SEARCH

SEARCH BY CITATION

Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature. Kang TW, Yevsa T, Woller N, Hoenicke L, Wuestefeld T, Dauch D, et al 2011;479:547-551

Jean-Charles Nault M.D.* †, Giuliana Amaddeo M.D.* †, Jessica Zucman-Rossi M.D., Ph.D.* †, * Inserm, UMR-674, Génomique fonctionnelle des tumeurs solides, Institut Universitaire d'Hématologie, Paris, France, † Université Paris Descartes, Labex Immuno-oncology, Sorbonne Paris Cité, Faculté de Médecine, Paris, France

Kang TW, Yevsa T, Woller N, Hoenicke L, Wuestefeld T, Dauch D, et al. Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature. 2011;479:547-551. www.nature.com. (Reprinted with permission.)

Abstract

  1. Top of page
  2. Abstract
  3. Comment
  4. Acknowledgements
  5. References

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.

Comment

  1. Top of page
  2. Abstract
  3. Comment
  4. Acknowledgements
  5. References

Oncogene activation can induce senescence in human cells. This mechanism, designated as oncogene-induced senescence (OIS), prevents the cells from a malignant transformation. Consequently, OIS acts as a tumor-suppressive barrier.1 In a recent report published in Nature, Lars Zender's group2 induced oncogene activation in mice by delivering a mutated oncogene (NrasG12V) in hepatocytes using in vivo hydrodynamic injection. The authors further analyzed the implication of different immune cell lineages in hepatocellular carcinoma (HCC) development surveillance. In immune-competent mice, NrasG12V-expressing hepatocytes underwent senescence and were progressively lost during the 60 days following oncogene injection. Enzyme-linked immunospot assays showed that NrasG12V-expressing mice generated TH cells specific for a peptide epitope of the mutated region of the NrasG12V protein, revealing a remarkable specificity of the response. Secretion of various cytokines and chemokines by the senescent hepatocytes was detected on whole liver lysates. Also, using flow cytometry, multiple types of infiltrating immune cells that mediate either an innate or an adaptive immune response (designated “senescence surveillance”) were identified in mouse liver.

OIS acts as a paradoxical tumor suppressor mechanism which prevents uncontrolled cells proliferation induced by oncogenic mutation. OIS was described in cell culture more than 10 years ago, mainly induced by activation of the RAS/RAF family of oncogenes (HRAS, KRAS and BRAF).1 In human carcinogenesis it has been shown that senescent cells, along with apoptotic cells, are more abundant in premalignant lesions (neurofibroma, pancreatic intraductal neoplasias, or colorectal adenomas) than in established malignant tumors.3 However, given that preneoplastic lesions frequently progress to malignant tumors, it is highly likely that accumulation of molecular alterations during carcinogenesis finally overcome OIS. Interestingly, full-blown malignancy can occur when the oncogenic event is combined with simultaneous inactivation of major mediators of the senescence response, such as p53 or p16.3 In the same line, the Zender and Lowe group4 induced HCC in mice by both expression of an oncogenic Hras mutant with a reversible inactivation of p53 in hepatocytes. In this model, conditional reactivation of p53 led to regression of HCC through senescence of tumor cells harboring the Hras oncogene. p53 reactivation and related tumor regression were dependent of the innate immune system, underlining again the possible role of immunity in OIS and tumor cell clearance.

In the present study, Zender and collaborators2 dissected the link between inflammation, immunity, and OIS at the preneoplastic stages of liver carcinogenesis. Classically, inflammation and immunity constitute the archetypal background where cancer is born.5 Many cancers arise in the chronic inflammation context, such as colorectal cancer in inflammatory bowel disease, cholangiocarcinoma in primary sclerosing cholangitis, or HCC in viral chronic hepatitis. In liver carcinogenesis, cytokine production by immune cell infiltrate but also by Kuppfer cells and hepatocytes promotes tumor formation.5 Another face of the relationship between immunity, inflammation, and liver cancer is inflammation induced by specific genetic alterations (also called “oncogene induced inflammation”). For example, in hepatocellular inflammatory adenoma, activation of STAT3 can be caused by either activating mutations targeting gp130 (the transducer of interleukin 6) or STAT3 itself in 60% and 5% of the tumors, respectively.6, 7 These two oncogenes are responsible for JAK/STAT pathway activation. In the liver, STAT3 activation also induces an inflammatory phenotype defined by the induction of inflammation target gene, cytokine production, immune cells attraction by chemokines release, and promotion of neoangiogenesis. Thus, STAT3 is a key player in liver benign tumorogenesis and hepatocyte could be considered a “bona fide” inflammatory cell. But inflammation and immunity have not only a “Mister Hyde” face. In advanced tumors, some chemotherapies like anthracyclines could elicit an immunogenic cancer cell death, triggering an anticancer immune response through secretion or exposure of an immunogenic signal (calreticulin, heat shock protein, or HMGB1).8

In this study, using the NrasG12V oncogene, Zender and collaborators demonstrated that clearance of cells that underwent OIS is dependent on the adaptive immune response (Fig. 1). Oncogene-bearing cells are cleared by the adaptive immune system and T CD4 lymphocytes are one of the most important actors in this mechanism. An antigen-specific NrasG12V Th1 response is triggered with NrasG12V presentation by antigen-presenting cells. Monocytes and macrophages are the final actors of the immune response; they directly destroy senescent cells. All these phenomena are dependent on cytokine and chemokine (the so-called “senescence associated secreted phenotype”) produced by both hepatocytes and the immune system in a paracrine loop. Disruption of the immune system or of the cytokine/chemokine network allows oncogenic cells to bypass senescence and form HCC. Thus, immunity acts as a barrier against oncogenic cell proliferation at the very early steps of tumorigenesis.

thumbnail image

Figure 1. Role of the immune system in OIS program. Hepatocyte NrasG12V enters the cellular senescence program which represents an important barrier against tumor development. Tumor immune surveillance by activation of specific immune responses is an extrinsic component of the senescence antitumor barrier. Secretion of chemokines and cytokines by hepatocytes and immune cells enhance the recruitment of immune cells and induction of cell death. Escape from OIS could occur due to inactivation of tumor suppressor gene or immunosuppression that promotes HCC development.

Download figure to PowerPoint

Clearance of senescent cells by the immune system is also dependent on the tumor suppressor gene P19/ARF. It is well known that the accumulation of multiple mutations in oncogene and tumor suppressor genes is required for tumor initiation and progression. For tumor cells, a consequence of the accumulation of genetic alterations is to escape the control of the immune system. It links two major mechanism of cancer: alterations of the genome and immunity/inflammation surveillance.

Zender and collaborators asked the question: What is the relevance of this model in human liver carcinogenesis and what lessons should be translated in clinical research? To this end, the authors analyzed patients with immunosuppression who are at higher risk factor for developing HCC. The authors described a high level of hepatocyte senescence in patients coinfected with hepatitis C virus (HCV) and human immunodeficiency virus (HIV and in patients with relapse of HCV after liver transplantation, two situations characterized by immune deficiency. Thus, in these two situations immunodeficiency impairs clearance of senescent cell, contributing to the accumulation of oncogene-induced preneoplastic cells. Interestingly, cirrhosis patients with impaired liver function also have a well-known immune deficiency that could overcome OIS and promote tumor initiation. In parallel, the high rate of hepatocyte death and senescence observed in advanced cirrhosis could induce a compensative proliferation of liver stem cells or surviving hepatocytes that accumulate genetic alterations and promote HCC formation. In this line, studies of a large cohort of cirrhosis patients should focus on the prevalence of senescence markers in liver biopsy in order to further elucidate its link with HCC development. Finally, HRAS mutations, like other mutations of the RAS family, are very rare events in human hepatocarcinogenesis.9 Consequently, the work of Zender and collaborators could open new hypotheses on the role of OIS in the prevention of liver tumor initiation induced by frequent oncogene activation, such as activating mutations of β-catenin.

To conclude, this elegant work enriches the interaction between immunity, inflammation, and initiation of liver tumorogenesis. It supports the crucial role of the immune system as a guardian against oncogene-driven tumorigenesis.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Comment
  4. Acknowledgements
  5. References

We thank Isabelle Desitter for critical reading of the article.

References

  1. Top of page
  2. Abstract
  3. Comment
  4. Acknowledgements
  5. References