Senescence surveillance of pre-malignant hepatocytes limits liver cancer development

Kang, T.-W. et al. 2011. Nature 479, 547-551

Speaker：Fang-Hsin Chang (張芳馨)                           Time：13:10~14:10, Jun. 6 2012

Commentator：Dr. Cheng-Chan Lu (呂政展老師)      Place：Room 601

Abstract：

Senescence, a stable status of cell cycle arrest that can be activated by oncogenic signaling or other stresses [1], plays critical roles in tumor suppression [2]. It is still unclear how senescence-mediated tumor suppression involves the immune system. In this study, the authors introduced an oncogenic Nras^G12V gene into immunocompetent mice through hydrodynamic injection, which caused senescence of hepatocytes. Interestingly, the Nras^G12V-expressing senescent hepatocytes were gradually cleared, accompanied by hepatic infiltration of immune cells. Clearance of the senescent hepatocytes, called “senescence surveillance”, was not observed if adaptive immunity was impaired. CD4 T (T_H1) cells responded to ras antigen and were essential for senescence surveillance. In the presence of functional CD4 T cells, monocytes and macrophages were also required for senescence surveillance, suggesting that CD4 T cells may coordinate innate immune cells to remove the senescent cells. More importantly, in the mouse model, when Nras^G12V-expressing premalignant hepatocytes were resistant to senescence or the immune system for senescence surveillance was impaired, liver cancer emerged eventually. In addition, the authors found accumulation of senescent premalignant cells in the livers of hepatitis C virus-positive patients whose immune response was compromised by co-infection with human immunodeficiency virus or by immunosuppressive therapy. Taken together, this study indicates that senescence surveillance, orchestrated by both adaptive and innate immunity, is important for controlling cancer development at the premalignant stage.

References :

1. Narita, M. & Lowe, S. W. Nature Med. 11, 920-922 (2005).
2. Collado, M. & Serrano, M. Nature Rev. Cancer 10, 51-57 (2010).