Eggert Tobias, Wolter Katharina, Ji Juling, Ma Chi, Yevsa Tetyana, Klotz Sabrina, Medina-Echeverz José, Longerich Thomas, Forgues Marshonna, Reisinger Florian, Heikenwalder Mathias, Wang Xin Wei, Zender Lars, Greten Tim F
Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Division of Gastrointestinal Oncology, Department of Internal Medicine I, University of Tübingen, 72076 Tübingen, Germany.
Cancer Cell. 2016 Oct 10;30(4):533-547. doi: 10.1016/j.ccell.2016.09.003.
Oncogene-induced senescence causes hepatocytes to secrete cytokines, which induce their immune-mediated clearance to prevent tumor initiation, a process termed "senescence surveillance." However, senescent hepatocytes give rise to hepatocellular carcinomas (HCCs), if the senescence program is bypassed or if senescent cells are not cleared. Here, we show context-specific roles for CCR2 myeloid cells in liver cancer. Senescence surveillance requires the recruitment and maturation of CCR2 myeloid cells, and CCR2 ablation caused outgrowth of HCC. In contrast, HCC cells block the maturation of recruited myeloid precursors, which, through NK cell inhibition, promote growth of murine HCC and worsen the prognosis and survival of human HCC patients. Thus, while senescent hepatocyte-secreted chemokines suppress liver cancer initiation, they may accelerate the growth of fully established HCC.
癌基因诱导的衰老会使肝细胞分泌细胞因子，这些细胞因子会诱导肝细胞进行免疫介导的清除，以防止肿瘤发生，这一过程被称为“衰老监测”。然而，如果衰老程序被绕过或者衰老细胞未被清除，衰老的肝细胞就会引发肝细胞癌（HCC）。在此，我们展示了CCR2髓系细胞在肝癌中的特定背景作用。衰老监测需要CCR2髓系细胞的募集和成熟，CCR2基因敲除会导致HCC生长。相反，HCC细胞会阻碍募集来的髓系前体细胞的成熟，这些前体细胞通过抑制自然杀伤细胞来促进小鼠HCC的生长，并恶化人类HCC患者的预后和生存情况。因此，虽然衰老肝细胞分泌的趋化因子会抑制肝癌的起始，但它们可能会加速完全形成的HCC的生长。
