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Vertebrate lonesome kinase (VLK) is the only known extracellular tyrosine kinase, but its physiological functions are largely unknown. We show that VLK is highly expressed in hepatocytes of neonatal mice, but downregulated during adulthood. To determine the role of VLK in liver homeostasis and regeneration, we generated mice with a hepatocyte-specific knockout of the VLK gene (Pkdcc). Cultured progenitor cells established from primary hepatocytes of Pkdcc knockout mice produced a secretome, which promoted their own proliferation in 3D spheroids and proliferation of cultured fibroblasts. In vivo, Pkdcc knockout mice developed liver steatosis with signs of inflammation and perivascular fibrosis upon aging, combined with expansion of liver progenitor cells. In response to chronic CCl4-induced liver injury, the pattern of deposited collagen was significantly altered in these mice. The liver injury marker alpha-fetoprotein (AFP) was increased in the secretome of VLK-deficient cultured progenitor cells and in liver tissues of aged or CCl4-treated knockout mice. These results support a key role for VLK and extracellular protein phosphorylation in liver homeostasis and repair through paracrine control of liver cell function and regulation of appropriate collagen deposition. This article has an associated First Person interview with the first author of the paper.
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Hepatocitos , Secretoma , Adulto , Anciano , Animales , Colágeno/metabolismo , Hepatocitos/metabolismo , Humanos , Inflamación/metabolismo , Hígado/metabolismo , Cirrosis Hepática/genética , Cirrosis Hepática/metabolismo , Ratones , Ratones Noqueados , Proteínas Tirosina Quinasas/metabolismoRESUMEN
BACKGROUND: In the spectrum of molecular alterations found in hepatocellular carcinoma (HCC), somatic mutations in the WNT/ß-catenin pathway and the p53/cell cycle control pathway are among the most frequent ones. It has been suggested that both mutations occur in a mutually exclusive manner and they are used as molecular classifiers in HCC classification proposals. CASE PRESENTATION: Here, we report the case of a treatment-naïve mixed hepatocellular/cholangiocellular carcinoma (HCC/CCC) with morphological and genetic intratumor heterogeneity. Within the predominant part of the tumor with hepatocellular differentiation, a p.D32V mutation in exon 3 of the CTNNB1 gene occurred concomitantly with a TP53 intron 7/exon 8 splice site mutation. CONCLUSION: Intratumor heterogeneity challenges the concept of CTNNB1 and TP53 gene mutations being mutually exclusive molecular classifiers in HCC, which has implications for HCC classification approaches.
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BACKGROUND: The survival time of patients with head and neck squamous cell carcinoma (HNSCC) is related to health behavior, such as tobacco smoking and alcohol consumption. Poor oral health (OH), dental care (DC) and the frequent use of mouthwash have been shown to represent independent risk factors for head and neck cancerogenesis, but their impact on the survival of HNSCC patients has not been systematically investigated. METHODS: Two hundred seventy-six incident HNSCC cases recruited for the ARCAGE study were followed through a period of 6-10 years. Interview-based information on wearing of dentures, gum bleeding, teeth brushing, use of floss and dentist visits were grouped into weighted composite scores, i.e. oral health (OH) and dental care (DH). Use of mouthwash was assessed as frequency per day. Also obtained were other types of health behavior, such as smoking, alcohol drinking and diet, appreciated as both confounding and study variables. Endpoints were progression-free survival, overall survival and tumor-specific survival. Prognostic values were estimated using Kaplan-Meier analysis and Cox proportional hazards regression models. RESULTS: A good dental care score, summarizing annual dental visits, daily teeth cleaning and use of floss was associated with longer overall survival time (p = .001). The results of the Cox regression models similarly suggested a higher risk of tumor progression and shortened overall survival in patients with poor dental care, but the results lost their statistical significance after other types of health behavior had been controlled for. Frequent use of mouthwash (≥ 2 times/day) significantly increased the risk of tumor-specific death (HR = 2.26; CI = 1.19-4.32). Alcohol consumption and tobacco smoking were dose-dependently associated with tumor progression and shorter overall survival. CONCLUSION: Frequent mouthwash use of ≥ 2 times/day seems to elevate the risk of tumor-specific death in HNSCC patients. Good dental care scores are associated with longer overall survival.
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Carcinoma de Células Escamosas/mortalidad , Neoplasias de Cabeza y Cuello/mortalidad , Higiene Bucal , Estudios de Casos y Controles , Humanos , Antisépticos Bucales/uso terapéutico , Análisis de SupervivenciaRESUMEN
We aimed to determine the rate of hepatitis E virus (HEV) infection, a recently increasingly recognized disease in the Western world, in liver transplant patients by direct molecular testing of liver tissue. A RT-PCR assay was designed for detecting the HEV open reading frame (ORF) 2/3 gene region in formalin-fixed, paraffin-embedded tissues, and applied to all liver biopsies (n=683) taken 4 weeks or later from all patients (n=282) after liver transplantation of two large academic centers. HEV-RNA was detected in ten biopsies from four different patients (rate: 1%). Histology in early HEV infection was variable including cases with only few hepatocellular apoptoses, no or only minute inflammation. Hepatitis lasted for at least 6 months in 3/4 patients. Serologic testing for HEV-RNA in a subcohort (159 patients) was positive in five patients (rate: 3%), resulting in an overall HEV detection rate of 3% (8/282). In case both liver tissue and sera of a patient were available from the same time period, all cases tested positive in one material were also tested positive in the other material, respectively. All patients had de novo autochthonous infection with HEV genotype 3. Our data confirm that HEV infection is a relevant cause of liver injury after liver transplantation. Molecular testing for HEV in routinely processed transplant liver biopsies is powerful for evaluating patients with elevated transaminases of unknown origin. Histology of HEV infection under immunosuppression in the early phase is distinct from HEV infection in immunocompetent individuals.
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Virus de la Hepatitis E/aislamiento & purificación , Hepatitis E/diagnóstico , Hígado/virología , Adulto , Femenino , Humanos , Hígado/patología , Hígado/cirugía , Trasplante de Hígado , Masculino , Persona de Mediana EdadRESUMEN
The prognosis of pancreatic neuroendocrine tumors is related to size, histology and proliferation rate. However, this stratification needs to be refined further. We conducted a proteome study on insulinomas, a well-defined pancreatic neuroendocrine tumor entity, in order to identify proteins that can be used as biomarkers for malignancy. Based on a long follow-up, insulinomas were divided into those with metastases (malignant) and those without (benign). Microdissected cells from six benign and six malignant insulinomas were subjected to a procedure combining fluorescence dye saturation labeling with high-resolution two-dimensional gel electrophoresis. Differentially expressed proteins were identified using nano liquid chromatography-electrospray ionization/multi-stage mass spectrometry and validated by immunohistochemistry on tissue microarrays containing 62 insulinomas. Sixteen differentially regulated proteins were identified among 3000 protein spots. Immunohistochemical validation revealed that aldehyde dehydrogenase 1A1 and voltage-dependent anion-selective channel protein 1 showed significantly stronger expression in malignant insulinomas than in benign insulinomas, whereas tumor protein D52 (TPD52) binding protein was expressed less strongly in malignant insulinomas than in benign insulinomas. Using multivariate analysis, low TPD52 expression was identified as a strong independent prognostic factor for both recurrence-free and overall disease-related survival.
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Biomarcadores de Tumor/análisis , Insulinoma/patología , Proteínas de Neoplasias/biosíntesis , Neoplasias Pancreáticas/patología , Proteómica/métodos , Adulto , Anciano , Cromatografía Liquida , Electroforesis en Gel Bidimensional , Femenino , Humanos , Inmunohistoquímica , Insulinoma/metabolismo , Insulinoma/mortalidad , Estimación de Kaplan-Meier , Masculino , Microdisección , Persona de Mediana Edad , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/mortalidad , Pronóstico , Modelos de Riesgos Proporcionales , Espectrometría de Masa por Ionización de Electrospray , Análisis de Matrices TisularesRESUMEN
Hypoxia activates pathways associated with tumor progression, metastatic spread, and alterations in the immune microenvironment leading to an immunosuppressive phenotype. In particular, the upregulation of PD-L1, a target for therapy with checkpoint inhibitors, is well-studied in several tumors. However, the relationship between hypoxia and PD-L1 regulation in pheochromocytomas and paragangliomas (PPGL), and especially in paragangliomas treated with embolization, is still largely unexplored. We investigated the expression of the hypoxia-marker HIF-2α and of PD-L1 in a PPGL-cohort with and without embolization as potential biomarkers that may predict the response to treatment with HIF-2α and checkpoint inhibitors. A total of 29 tumor samples from 25 patients who were operated at a single center were included and analyzed utilizing immunohistochemistry (IHC) for PD-L1 and HIF-2α. Embolization prior to surgery was performed in seven (24%) tumors. PD-L1 expression in tumor cells of head and neck paragangliomas (HNPGLs) receiving prior embolization (median PD-L1 positivity: 15%) was significantly higher as compared to PD-L1 expression in HNPGLs without prior embolization (median PD-L1 positivity: 0%) (p = 0.008). Consistently, significantly more HNPGLs with prior embolization were positive for HIF-2α (median nuclear HIF-2α positivity: 40%) as compared to HNPGLs without prior embolization (median nuclear HIF-2α positivity: 0%) (p = 0.016). Our results support the hypothesis that embolization with subsequent hypoxia leads to the upregulation of both PD-L1 and HIF-2α in HNPGLs, and could thus facilitate targeted treatment with HIF-2α and checkpoint inhibitors in the case of inoperable, locally advanced, or metastatic disease.
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CONTEXT: Pheochromocytomas and paragangliomas (PPGLs) with pathogenic mutations in the succinate dehydrogenase subunit B (SDHB) are associated with a high metastatic risk. Somatostatin receptor 2 (SSTR2)-dependent imaging is the most sensitive imaging modality for SDHB-related PPGLs, suggesting that SSTR2 expression is a significant cell surface therapeutic biomarker of such tumors. OBJECTIVE: Exploration of the relationship between SSTR2 immunoreactivity and SDHB immunoreactivity, mutational status, and clinical behavior of PPGLs. Evaluation of SSTR-based therapies in metastatic PPGLs. METHODS: Retrospective analysis of a multicenter cohort of PPGLs at 6 specialized Endocrine Tumor Centers in Germany, The Netherlands, and Switzerland. Patients with PPGLs participating in the ENSAT registry were included. Clinical data were extracted from medical records, and immunohistochemistry (IHC) for SDHB and SSTR2 was performed in patients with available tumor tissue. Immunoreactivity of SSTR2 was investigated using Volante scores. The main outcome measure was the association of SSTR2 IHC positivity with genetic and clinical-pathological features of PPGLs. RESULTS: Of 202 patients with PPGLs, 50% were SSTR2 positive. SSTR2 positivity was significantly associated with SDHB- and SDHx-related PPGLs, with the strongest SSTR2 staining intensity in SDHB-related PPGLs (P = .01). Moreover, SSTR2 expression was significantly associated with metastatic disease independent of SDHB/SDHx mutation status (P < .001). In metastatic PPGLs, the disease control rate with first-line SSTR-based radionuclide therapy was 67% (n = 22, n = 11 SDHx), and with first-line "cold" somatostatin analogs 100% (n = 6, n = 3 SDHx). CONCLUSION: SSTR2 expression was independently associated with SDHB/SDHx mutations and metastatic disease. We confirm a high disease control rate of somatostatin receptor-based therapies in metastatic PPGLs.
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Neoplasias de las Glándulas Suprarrenales , Neoplasias Primarias Secundarias , Paraganglioma , Feocromocitoma , Humanos , Neoplasias de las Glándulas Suprarrenales/genética , Neoplasias de las Glándulas Suprarrenales/terapia , Neoplasias de las Glándulas Suprarrenales/metabolismo , Paraganglioma/genética , Paraganglioma/terapia , Paraganglioma/metabolismo , Feocromocitoma/genética , Feocromocitoma/terapia , Feocromocitoma/metabolismo , Receptores de Somatostatina/genética , Receptores de Somatostatina/metabolismo , Estudios Retrospectivos , Succinato Deshidrogenasa/genética , Succinato Deshidrogenasa/metabolismoRESUMEN
Pancreatic neuroendocrine tumors (pNETs) are a vast growing disease. Over 50% of these tumors are recognized at advanced stages with lymph node, liver, or distant metastasis. An ongoing controversy is the role of surgery in the metastatic setting as dedicated systemic treatments have emerged recently and shown benefits in randomized trials. Today, liver surgery is an option for advanced pNETs if the tumor has a favorable prognosis, reflected by a low to moderate proliferation index (G1 and G2). Surgery in this well-selected population may prolong progression-free and overall survival. Optimal selection of a treatment plan for an individual patient should be considered in a multidisciplinary tumor board. However, while current guidelines offer a variety of modalities, there is so far only a limited focus on the right timing. Available data is based on small case series or retrospective analyses. The focus of this review is to highlight the right time-point for surgery in the setting of the multimodal treatment of an advanced pancreatic neuroendocrine tumor.
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Nonalcoholic steatohepatitis (NASH)-induced hepatocellular carcinoma (HCC) and its precursor, nonalcoholic fatty liver disease (NAFLD) are an unmet health issue due to widespread obesity. We assessed copy number changes of genes associated with hepatocarcinogenesis and oxidative pathways at a single-cell level. Eleven patients with NASH-HCC and 11 patients with NAFLD were included. Eight probes were analyzed using multiplex interphase fluorescence in situ hybridization (miFISH), single-cell imaging and phylogenetic tree modelling: Telomerase reverse transcriptase (TERT), C-Myc (MYC), hepatocyte growth factor receptor tyrosine kinase (MET), tumor protein 53 (TP53), cyclin D1 (CCND1), human epidermal growth factor receptor 2 (HER2), the fragile histidine triad gene (FHIT) and FRA16D oxidoreductase (WWOX). Each NASH-HCC tumor had up to 14 distinct clonal signal patterns indicating multiclonality, which correlated with high tumor grade. Changes frequently observed were TP53 losses, 45%; MYC gains, 36%; WWOX losses, 36%; and HER2 gains, 18%. Whole-genome duplications were frequent (82%) with aberrant tetraploid cells evolving from diploid ancestors. Non-tumorous NAFLD/NASH biopsies did not harbor clonal copy number changes. Fine mapping of NASH-HCC using single-cell multiplex FISH shows that branched tumor evolution involves genome duplication and that multiclonality increases with tumor grade. The loss of oxidoreductase WWOX and HER2 gains could be potentially associated with NASH-induced hepatocellular carcinoma.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Enfermedad del Hígado Graso no Alcohólico , Humanos , Carcinoma Hepatocelular/patología , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/patología , Neoplasias Hepáticas/patología , Hibridación Fluorescente in Situ , Filogenia , Aberraciones Cromosómicas , Proteínas de Neoplasias/genética , Ploidias , Oxidorreductasas/genéticaRESUMEN
Aggressive pheochromocytomas and paragangliomas (PPGLs) are difficult to treat, and molecular targeting is being increasingly considered, but with variable results. This study investigates established and novel molecular-targeted drugs and chemotherapeutic agents for the treatment of PPGLs in human primary cultures and murine cell line spheroids. In PPGLs from 33 patients, including 7 metastatic PPGLs, we identified germline or somatic driver mutations in 79% of cases, allowing us to assess potential differences in drug responsivity between pseudohypoxia-associated cluster 1-related (n = 10) and kinase signaling-associated cluster 2-related (n = 14) PPGL primary cultures. Single anti-cancer drugs were either more effective in cluster 1 (cabozantinib, selpercatinib, and 5-FU) or similarly effective in both clusters (everolimus, sunitinib, alpelisib, trametinib, niraparib, entinostat, gemcitabine, AR-A014418, and high-dose zoledronic acid). High-dose estrogen and low-dose zoledronic acid were the only single substances more effective in cluster 2. Neither cluster 1- nor cluster 2-related patient primary cultures responded to HIF-2a inhibitors, temozolomide, dabrafenib, or octreotide. We showed particular efficacy of targeted combination treatments (cabozantinib/everolimus, alpelisib/everolimus, alpelisib/trametinib) in both clusters, with higher efficacy of some targeted combinations in cluster 2 and overall synergistic effects (cabozantinib/everolimus, alpelisib/trametinib) or synergistic effects in cluster 2 (alpelisib/everolimus). Cabozantinib/everolimus combination therapy, gemcitabine, and high-dose zoledronic acid appear to be promising treatment options with particularly high efficacy in SDHB-mutant and metastatic tumors. In conclusion, only minor differences regarding drug responsivity were found between cluster 1 and cluster 2: some single anti-cancer drugs were more effective in cluster 1 and some targeted combination treatments were more effective in cluster 2.
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Neoplasias de las Glándulas Suprarrenales , Antineoplásicos , Paraganglioma , Feocromocitoma , Neoplasias de las Glándulas Suprarrenales/tratamiento farmacológico , Neoplasias de las Glándulas Suprarrenales/genética , Neoplasias de las Glándulas Suprarrenales/metabolismo , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Everolimus/uso terapéutico , Humanos , Ratones , Paraganglioma/tratamiento farmacológico , Paraganglioma/genética , Paraganglioma/patología , Feocromocitoma/tratamiento farmacológico , Feocromocitoma/genética , Feocromocitoma/metabolismo , Ácido Zoledrónico/uso terapéuticoRESUMEN
OBJECTIVE: Within the past decade, important genetic drivers of pheochromocytoma and paraganglioma (PPGLs) development have been identified. The pathophysiological mechanism that translates these alterations into functional autonomy and potentially malignant behavior has not been elucidated in detail. Here we used MALDI-mass spectrometry imaging (MALDI-MSI) of formalin-fixed paraffin-embedded tissue specimens to comprehensively characterize the metabolic profiles of PPGLs. DESIGN AND METHODS: MALDI-MSI was conducted in 344 PPGLs and results correlated with genetic and phenotypic information. We experimentally silenced genetic drivers by siRNA in PC12 cells to confirm their metabolic impact in vitro. RESULTS: Tissue abundance of kynurenine pathway metabolites such as xanthurenic acid was significantly lower (P = 2.35E-09) in the pseudohypoxia pathway cluster 1 compared to PPGLs of the kinase-driven PPGLs cluster 2. Lower abundance of xanthurenic acid was associated with shorter metastasis-free survival (log-rank tests P = 7.96E-06) and identified as a risk factor for metastasis independent of the genetic status (hazard ratio, 32.6, P = 0.002). Knockdown of Sdhb and Vhl in an in vitro model demonstrated that inositol metabolism and sialic acids were similarly modulated as in tumors of the respective cluster. CONCLUSIONS: The present study has identified distinct tissue metabolomic profiles of PPGLs in relation to tumor genotypes. In addition, we revealed significantly altered metabolites in the kynurenine pathway in metastatic PPGLs, which can aid in the prediction of its malignant potential. However, further validation studies will be required to confirm our findings.
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Neoplasias de las Glándulas Suprarrenales/patología , Espectrometría de Masas/métodos , Metaboloma , Paraganglioma/patología , Feocromocitoma/patología , Neoplasias de las Glándulas Suprarrenales/diagnóstico , Neoplasias de las Glándulas Suprarrenales/genética , Neoplasias de las Glándulas Suprarrenales/metabolismo , Adulto , Animales , Estudios de Cohortes , Progresión de la Enfermedad , Femenino , Estudios de Asociación Genética , Humanos , Masculino , Metabolómica/métodos , Persona de Mediana Edad , Metástasis de la Neoplasia , Células PC12 , Paraganglioma/diagnóstico , Paraganglioma/genética , Paraganglioma/metabolismo , Feocromocitoma/diagnóstico , Feocromocitoma/genética , Feocromocitoma/metabolismo , Pronóstico , Ratas , Análisis de Matrices Tisulares/métodosRESUMEN
Acute myeloid leukemia (AML) initiating and sustaining cells maintain high cell-surface similarity with their cells-of-origin, i.e., hematopoietic stem and progenitor cells (HSPCs), and identification of truly distinguishing leukemia-private antigens has remained elusive to date. To nonetheless utilize surface antigen-directed immunotherapy in AML, we here propose targeting both, healthy and malignant human HSPC, by chimeric antigen receptor (CAR) T-cells with specificity against CD117, the cognate receptor for stem cell factor. This approach should spare most mature hematopoietic cells and would require CAR T termination followed by subsequent transplantation of healthy HSPCs to rescue hematopoiesis. We successfully generated anti-CD117 CAR T-cells from healthy donors and AML patients. Anti-CD117 CAR T-cells efficiently targeted healthy and leukemic CD117-positive cells in vitro. In mice xenografted with healthy human hematopoiesis, they eliminated CD117-expressing, but not CD117-negative human cells. Importantly, in mice xenografted with primary human CD117-positive AML, they eradicated disease in a therapeutic setting. Administration of ATG in combination with rituximab, which binds to the co-expressed CAR T-cell transduction/selection marker RQR8, led to CAR T-cell depletion. Thus, we here provide the first proof of concept for the generation and preclinical efficacy of CAR T-cells directed against CD117-expressing human hematopoietic cells.
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Inmunoterapia Adoptiva , Proteínas Proto-Oncogénicas c-kit/antagonistas & inhibidores , Receptores de Antígenos de Linfocitos T/inmunología , Receptores Quiméricos de Antígenos/inmunología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Animales , Biomarcadores , Biopsia , Médula Ósea/metabolismo , Médula Ósea/patología , Línea Celular Tumoral , Modelos Animales de Enfermedad , Expresión Génica , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/inmunología , Neoplasias Hematológicas/metabolismo , Neoplasias Hematológicas/terapia , Células Madre Hematopoyéticas/inmunología , Células Madre Hematopoyéticas/metabolismo , Humanos , Inmunofenotipificación , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/inmunología , Leucemia Mieloide Aguda/patología , Leucemia Mieloide Aguda/terapia , Depleción Linfocítica , Ratones , Proteínas Proto-Oncogénicas c-kit/genética , Proteínas Proto-Oncogénicas c-kit/metabolismo , Receptores de Antígenos de Linfocitos T/genética , Receptores Quiméricos de Antígenos/genética , Resultado del Tratamiento , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
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.
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Carcinoma Hepatocelular/genética , Neoplasias Hepáticas Experimentales/genética , Neoplasias Hepáticas/genética , Hígado/metabolismo , Animales , Carcinoma Hepatocelular/clasificación , Carcinoma Hepatocelular/patología , Hibridación Genómica Comparativa , Modelos Animales de Enfermedad , Hepatocitos/metabolismo , Hepatocitos/patología , Humanos , Hígado/patología , Neoplasias Hepáticas/clasificación , Neoplasias Hepáticas/patología , Neoplasias Hepáticas Experimentales/clasificación , Neoplasias Hepáticas Experimentales/patología , Quinasas Quinasa Quinasa PAM/genética , Ratones , Ratones TransgénicosRESUMEN
BACKGROUND: The transcription factor high-mobility AT-hook 2 (HMGA2) is involved in stem cell renewal and is expressed in many tumor tissues. Head and neck squamous cell carcinomas (HNSCC) comprise tumors of the upper aerodigestive tract and are characterized by high recurrence rates that represent a challenge to patient management. The study addresses the potential of HMGA2 as a molecular biomarker for HNSCC patient survival. METHODS: Patients with HNSCC of the larynx, pharynx, tonsils, or oral cavity were recruited in a hospital-based case-control study (n = 202). Quantitative expression of HMGA2 in tumor tissues was measured by RT-PCR. In a 6- to 10-year follow-up, secondary cancers, vital status, and cause of death were ascertained. The HR and 95% confidence intervals (CI) for overall, tumor-specific, and progression-free survival were estimated by Cox proportional hazards with HMGA2 expression level as the independent variable. RESULTS: High HMGA2 expression in tumor tissues of HNSCC patients was significantly correlated with negative HPV status (P = 0.01), and associated with shorter overall survival time. In Cox regression modeling, HMGA2 expression yielded a risk increase for overall and tumor-specific death in subsets of HNSCC patients, that is, laryngeal cancer patients (overall survival: HR = 4.00; 95% CI, 1.18-13.62) and in oral cancer patients (tumor-specific survival: HR = 2.88; 95% CI, 1.06-7.84), but not in patients with pharyngeal and tonsillar HNSCC. CONCLUSIONS: HMGA2 expression is associated with a risk increase for adverse outcomes in patients with HNSCC of the larynx and oral cavity. IMPACT: The understanding of stem cell signaling in HNSCC may offer new strategies for cancer treatment. Cancer Epidemiol Biomarkers Prev; 26(2); 197-205. ©2016 AACR.
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Carcinoma de Células Escamosas/genética , Predicción , Proteína HMGA2/genética , Neoplasias de Cabeza y Cuello/genética , ARN Neoplásico/genética , Factor de Células Madre/genética , Carcinoma de Células Escamosas/epidemiología , Carcinoma de Células Escamosas/metabolismo , ADN Viral/análisis , Femenino , Estudios de Seguimiento , Alemania/epidemiología , Proteína HMGA2/biosíntesis , Neoplasias de Cabeza y Cuello/epidemiología , Neoplasias de Cabeza y Cuello/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Morbilidad/tendencias , Papillomaviridae/genética , Reacción en Cadena de la Polimerasa , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Carcinoma de Células Escamosas de Cabeza y Cuello , Factor de Células Madre/biosíntesis , Tasa de Supervivencia/tendenciasRESUMEN
PURPOSE: Morphologic intratumor heterogeneity is well known to exist in hepatocellular carcinoma (HCC), but very few systematic analyses of this phenomenon have been performed. The aim of this study was to comprehensively characterize morphologic intratumor heterogeneity in HCC. Also, taken into account were well-known immunohistochemical markers and molecular changes in liver cells that are considered in proposed classifications of liver cell neoplasms or discussed as molecular therapeutic targets. EXPERIMENTAL DESIGN: In HCC of 23 patients without medical pretreatment, a total of 120 tumor areas were defined. Analyzed were cell and tissue morphology, expression of the liver cell markers cytokeratin (CK)7, CD44, α-fetoprotein (AFP), epithelial cell adhesion molecule (EpCAM), and glutamine synthetase (GS) along with mutations of TP53 and CTNNB1, assayed by both Sanger and next-generation sequencing. RESULTS: Overall, intratumor heterogeneity was detectable in the majority of HCC cases (20 of 23, 87%). Heterogeneity solely on the level of morphology was found in 6 of 23 cases (26%), morphologic heterogeneity combined with immunohistochemical heterogeneity in 9 of 23 cases (39%), and heterogeneity with respect to morphologic, immunohistochemical, and mutational status of TP53 and CTNNB1 in 5 of 23 cases (22%). CONCLUSIONS: Our findings demonstrate that intratumor heterogeneity represents a challenge for the establishment of a robust HCC classification and may contribute to treatment failure and drug resistance in many cases of HCC.
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Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/metabolismo , Femenino , Humanos , Inmunohistoquímica , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/metabolismo , Masculino , Persona de Mediana Edad , Mutación , Clasificación del Tumor , Estadificación de Neoplasias , Fenotipo , Factores de Riesgo , Carga Tumoral , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Adulto Joven , beta Catenina/genética , beta Catenina/metabolismoRESUMEN
Here we describe the clinicopathological course of a 20-year-old female patient with enterocolic lymphocytic phlebitis (ELP) of the appendix vermiformis and cecal pole with increase of IgG4-positive plasma cells. The patient presented with acute abdomen, suspicious of acute appendicitis. Diagnostic laparoscopy showed tumefaction of the cecal pole and appendix vermiformis. Histologic examination revealed mural thickening and a dense lymphoplasmocytic, partly obliterative infiltrate of the veins with sparing of the arteries, diagnostic of ELP. In addition, we found an elevated number of IgG4-positive plasma cells blended in with the lymphocytes. The IgG4-to-IgG ratio accounted for >40 %. This case meets the histopathological criteria requested for IgG4-related disease (IgG4-RD) and thus opens the possibility that ELP might be part of the IgG4-RD spectrum.
Asunto(s)
Apéndice/irrigación sanguínea , Ciego/irrigación sanguínea , Inmunoglobulina G/sangre , Flebitis/inmunología , Células Plasmáticas/inmunología , Adulto , Apéndice/patología , Ciego/patología , Femenino , Humanos , Flebitis/patologíaRESUMEN
Pancreatic neuroendocrine neoplasms (PNENs) constitute a rare tumour entity, and prognosis and treatment options depend on tumour-mediating hallmarks such as angiogenesis, proliferation rate and resistance to apoptosis. The molecular pathways that determine the malignant phenotype are still insufficiently understood and this has limited the use of effective combination therapies in the past. In this study, we aimed to characterise the effect of the oncogenic transcription factor Cut homeobox 1 (CUX1) on proliferation, resistance to apoptosis and angiogenesis in murine and human PNENs. The expression and function of CUX1 were analysed using knockdown and overexpression strategies in Ins-1 and Bon-1 cells, xenograft models and a genetically engineered mouse model of insulinoma (RIP1Tag2). Regulation of angiogenesis was assessed using RNA profiling and functional tube-formation assays in HMEC-1 cells. Finally, CUX1 expression was assessed in a tissue microarray of 59 human insulinomas and correlated with clinicopathological data. CUX1 expression was upregulated during tumour progression in a time- and stage-dependent manner in the RIP1Tag2 model, and associated with pro-invasive and metastatic features of human insulinomas. Endogenous and recombinant CUX1 expression increased tumour cell proliferation, tumour growth, resistance to apoptosis, and angiogenesis in vitro and in vivo. Mechanistically, the pro-angiogenic effect of CUX1 was mediated via upregulation of effectors such as HIF1α and MMP9. CUX1 mediates an invasive pro-angiogenic phenotype and is associated with malignant behaviour in human insulinomas.