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PMID: 26502405 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Ectopic lymphoid structures function as microniches for tumor progenitor cells in hepatocellular carcinoma.

Nature immunology ·Vol. 16 ·No. 12 ·2015-12-00 ·Pages 1235-44

Finkin S, Yuan D, Stein I, Taniguchi K, Weber A, Unger K, Browning JL, Goossens N, Nakagawa S, Gunasekaran G, Schwartz ME, Kobayashi M, Kumada H, Berger M, Pappo O, Rajewsky K, Hoshida Y, Karin M, Heikenwalder M, Ben-Neriah Y, Pikarsky E

Abstract

Ectopic lymphoid-like structures (ELSs) are often observed in cancer, yet their function is obscure. Although ELSs signify good prognosis in certain malignancies, we found that hepatic ELSs indicated poor prognosis for hepatocellular carcinoma (HCC). We studied an HCC mouse model that displayed abundant ELSs and found that they constituted immunopathological microniches wherein malignant hepatocyte progenitor cells appeared and thrived in a complex cellular and cytokine milieu until gaining self-sufficiency. The egress of progenitor cells and tumor formation were associated with the autocrine production of cytokines previously provided by the niche. ELSs developed via cooperation between the innate immune system and adaptive immune system, an event facilitated by activation of the transcription factor NF-κB and abolished by depletion of T cells. Such aberrant immunological foci might represent new targets for cancer therapy.

MeSH Terms
Adaptive Immunity/genetics,immunology Animals Carcinoma, Hepatocellular/genetics,immunology,metabolism Comparative Genomic Hybridization Cytokines/genetics,immunology,metabolism Disease Models, Animal Hepatocytes/immunology,metabolism,pathology Humans I-kappa B Kinase/genetics,immunology,metabolism Immunity, Innate/genetics,immunology Immunoblotting In Situ Hybridization Liver Neoplasms/genetics,immunology,metabolism Lymphoid Tissue/immunology,metabolism,pathology Mice, Inbred C57BL Mice, Knockout Mice, Transgenic NF-kappa B/genetics,immunology,metabolism Neoplastic Stem Cells/immunology,metabolism Reverse Transcriptase Polymerase Chain Reaction Stem Cell Niche/genetics,immunology T-Lymphocytes/immunology,metabolism Transcriptome/genetics,immunology
Chemicals
Cytokines NF-kappa B I-kappa B Kinase
Authors & Affiliations
21 authors, click to expand affiliations / ORCID
Finkin Shlomi
Department of Immunology and Cancer Research, Institute for Medical Research Israel Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel. | Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Yuan Detian
Institute of Virology, Technische Universität München, Helmholtz Zentrum München, Munich, Germany.
Stein Ilan
Department of Immunology and Cancer Research, Institute for Medical Research Israel Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel. | Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Taniguchi Koji
Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California, San Diego, La Jolla, California, USA.
Weber Achim
Institute of Surgical Pathology, University and University-Hospital Zurich, Zurich, Switzerland.
Unger Kristian
Research Unit of Radiation Cytogenetics, Helmholtz-Zentrum München, Ingolstädter-Landstrasse, Neuherberg, Germany.
Browning Jeffrey L
Department of Microbiology, Boston University School of Medicine, Boston, Massachusetts, USA.
Goossens Nicolas
Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA. | Division of Gastroenterology &Hepatology Geneva University Hospital, Geneva, Switzerland.
Nakagawa Shigeki
Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA.
Gunasekaran Ganesh
Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Schwartz Myron E
Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Kobayashi Masahiro
Department of Hepatology, Toranomon Hospital, Tokyo, Japan.
Kumada Hiromitsu
Department of Hepatology, Toranomon Hospital, Tokyo, Japan.
Berger Michael ORCID
Department of Immunology and Cancer Research, Institute for Medical Research Israel Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Pappo Orit
Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Rajewsky Klaus
Max Delbrück Center for Molecular Medicine, Berlin, Germany.
Hoshida Yujin ORCID
Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA.
Karin Michael
Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California, San Diego, La Jolla, California, USA.
Heikenwalder Mathias
Institute of Virology, Technische Universität München, Helmholtz Zentrum München, Munich, Germany. | Division of Chronic Inflammation and Cancer, German Cancer Research Center, Heidelberg, Germany.
Ben-Neriah Yinon
Department of Immunology and Cancer Research, Institute for Medical Research Israel Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Pikarsky Eli
Department of Immunology and Cancer Research, Institute for Medical Research Israel Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel. | Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
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Article Info
Journal
Nature immunology
Abbr.
Nat Immunol
ISSN
1529-2916
DOI
10.1038/ni.3290
Published
2015-12-00
Epub
2015-00-26
Pages
1235-44
Language
English
Region
United States
NLM ID
100941354
PMCID
PMC4653079
Subset
IM
Grants
NCI NIH HHS · CA118165 · United States
Worldwide Cancer Research · 05-0121 · United Kingdom
NIEHS NIH HHS · P42 ES010337 · United States
NIDDK NIH HHS · DK099558 · United States
NIEHS NIH HHS · ES010337 · United States
NCI NIH HHS · R01 CA118165 · United States
NIAID NIH HHS · R01 AI043477 · United States
NIDDK NIH HHS · R01 DK099558 · United States
NIAID NIH HHS · AI0043477 · United States
NCI NIH HHS · P30 CA196521 · United States
Corrections
CommentIn
PMID: 26553418
External Links
PubMed source DOI: 10.1038/ni.3290 PMC Full Text View journal details
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