ABSTRACT
BACKGROUND: Lymphoepithelial carcinoma of the salivary glands (LECSG) is a rare disease in the Western hemisphere that is typically associated with an EBV infection. The molecular mechanisms of LECSG tumorigenesis are poorly understood. RESULTS: Here we report a case of EBV-associated LECSG with an unusual immunophenotype. The tumor exhibited bi-morphic histological features with a mutually exclusive expression of HER2 and p16. The p16-positive domain of the tumor immunohistochemically co-expressed late membrane protein 1 (LMP-1), while the HER2 positive domain did not. Both tumor regions expressed SSTR2. METHODS: In situ hybridization confirmed the EBV origin of the tumor while extensive immunohistochemical characterization and the recently established RNA-based next generation sequencing panel ("SalvGlandDx" panel) did not reveal evidence for another salivary gland neoplasm. No HPV co-infection was detected by in situ hybridization or PCR-based screenings and no ERBB2 gene amplification was detected by fluorescence in situ hybridization. CONCLUSION: These findings suggest tumor heterogeneity and lack of genomic aberrations in EBV-associated LECSGs. The heterogenous and unusual immunohistochemical features explain the diagnostic difficulties and simultaneously extend the immunophenotype spectrum of this tumor entity.
Subject(s)
Carcinoma, Squamous Cell , Papillomavirus Infections , Salivary Gland Neoplasms , Humans , Herpesvirus 4, Human/genetics , In Situ Hybridization, Fluorescence , Carcinoma, Squamous Cell/pathology , Salivary Glands/pathology , Salivary Gland Neoplasms/pathology , Papillomavirus Infections/complicationsABSTRACT
It is currently not well known how necroptosis and necroptosis responses manifest in vivo. Here, we uncovered a molecular switch facilitating reprogramming between two alternative modes of necroptosis signaling in hepatocytes, fundamentally affecting immune responses and hepatocarcinogenesis. Concomitant necrosome and NF-κB activation in hepatocytes, which physiologically express low concentrations of receptor-interacting kinase 3 (RIPK3), did not lead to immediate cell death but forced them into a prolonged "sublethal" state with leaky membranes, functioning as secretory cells that released specific chemokines including CCL20 and MCP-1. This triggered hepatic cell proliferation as well as activation of procarcinogenic monocyte-derived macrophage cell clusters, contributing to hepatocarcinogenesis. In contrast, necrosome activation in hepatocytes with inactive NF-κB-signaling caused an accelerated execution of necroptosis, limiting alarmin release, and thereby preventing inflammation and hepatocarcinogenesis. Consistently, intratumoral NF-κB-necroptosis signatures were associated with poor prognosis in human hepatocarcinogenesis. Therefore, pharmacological reprogramming between these distinct forms of necroptosis may represent a promising strategy against hepatocellular carcinoma.
Subject(s)
Liver Neoplasms , NF-kappa B , Humans , NF-kappa B/metabolism , Protein Kinases/metabolism , Necroptosis , Inflammation/pathology , Receptor-Interacting Protein Serine-Threonine Kinases/genetics , Receptor-Interacting Protein Serine-Threonine Kinases/metabolism , ApoptosisABSTRACT
How lymphoma cells (LCs) invade the brain during the development of central nervous system lymphoma (CNSL) is unclear. We found that NF-κB-induced gliosis promotes CNSL in immunocompetent mice. Gliosis elevated cell-adhesion molecules, which increased LCs in the brain but was insufficient to induce CNSL. Astrocyte-derived CCL19 was required for gliosis-induced CNSL. Deleting CCL19 in mice or CCR7 from LCs abrogated CNSL development. Two-photon microscopy revealed LCs transiently entering normal brain parenchyma. Astrocytic CCL19 enhanced parenchymal CNS retention of LCs, thereby promoting CNSL formation. Aged, gliotic wild-type mice were more susceptible to forming CNSL than young wild-type mice, and astrocytic CCL19 was observed in both human gliosis and CNSL. Therefore, CCL19-CCR7 interactions may underlie an increased age-related risk for CNSL.
Subject(s)
Aging/pathology , Central Nervous System Neoplasms/pathology , Chemokine CCL19/metabolism , Gliosis/pathology , Lymphoma/pathology , Adolescent , Adult , Aged , Animals , Astrocytes/metabolism , Astrocytes/pathology , Blood-Brain Barrier/cytology , Blood-Brain Barrier/diagnostic imaging , Blood-Brain Barrier/pathology , Cell Line, Tumor/transplantation , Central Nervous System Neoplasms/diagnostic imaging , Central Nervous System Neoplasms/surgery , Chemokine CCL19/genetics , Chemokine CXCL12 , Disease Models, Animal , Female , Gliosis/diagnostic imaging , Humans , Intravital Microscopy , Lymphoma/diagnostic imaging , Lymphoma/surgery , Male , Mice , Mice, Transgenic , Microscopy, Fluorescence, Multiphoton , Middle Aged , NF-kappa B/metabolism , Receptors, CCR7/genetics , Receptors, CCR7/metabolism , Time-Lapse Imaging , Young AdultABSTRACT
Murine liver tumors often fail to recapitulate the complexity of human hepatocellular carcinoma (HCC), which might explain the difficulty to translate preclinical mouse studies into clinical science. The aim of this study was to evaluate a subtyping approach for murine liver cancer models with regard to etiology-defined categories of human HCC, comparing genomic changes, histomorphology, and IHC profiles. Sequencing and analysis of gene copy-number changes [by comparative genomic hybridization (CGH)] in comparison with etiology-dependent subsets of HCC patients of The Cancer Genome Atlas (TCGA) database were conducted using specimens (75 tumors) of five different HCC mouse models: diethylnitrosamine (DEN) treated wild-type C57BL/6 mice, c-Myc and AlbLTαß transgenic mice as well as TAK1LPC-KO and Mcl-1Δhep mice. Digital microscopy was used for the assessment of morphology and IHC of liver cell markers (A6-CK7/19, glutamine synthetase) in mouse and n = 61 human liver tumors. Tumor CGH profiles of DEN-treated mice and c-Myc transgenic mice matched alcohol-induced HCC, including morphologic findings (abundant inclusion bodies, fatty change) in the DEN model. Tumors from AlbLTαß transgenic mice and TAK1LPC-KO models revealed the highest overlap with NASH-HCC CGH profiles. Concordant morphology (steatosis, lymphocyte infiltration, intratumor heterogeneity) was found in AlbLTαß murine livers. CGH profiles from the Mcl-1Δhep model displayed similarities with hepatitis-induced HCC and characteristic human-like phenotypes (fatty change, intertumor and intratumor heterogeneity). IMPLICATIONS: Our findings demonstrate that stratifying preclinical mouse models along etiology-oriented genotypes and human-like phenotypes is feasible. This closer resemblance of preclinical models is expected to better recapitulate HCC subgroups and thus increase their informative value.
Subject(s)
Carcinoma, Hepatocellular/genetics , Liver Neoplasms, Experimental/genetics , Liver Neoplasms/genetics , Liver/metabolism , Animals , Carcinoma, Hepatocellular/classification , Carcinoma, Hepatocellular/pathology , Comparative Genomic Hybridization , Disease Models, Animal , Hepatocytes/metabolism , Hepatocytes/pathology , Humans , Liver/pathology , Liver Neoplasms/classification , Liver Neoplasms/pathology , Liver Neoplasms, Experimental/classification , Liver Neoplasms, Experimental/pathology , MAP Kinase Kinase Kinases/genetics , Mice , Mice, TransgenicABSTRACT
In many organs, including the intestine and skin, cancers originate from cells of the stem or progenitor compartment. Despite its nomenclature, the cellular origin of hepatocellular carcinoma (HCC) remains elusive. In contrast to most organs, the liver lacks a defined stem cell population for organ maintenance. Previous studies suggest that both hepatocytes and facultative progenitor cells within the biliary compartment are capable of generating HCC. As HCCs with a progenitor signature carry a worse prognosis, understanding the origin of HCC is of clinical relevance. Here, we used complementary fate-tracing approaches to label the progenitor/biliary compartment and hepatocytes in murine hepatocarcinogenesis. In genotoxic and genetic models, HCCs arose exclusively from hepatocytes but never from the progenitor/biliary compartment. Cytokeratin 19-, A6- and α-fetoprotein-positive cells within tumors were hepatocyte derived. In summary, hepatocytes represent the cell of origin for HCC in mice, and a progenitor signature does not reflect progenitor origin, but dedifferentiation of hepatocyte-derived tumor cells.
Subject(s)
Hepatocytes/pathology , Liver Neoplasms, Experimental/pathology , Neoplastic Stem Cells/pathology , Animals , Bile Ducts/cytology , Biomarkers, Tumor/analysis , Carbon Tetrachloride/toxicity , Carcinogens , Cell Dedifferentiation , Cell Lineage , Cocarcinogenesis , Comparative Genomic Hybridization , Diethylnitrosamine , Gene Expression Profiling , Genes, Reporter , Hepatocytes/chemistry , Hepatocytes/drug effects , Keratin-19/analysis , Liver Cirrhosis, Experimental/pathology , Liver Neoplasms, Experimental/chemically induced , Liver Neoplasms, Experimental/etiology , Male , Mice , Mice, Transgenic , Microfilament Proteins/analysis , Neoplastic Stem Cells/chemistry , Osteopontin/analysis , PTEN Phosphohydrolase/deficiency , PTEN Phosphohydrolase/genetics , PTEN Phosphohydrolase/physiology , Precancerous Conditions/chemically induced , Precancerous Conditions/pathology , Tamoxifen/pharmacology , alpha-Fetoproteins/analysisABSTRACT
The cellular prion protein (PrPC) consists of a flexible N-terminal tail (FT, aa 23-128) hinged to a membrane-anchored globular domain (GD, aa 129-231). Ligation of the GD with antibodies induces rapid neurodegeneration, which is prevented by deletion or functional inactivation of the FT. Therefore, the FT is an allosteric effector of neurotoxicity. To explore its mechanism of action, we generated transgenic mice expressing the FT fused to a GPI anchor, but lacking the GD (PrPΔ141-225, or "FTgpi"). Here we report that FTgpi mice develop a progressive, inexorably lethal neurodegeneration morphologically and biochemically similar to that triggered by anti-GD antibodies. FTgpi was mostly retained in the endoplasmic reticulum, where it triggered a conspicuous unfolded protein response specifically activating the PERK pathway leading to phosphorylation of eIF2α and upregulation of CHOP ultimately leading to neurodegeration similar to what was observed in prion infection.
Subject(s)
Cerebellum/pathology , PrPC Proteins/metabolism , Prion Diseases/metabolism , Prion Diseases/pathology , Unfolded Protein Response , Animals , Cerebellum/metabolism , Endoplasmic Reticulum Stress , Mice , Mice, Transgenic , PrPC Proteins/analysis , PrionsABSTRACT
Hepatocellular carcinoma (HCC), the fastest rising cancer in the United States and increasing in Europe, often occurs with nonalcoholic steatohepatitis (NASH). Mechanisms underlying NASH and NASH-induced HCC are largely unknown. We developed a mouse model recapitulating key features of human metabolic syndrome, NASH, and HCC by long-term feeding of a choline-deficient high-fat diet. This induced activated intrahepatic CD8(+) T cells, NKT cells, and inflammatory cytokines, similar to NASH patients. CD8(+) T cells and NKT cells but not myeloid cells promote NASH and HCC through interactions with hepatocytes. NKT cells primarily cause steatosis via secreted LIGHT, while CD8(+) and NKT cells cooperatively induce liver damage. Hepatocellular LTßR and canonical NF-κB signaling facilitate NASH-to-HCC transition, demonstrating that distinct molecular mechanisms determine NASH and HCC development.