Ectopic lymphoid structures function as microniches for tumor progenitor cells in hepatocellular carcinoma.
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.
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.
Shlomi
S
Finkin
Institute of Virology, Technische Universität München, Helmholtz Zentrum München, Munich, Germany.
Detian
D
Yuan
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.
Ilan
I
Stein
Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California, San Diego, La Jolla, California, USA.
Koji
K
Taniguchi
Institute of Surgical Pathology, University and University-Hospital Zurich, Zurich, Switzerland.
Achim
A
Weber
Research Unit of Radiation Cytogenetics, Helmholtz-Zentrum München, Ingolstädter-Landstrasse, Neuherberg, Germany.
Kristian
K
Unger
Department of Microbiology, Boston University School of Medicine, Boston, Massachusetts, USA.
Jeffrey L
JL
Browning
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.
Nicolas
N
Goossens
Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA.
Shigeki
S
Nakagawa
Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Ganesh
G
Gunasekaran
Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Myron E
ME
Schwartz
Department of Hepatology, Toranomon Hospital, Tokyo, Japan.
Masahiro
M
Kobayashi
Department of Hepatology, Toranomon Hospital, Tokyo, Japan.
Hiromitsu
H
Kumada
Department of Immunology and Cancer Research, Institute for Medical Research Israel Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Michael
http://orcid.org/0000-0002-3469-0076
M
Berger
Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Orit
O
Pappo
Max Delbrück Center for Molecular Medicine, Berlin, Germany.
Klaus
K
Rajewsky
Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA.
Yujin
http://orcid.org/0000-0001-9430-1426
Y
Hoshida
Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California, San Diego, La Jolla, California, USA.
Michael
M
Karin
Institute of Virology, Technische Universität München, Helmholtz Zentrum München, Munich, Germany.|Division of Chronic Inflammation and Cancer, German Cancer Research Center, Heidelberg, Germany.
Mathias
M
Heikenwalder
Department of Immunology and Cancer Research, Institute for Medical Research Israel Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Yinon
Y
Ben-Neriah
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.
Eli
E
Pikarsky
D056704:Adaptive Immunity / Q000235:genetics / Q000276:immunology; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D055028:Comparative Genomic Hybridization; D016207:Cytokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D022781:Hepatocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology; D015151:Immunoblotting; D017403:In Situ Hybridization; D008113:Liver Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008221:Lymphoid Tissue / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055153:Stem Cell Niche / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D059467:Transcriptome / Q000235:genetics / Q000276:immunology
D016207:Cytokines; D016328:NF-kappa B; D051550:I-kappa B Kinase