title: Distinct Functions of Senescence-Associated Immune Responses in Liver Tumor Surveillance and Tumor Progression.
abstract: 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.
authors.affiliation: Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Tobias
authors.initials: T
authors.lastname: Eggert
authors.affiliation: Division of Gastrointestinal Oncology, Department of Internal Medicine I, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Wolter
authors.affiliation: Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Juling
authors.initials: J
authors.lastname: Ji
authors.affiliation: Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Chi
authors.initials: C
authors.lastname: Ma
authors.affiliation: Division of Gastrointestinal Oncology, Department of Internal Medicine I, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Tetyana
authors.initials: T
authors.lastname: Yevsa
authors.affiliation: Division of Gastrointestinal Oncology, Department of Internal Medicine I, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Klotz
authors.affiliation: Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: José
authors.initials: J
authors.lastname: Medina-Echeverz
authors.affiliation: Institute of Pathology, University Hospital RWTH Aachen, 52074 Aachen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Longerich
authors.affiliation: Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Marshonna
authors.initials: M
authors.lastname: Forgues
authors.affiliation: Institute of Virology, Technische Universität München and Helmholtz Zentrum München, 81675 Munich, Germany; Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Reisinger
authors.affiliation: Institute of Virology, Technische Universität München and Helmholtz Zentrum München, 81675 Munich, Germany; Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Heikenwalder
authors.affiliation: Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Xin Wei
authors.initials: XW
authors.lastname: Wang
authors.affiliation: Division of Gastrointestinal Oncology, Department of Internal Medicine I, University of Tübingen, 72076 Tübingen, Germany; Translational Gastrointestinal Oncology Group within the German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. Electronic address: lars.zender@med.uni-tuebingen.de.
authors.forename: Lars
authors.initials: L
authors.lastname: Zender
authors.affiliation: Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: tim.greten@nih.gov.
authors.forename: Tim F
authors.initials: TF
authors.lastname: Greten
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000276:immunology* / Q000473:pathology; D016922:Cellular Senescence / Q000276:immunology; D018450:Disease Progression; D005260:Female; D006801:Humans; D007157:Immunologic Surveillance; D008113:Liver Neoplasms / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
keywords: CCL2; CCR2; HCC; MDSC; NK cells; hepatocellular carcinoma; liver cancer; macrophages; myeloid cells; senescence