1. Ectopic lymphoid structures function as microniches for tumor progenitor cells in hepatocellular carcinoma.
- Author
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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, and Pikarsky E
- Subjects
- Adaptive Immunity genetics, Adaptive Immunity immunology, Animals, Carcinoma, Hepatocellular genetics, Carcinoma, Hepatocellular metabolism, Comparative Genomic Hybridization, Cytokines genetics, Cytokines immunology, Cytokines metabolism, Disease Models, Animal, Hepatocytes immunology, Hepatocytes metabolism, Hepatocytes pathology, Humans, I-kappa B Kinase genetics, I-kappa B Kinase immunology, I-kappa B Kinase metabolism, Immunity, Innate genetics, Immunity, Innate immunology, Immunoblotting, In Situ Hybridization, Liver Neoplasms genetics, Liver Neoplasms metabolism, Lymphoid Tissue metabolism, Lymphoid Tissue pathology, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, NF-kappa B genetics, NF-kappa B immunology, NF-kappa B metabolism, Neoplastic Stem Cells metabolism, Reverse Transcriptase Polymerase Chain Reaction, Stem Cell Niche genetics, T-Lymphocytes immunology, T-Lymphocytes metabolism, Transcriptome genetics, Transcriptome immunology, Carcinoma, Hepatocellular immunology, Liver Neoplasms immunology, Lymphoid Tissue immunology, Neoplastic Stem Cells immunology, Stem Cell Niche immunology
- 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.
- Published
- 2015
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