstract

We have previously shown that coexpression of c-myc and transforming growth factor alpha (TGF-alpha) in transgenic mouse liver accelerates growth of tumors induced by either transgene alone. We now describe the consequences of constitutive expression of these transgenes on the kinetics of hepatocyte proliferation after partial hepatectomy (PH) in young adult c-myc monotransgenic and c-myc/TGF-alpha double transgenic mice. The results demonstrate that transgenic mice with liver specific expression of c-myc or c-myc plus TGF-alpha respond differently to PH. Constitutive expression of c-myc enhanced liver regeneration whereas coexpression of c-myc and TGF-alpha diminished proliferative response following PH. The c-myc/TGF-alpha transgenic mice displayed abnormalities of cell cycle progression associated with a senescent phenotype that includes a decreased rate of DNA synthesis accompanied by a decline in the steady-state levels of cyclins A and B mRNAs and a reduced replicative capacity of mature hepatocytes. These data suggest that prolonged and excessive stimulation of cell proliferation driven by coexpression of c-myc and TGF-alpha accelerates the normal process of liver aging. The c-myc/TGF-alpha transgenic mice may provide a model system for a replicative cellular senescence in vivo and its contribution to hepatic tumor development.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Cancer Institute (NCI)
• Type: Intramural Research (Z01)
• Project #: 1Z01BC010036-01
• Application #: 2463831
• Study Section: Special Emphasis Panel (LEC)
• Support Year: 1
• Fiscal Year: 1996

Institution

• Name: National Cancer Institute Division of Basic Sciences
• Country: United States

Publications

Matter, Matthias S; Marquardt, Jens U; Andersen, Jesper B et al. (2016) Oncogenic driver genes and the inflammatory microenvironment dictate liver tumor phenotype. Hepatology 63:1888-99

Coulouarn, Cedric; Factor, Valentina M; Thorgeirsson, Snorri S (2008) Transforming growth factor-beta gene expression signature in mouse hepatocytes predicts clinical outcome in human cancer. Hepatology 47:2059-67

van Hagen, J M; van der Geest, J N; van der Giessen, R S et al. (2007) Contribution of CYLN2 and GTF2IRD1 to neurological and cognitive symptoms in Williams Syndrome. Neurobiol Dis 26:112-24

Martin, Juliette; Magnino, Fabrice; Schmidt, Karin et al. (2006) Hint2, a mitochondrial apoptotic sensitizer down-regulated in hepatocellular carcinoma. Gastroenterology 130:2179-88

Calvisi, Diego F; Thorgeirsson, Snorri S (2005) Molecular mechanisms of hepatocarcinogenesis in transgenic mouse models of liver cancer. Toxicol Pathol 33:181-4

Karlsson, Goran; Liu, Yingchun; Larsson, Jonas et al. (2005) Gene expression profiling demonstrates that TGF-beta1 signals exclusively through receptor complexes involving Alk5 and identifies targets of TGF-beta signaling. Physiol Genomics 21:396-403

Cavin, Lakita G; Wang, Fang; Factor, Valentina M et al. (2005) Transforming growth factor-alpha inhibits the intrinsic pathway of c-Myc-induced apoptosis through activation of nuclear factor-kappaB in murine hepatocellular carcinomas. Mol Cancer Res 3:403-12

Durkin, Marian E; Avner, Miriam R; Huh, Chang-Goo et al. (2005) DLC-1, a Rho GTPase-activating protein with tumor suppressor function, is essential for embryonic development. FEBS Lett 579:1191-6

Meyer, Kirstin; Lee, Ju-Seog; Dyck, Patricia A et al. (2003) Molecular profiling of hepatocellular carcinomas developing spontaneously in acyl-CoA oxidase deficient mice: comparison with liver tumors induced in wild-type mice by a peroxisome proliferator and a genotoxic carcinogen. Carcinogenesis 24:975-84

Arsura, Marcello; Panta, Ganesh R; Bilyeu, Jennifer D et al. (2003) Transient activation of NF-kappaB through a TAK1/IKK kinase pathway by TGF-beta1 inhibits AP-1/SMAD signaling and apoptosis: implications in liver tumor formation. Oncogene 22:412-25