Senescence surveillance of pre-malignant hepatocytes limits liver cancer development

Abstract

Upon the aberrant activation of oncogenes, normal cells can enter the cellular senescence program, a state of stable cell-cycle arrest, which represents an important barrier against tumour development in vivo. Senescent cells communicate with their environment by secreting various cytokines and growth factors, and it was reported that this 'secretory phenotype' can have pro- as well as anti-tumorigenic effects. Here we show that oncogene-induced senescence occurs in otherwise normal murine hepatocytes in vivo. Pre-malignant senescent hepatocytes secrete chemo- and cytokines and are subject to immune-mediated clearance (designated as 'senescence surveillance'), which depends on an intact CD4(+) T-cell-mediated adaptive immune response. Impaired immune surveillance of pre-malignant senescent hepatocytes results in the development of murine hepatocellular carcinomas (HCCs), thus showing that senescence surveillance is important for tumour suppression in vivo. In accordance with these observations, ras-specific Th1 lymphocytes could be detected in mice, in which oncogene-induced senescence had been triggered by hepatic expression of Nras(G12V). We also found that CD4(+) T cells require monocytes/macrophages to execute the clearance of senescent hepatocytes. Our study indicates that senescence surveillance represents an important extrinsic component of the senescence anti-tumour barrier, and illustrates how the cellular senescence program is involved in tumour immune surveillance by mounting specific immune responses against antigens expressed in pre-malignant senescent cells.

Cellular senescence impact on immune cell fate and function

“…The presence of Th1 cells is required for proper in vivo macrophage‐dependent elimination of senescent cells found in damaged tissue, as recently revealed by Kang et al . (2011) using a premalignant hepatocyte murine model. Furthermore, Th1 cells can also contribute directly to tissue homeostasis by triggering cellular senescence on tissue‐damaged cells.…”

The SCN9A channel and plasma membrane depolarization promote cellular senescence through Rb pathway

“…Normal human cells enter into a state of senescence in response to numerous stresses, such as oncogenic signals, short telomeres, genotoxic or oxidative stresses. Senescence is a protective mechanism against tumor development, as it avoids cell division and it allows the elimination of potentially harmful cells by the immune system, through the SASP (Adams, 2009; Collado & Serrano, 2010; Kang et al., 2011). …”

Senescence from G2 arrest, revisited

“…This is consistent with the hypothesis that senescence restricts tumor progression during the early stages of tumorigenesis, whereas progression to malignancy would involve evading senescence. 1 However, senescence has also been implicated both in promoting carcinogenesis 15 and in age-related pathologies 16,17 through its autocrine and paracrine effects, known as the senescence-associated secretory phenotype (SASP) originally described by the Campisi group. 18,19 SASP factors can act cell autonomously by reinforcing cell-cycle arrest and non-cell autonomously by influencing cells in the surrounding environment and promoting immune surveillance, leading to the elimination of senescent cells.…”