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Low absolute lymphocyte counts (ALC) and high absolute monocyte counts (AMC) are associated with poor survival in patients with diffuse large B-cell lymphoma (DLBCL). We studied the prognostic impact of the ALC and AMC in patients with testicular DLBCL (T-DLBCL). T-DLBCL patients were searched using Southern Finland University Hospital databases and the Danish lymphoma registry. The progression free survival (PFS) and overall survival (OS) were assessed using Kaplan-Meier and Cox proportional hazards methods. We identified 178 T-DLBCL patients, of whom 78 (44%) had a low ALC at diagnosis. The ALC did not correlate with survival in the whole cohort. However, among the patients treated with rituximab (R) containing regimen, a pre-therapeutic low ALC was associated with an increased risk of progression (HR 1.976, 95% CI 1.267-3.086, p = 0.003). Conversely, intravenous (iv) CNS directed chemotherapy translated to favorable outcome. In multivariate analyses, the advantage of an iv CNS directed chemotherapy was sustained (PFS, HR 0.364, 95% CI 0.175-0.757, p = 0.007). The benefit of R and intravenous CNS directed chemotherapy was observed only in non-lymphopenic patients. The AMC did not correlate with survival. A low ALC is an adverse prognostic factor in patients with T-DLBCL. Alternative treatment options for lymphopenic patients are needed.
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Survival of patients with high-risk diffuse large B-cell lymphoma (DLBCL) is suboptimal, and the risk of central nervous system (CNS) progression is relatively high. We conducted a phase 2 trial in 139 patients aged 18 to 64 years who had primary DLBCL with an age-adjusted International Prognostic Index (aaIPI) score of 2 to 3 or site-specific risk factors for CNS recurrence. The goal was to assess whether a dose-dense immunochemotherapy with early systemic CNS prophylaxis improves the outcome and reduces the incidence of CNS events. Treatment consisted of 2 courses of high-dose methotrexate in combination with biweekly rituximab (R), cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP-14), followed by 4 courses of R-CHOP-14 with etoposide (R-CHOEP) and 1 course of high-dose cytarabine with R. In addition, liposomal cytarabine was administered intrathecally at courses 1, 3, and 5. Coprimary endpoints were failure-free survival and CNS progression rates. Thirty-six (26%) patients experienced treatment failure. Progression occurred in 23 (16%) patients, including three (2.2%) CNS events. At 5 years of median follow-up, failure-free survival, overall survival, and CNS progression rates were 74%, 83%, and 2.3%, respectively. Treatment reduced the risk of progression compared with our previous trial, in which systemic CNS prophylaxis was given after 6 courses of biweekly R-CHOEP (hazard ratio, 0.49; 95% CI, 0.31-0.77; P = .002) and overcame the adverse impact of an aaIPI score of 3 on survival. In addition, outcome of the patients with BCL2/MYC double-hit lymphomas was comparable to the patients without the rearrangements. The results are encouraging, with a low toxic death rate, low number of CNS events, and favorable survival rates. This trial was registered at www.clinicaltrials.gov as #NCT01325194.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Linfoma Difuso de Grandes Células B , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Rituximab/uso terapêutico , Vincristina/uso terapêutico , Adulto JovemRESUMO
Peripheral T-cell lymphomas (PTCL) are a heterogeneous, and often aggressive group of non-Hodgkin lymphomas. Recent advances in the molecular and genetic characterization of PTCLs have helped to delineate differences and similarities between the various subtypes, and the JAK/STAT pathway has been found to play an important oncogenic role. Here, we aimed to characterize the JAK/STAT pathway in PTCL subtypes and investigate whether the activation of the pathway correlates with the frequency of STAT gene mutations. Patient samples from AITL (n = 30), ALCL (n = 21) and PTCL-NOS (n = 12) cases were sequenced for STAT3, STAT5B, JAK1, JAK3, and RHOA mutations using amplicon sequencing and stained immunohistochemically for pSTAT3, pMAPK, and pAKT. We discovered STAT3 mutations in 13% of AITL, 13% of ALK+ ALCL, 38% of ALK- ALCL and 17% of PTCL-NOS cases. However, no STAT5B mutations were found and JAK mutations were only present in ALK- ALCL (15%). Concurrent mutations were found in all subgroups except ALK+ ALCL where STAT3 mutations were always seen alone. High pY-STAT3 expression was observed especially in AITL and ALCL samples. When studying JAK-STAT pathway mutations, pY-STAT3 expression was highest in PTCLs harboring either JAK1 or STAT3 mutations and CD30+ phenotype representing primarily ALK- ALCLs. Further investigation is needed to elucidate the molecular mechanisms of JAK-STAT pathway activation in PTCL.
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Introduction: To minimize the radiation exposure of mostly young testicular cancer patients, it is essential to find out whether CT could be replaced by magnetic resonance imaging (MRI) in the staging and follow-up of the patients. In this trial, we examined whether abdominal MRI is as effective as computed tomography (CT) in the detection of retroperitoneal metastases of testicular cancer.Material and methods: This prospective study included 50 patients, 46 cases of retroperitoneal metastases and 4 controls without abdominal metastases (mean age 33, 5 years, range 20-65 years). Imaging of the retroperitoneum was performed using CT and 1.5 T MRI with diffusion weighted imaging (DWI). One experienced radiologist re-analyzed all of the examinations without knowledge of clinical information. All metastatic or suspicious lymph nodes were noted and measured two-dimensionally from axial images. Nodal detection and the size of detected nodes on CT and MRI were compared.Results: There was no significant difference in the detection of retroperitoneal metastasis between CT and MRI. The sensitivity of MRI was 0.98. There was no statistically significant difference in the sizes of lymph nodes found in CT and MRI, and even very small lymph nodes could be detected in MRI as well as in CT.Conclusion: MRI with DWI is as good as CT in detection of retroperitoneal lymph node metastases regardless of lymph node size, and it can be used as part of follow-up of testicular cancer patients instead of ionizing radiation producing imaging methods.
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Imagem de Difusão por Ressonância Magnética , Neoplasias Embrionárias de Células Germinativas/diagnóstico por imagem , Neoplasias Retroperitoneais/diagnóstico por imagem , Neoplasias Testiculares/patologia , Tomografia Computadorizada Espiral , Adulto , Idoso , Estudos de Casos e Controles , Meios de Contraste/administração & dosagem , Reações Falso-Negativas , Reações Falso-Positivas , Humanos , Metástase Linfática/diagnóstico por imagem , Metástase Linfática/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias Embrionárias de Células Germinativas/secundário , Estudos Prospectivos , Exposição à Radiação/prevenção & controle , Neoplasias Retroperitoneais/secundário , Espaço Retroperitoneal/diagnóstico por imagem , Sensibilidade e Especificidade , Adulto JovemRESUMO
PURPOSE: Sinonasal tract diffuse large B-cell lymphoma (SNT-DLBCL), a rare extranodal lymphoma, is not well characterized. We performed a population-based study to determine cell-of-origin, clinical presentation and impact of rituximab (R) and central nervous system (CNS) directed chemotherapy on survival. PATIENTS AND METHODS: Patients with SNT-DLBCL were identified from pathology databases. Clinical information was collected and outcomes between different treatment modalities evaluated. RESULTS: Thirty-two percent of the patients had germinal centre B-cell phenotype. Forty-six patients were treated with curative intent using CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or CHOP-like chemotherapy, 21 (46%) before and 25 (54%) in the R-era. Additionally, 24 (52%) received CNS-directed chemotherapy. Addition of R to chemotherapy reduced the risk of progression (RR = 0.368, 95% CI 0.138-0.976, P = 0.045) and death (RR = 0.245, 95% CI 0.068-0.883, P = 0.032), and translated into better survival (5-year PFS, 67% vs 38%, P = 0.037; 5-year OS, 81% vs 48%, P = 0.020). CNS-directed chemotherapy reduced the risk of progression (RR = 0.404, 95% CI 0.159-1.029, P = 0.057) and death (RR = 0.298, 95% CI 0.093-0.950, P = 0.041), and translated into favorable survival (5-year PFS, 67% vs 32%, P = 0.050; 5-year OS 82% vs 43%, P = 0.030). CONCLUSION: Patients with SNT-DLBCL benefit from rituximab and CNS-directed chemotherapy.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Neoplasias Nasais/diagnóstico , Neoplasias Nasais/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores , Ciclofosfamida/efeitos adversos , Ciclofosfamida/uso terapêutico , Progressão da Doença , Doxorrubicina/efeitos adversos , Doxorrubicina/uso terapêutico , Feminino , Humanos , Imuno-Histoquímica , Imunofenotipagem , Estimativa de Kaplan-Meier , Linfoma Difuso de Grandes Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Nasais/mortalidade , Prednisona/efeitos adversos , Prednisona/uso terapêutico , Prognóstico , Modelos de Riscos Proporcionais , Avaliação de Sintomas , Resultado do Tratamento , Vincristina/efeitos adversos , Vincristina/uso terapêuticoRESUMO
Primary testicular lymphoma is a rare lymphoid malignancy, most often, histologically, representing diffuse large B-cell lymphoma. The tumor microenvironment and limited immune surveillance have a major impact on diffuse large B-cell lymphoma pathogenesis and survival, but the impact on primary testicular lymphoma is unknown. Here, the purpose of the study was to characterize the tumor microenvironment in primary testicular lymphoma, and associate the findings with outcome. We profiled the expression of 730 immune response genes in 60 primary testicular lymphomas utilizing the Nanostring platform, and used multiplex immunohistochemistry to characterize the immune cell phenotypes in the tumor tissue. We identified a gene signature enriched for T-lymphocyte markers differentially expressed between the patients. Low expression of the signature predicted poor outcome independently of the International Prognostic Index (progression-free survival: HR=2.810, 95%CI: 1.228-6.431, P=0.014; overall survival: HR=3.267, 95%CI: 1.406-7.590, P=0.006). The T-lymphocyte signature was associated with outcome also in an independent diffuse large B-cell lymphoma cohort (n=96). Multiplex immunohistochemistry revealed that poor survival of primary testicular lymphoma patients correlated with low percentage of CD3+CD4+ and CD3+CD8+ tumor-infiltrating lymphocytes (P<0.001). Importantly, patients with a high T-cell inflamed tumor microenvironment had a better response to rituximab-based immunochemotherapy, as compared to other patients. Furthermore, loss of membrane-associated human-leukocyte antigen complexes was frequent and correlated with low T-cell infiltration. Our results demonstrate that a T-cell inflamed tumor microenvironment associates with favorable survival in primary testicular lymphoma. This further highlights the importance of immune escape as a mechanism of treatment failure.
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Linfócitos do Interstício Tumoral/metabolismo , Linfócitos T/metabolismo , Neoplasias Testiculares/etiologia , Neoplasias Testiculares/patologia , Microambiente Tumoral , Adulto , Idoso , Biomarcadores , Biomarcadores Tumorais , Biologia Computacional/métodos , Feminino , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Contagem de Linfócitos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Linfócitos T/imunologia , Linfócitos T/patologia , Neoplasias Testiculares/mortalidade , Transcriptoma , Microambiente Tumoral/genética , Microambiente Tumoral/imunologiaRESUMO
Primary testicular lymphoma is a rare and aggressive lymphoid malignancy, most often representing diffuse large B-cell lymphoma histologically. Tumor-associated macrophages and tumor-infiltrating lymphocytes have been associated with survival in diffuse large B-cell lymphoma, but their prognostic impact in primary testicular lymphoma is unknown. Here, we aimed to identify macrophages, their immunophenotypes and association with lymphocytes, and translate the findings into survival of patients with primary testicular lymphoma. We collected clinical data and tumor tissue from 74 primary testicular lymphoma patients, and used multiplex immunohistochemistry and digital image analysis to examine macrophage markers (CD68, CD163, and c-Maf), T-cell markers (CD3, CD4, and CD8), B-cell marker (CD20), and three checkpoint molecules (PD-L1, PD-L2, and PD-1). We demonstrate that a large proportion of macrophages (median 41%, range 0.08-99%) and lymphoma cells (median 34%, range 0.1-100%) express PD-L1. The quantity of PD-L1+ CD68+ macrophages correlates positively with the amount of PD-1+ lymphocytes, and a high proportion of either PD-L1+ CD68+ macrophages or PD-1+ CD4+ and PD-1+ CD8+ T cells translates into favorable survival. In contrast, the number of PD-L1+lymphoma cells or PD-L1- macrophages do not associate with outcome. In multivariate analyses with IPI, PD-L1+ CD68+ macrophage and PD-1+ lymphocyte contents remain as independent prognostic factors for survival. In conclusion, high PD-L1+ CD68+ macrophage and PD-1+ lymphocyte contents predict favorable survival in patients with primary testicular lymphoma. The findings implicate that the tumor microenvironment and PD-1 - PD-L1 pathway have a significant role in regulating treatment outcome. They also bring new insights to the targeted thera py of primary testicular lymphoma.
Assuntos
Antígenos de Diferenciação/imunologia , Antígeno B7-H1/imunologia , Linfócitos do Interstício Tumoral , Linfoma Difuso de Grandes Células B , Proteínas de Neoplasias/imunologia , Receptor de Morte Celular Programada 1/imunologia , Neoplasias Testiculares , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Humanos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/patologia , Linfoma Difuso de Grandes Células B/imunologia , Linfoma Difuso de Grandes Células B/mortalidade , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias Testiculares/imunologia , Neoplasias Testiculares/mortalidade , Neoplasias Testiculares/patologiaRESUMO
OBJECTIVES: Extramedullary plasmacytoma in the sinonasal tract or nasopharynx is rare. The aim of the study was to review data on symptoms, clinical findings, treatment and follow-up of plasmacytomas in the sinonasal and nasopharyngeal regions in order to delineate the main clinical characteristics and the optimal management. METHOD: Twenty-five patients with sinonasal or nasopharyngeal plasmacytoma, diagnosed and treated at the Helsinki University Hospital during a 39-year period from 1975 to 2013 were retrospectively reviewed. RESULTS: There were 18 males and 7 females with a median age of 66 years (range, 36-80). Sixty-eight percent received only radiotherapy or (chemo)radiotherapy. Forty-seven percent of them had a complete response to primary radiotherapy and one patient had a complete response after receiving additional brachytherapy. Four patients were treated primarily with surgery only. Two of them had a local recurrence, but were then successfully treated with radiotherapy. Altogether, four patients received a combination of surgery and (chemo)radiotherapy. Forty-four percent were alive with no evidence of disease after a median follow-up time of 78 months. Forty percent died of their disease and 16% died of other causes. CONCLUSIONS: Our study supports radiotherapy as a treatment of choice, but for small tumours surgery alone or in combination with radiotherapy may also be considered.
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Neoplasias Nasofaríngeas/terapia , Neoplasias dos Seios Paranasais/terapia , Plasmocitoma/terapia , Idoso , Idoso de 80 Anos ou mais , Feminino , Finlândia/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Nasofaríngeas/diagnóstico , Neoplasias Nasofaríngeas/mortalidade , Neoplasias dos Seios Paranasais/diagnóstico , Neoplasias dos Seios Paranasais/mortalidade , Plasmocitoma/diagnóstico , Plasmocitoma/mortalidade , Estudos RetrospectivosRESUMO
Enteropathy-associated T cell lymphoma (EATL) is a lethal, and the most common, neoplastic complication of celiac disease. Here, we defined the genetic landscape of EATL through whole-exome sequencing of 69 EATL tumors. SETD2 was the most frequently silenced gene in EATL (32% of cases). The JAK-STAT pathway was the most frequently mutated pathway, with frequent mutations in STAT5B as well as JAK1, JAK3, STAT3, and SOCS1 We also identified mutations in KRAS, TP53, and TERT Type I EATL and type II EATL (monomorphic epitheliotropic intestinal T cell lymphoma) had highly overlapping genetic alterations indicating shared mechanisms underlying their pathogenesis. We modeled the effects of SETD2 loss in vivo by developing a T cell-specific knockout mouse. These mice manifested an expansion of γδ T cells, indicating novel roles for SETD2 in T cell development and lymphomagenesis. Our data render the most comprehensive genetic portrait yet of this uncommon but lethal disease and may inform future classification schemes.
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Linfoma de Células T Associado a Enteropatia/fisiopatologia , Histona-Lisina N-Metiltransferase/fisiologia , Animais , Variações do Número de Cópias de DNA/genética , Linfoma de Células T Associado a Enteropatia/classificação , Linfoma de Células T Associado a Enteropatia/genética , Feminino , Perfilação da Expressão Gênica , Inativação Gênica , Humanos , Masculino , Camundongos Knockout , Pessoa de Meia-Idade , Mutação/genética , Análise de Sequência de DNA , Linfócitos T/fisiologiaRESUMO
Redox state-regulating enzymes may have roles in chemoresistance and also in lymphomagenesis, but there have been only a limited number of studies on this topic in lymphomas. Our aim was to assess expression of the redox state-regulating enzymes peroxiredoxins (Prxs) I-VI and thioredoxin (Trx) and the oxidative stress marker nitrotyrosine in follicular lymphomas (FLs). We immunohistochemically assessed Prxs I-VI, Trx and nitrotyrosine in a cohort of 76 histologically confirmed, untreated FLs. We also studied the localisation of Prxs I, II, III, V and VI by means of immunoelectron microscopy (IEM). Immunohistochemistry results were correlated with disease-specific survival (DSS), progression-free survival (PFS), overall survival (OS) and clinical prognostic factors. When all Prx expression intensities were grouped as a single variable, we discovered that high total Prx intensity correlated with favourable DSS (p = 0.024) and OS (p = 0.035) but not with PFS. No deaths due to lymphoma were recorded amongst patients with high total Prx expression during the median follow-up period of 7.6 years. IEM results were in line with earlier ones demonstrating wide subcellular localisation of Prx isoenzymes. In conclusion, our results demonstrate an association between high total Prx expression and prolonged survival and suggest that Prxs may have a protective role in FL that cannot be compensated by other antioxidant mechanisms.
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Antioxidantes/metabolismo , Linfoma Folicular/metabolismo , Linfoma Folicular/mortalidade , Peroxirredoxinas/metabolismo , Adulto , Idoso , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica/métodos , Linfoma Folicular/patologia , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo/fisiologia , Tiorredoxinas/metabolismoRESUMO
Sinonasally located lymphoid malignancies are rare lesions with first symptoms similar to other obstructive conditions. Additionally, they often coexist with nasal inflammation and mucosal necrosis. Therefore, time from the first symptoms to diagnosis tends to be long. Awareness and early diagnosis of this disease entity could improve treatment outcome. Altogether, 142 patients with sinonasal or nasopharyngeal (i.e. sinonasal tract, SNT) lymphoid malignancies, diagnosed and treated at the Helsinki University Hospital, during a 39-year period from 1975 to 2013, were retrospectively reviewed. There were 90 males (63 %) and 52 females (37 %) with a median age of 64 years (range 26-92). Eighty-four percent of the patients had primary diseases and 16 % had relapses of lymphoid malignancies primarily diagnosed at other locations. The mean duration of symptoms prior to diagnosis was 4.8 months (range 0.5-24). The most common histological entity was diffuse large B-cell lymphoma (43 %), followed by plasmacytoma (18 %). The most common location was nasopharynx (58 %) followed by nasal cavity (44 %) and paranasal sinuses (35 %). Sixty-nine percent of the lesions were at a single anatomic location of the sinonasal tract. Fifty-two percent of the cases were of Ann Arbor Stage I. Lymphoid malignancies form an important and diverse group in the differential diagnosis of SNT tumours. They most often present with general obstructive nasal symptoms due to tumour location. Most of them are primary lesions, highlighting the importance of an accurate diagnosis as early as possible.
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Transtornos Linfoproliferativos/epidemiologia , Neoplasias Nasais/epidemiologia , Neoplasias dos Seios Paranasais/epidemiologia , Neoplasias Faríngeas/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Finlândia/epidemiologia , Humanos , Incidência , Transtornos Linfoproliferativos/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias Nasais/patologia , Neoplasias dos Seios Paranasais/patologia , Neoplasias Faríngeas/patologia , Estudos RetrospectivosRESUMO
BACKGROUND: Primary central nervous system lymphoma (PCNSL) is a rare brain tumour with a dismal prognosis. Several phase II studies with high-dose methotrexate-based regimens have shown promising early results, but in all hospital-based data published so far, the disease outcome is poor. MATERIAL AND METHODS: We performed a hospital-based retrospective analysis to evaluate the long-term results of the Nordic type of Bonn chemotherapy regimen in PCNSL patients. The study included 54 patients with newly diagnosed PCNSL who received chemotherapy with curative intent as their first-line treatment. RESULTS: We found promising response rates, 76% of the patients achieving CR and 22% patients achieving PR, with corresponding two-year EFS 53% and OS 76%. However, with longer follow-up a constant pattern of relapses was observed with only one patient remaining in primary remission after 60 months. DISCUSSION: The finding suggests that basic biological differences exist between PCNSL and systemic diffuse large B-cell lymphoma and there is a need for consolidation or maintenance therapy after achieving a remission in patients with PCNSL.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Linfoma/tratamento farmacológico , Metotrexato/administração & dosagem , Idoso , Citarabina/administração & dosagem , Intervalo Livre de Doença , Feminino , Finlândia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Estudos Retrospectivos , Rituximab/administração & dosagem , Taxa de Sobrevida , Resultado do TratamentoRESUMO
OBJECTIVE: Testicular germ cell cancer is the most common malignancy among young males. The pre-invasive precursor, carcinoma in situ testis (CIS), presumably originates from arrested and transformed fetal gonocytes. Given that GATA transcription factors have essential roles in embryonic and testicular development, we explored the expression of GATA-4, GATA-6, cofactor friend of GATA (FOG)-2, and downstream target genes during human testis development and addressed the question whether changes in this pathway may contribute to germ cell neoplasms. METHODS: Fetal testis, testicular CIS, and overt tumor samples were analyzed by immunohistochemistry for GATA-4, GATA-6, FOG-2, steroidogenic factor 1 (NR5A1/SF1), anti-Müllerian hormone/Müllerian-inhibiting substance (AMH), and inhibin-alpha (INHalpha). RESULTS: GATA-4 was not expressed in normal germ cells, except for a subset of gonocytes at the 15th gestational week. The CIS cells expressed GATA-4 and GATA-6 heterogeneously, whereas most of the CIS cells expressed GATA-4 cofactor FOG-2. GATA target gene SF-1 was expressed heterogeneously in CIS cells, whereas INHalpha and AMH were mostly negative. Seminomas and yolk sac tumors were positive for GATA-4 and GATA-6, but mostly negative for FOG-2 and the GATA target genes. In contrast, pluripotent embryonal carcinomas and choriocarcinomas were GATA-4 and GATA-6 negative. CONCLUSIONS: Differential expression of the GATA-4 target genes suggested cell-specific functions of GATA-4 in the germ and somatic cells. The GATA-4 expression in early fetal gonocytes, CIS, and seminoma cells but the absence in more mature germ cells is consistent with the early fetal origin of CIS cells and suggests that GATA-4 is involved in early germ cell differentiation.
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Carcinoma in Situ/metabolismo , Proteínas de Ligação a DNA/metabolismo , Fator de Transcrição GATA4/metabolismo , Fator de Transcrição GATA6/metabolismo , Neoplasias Embrionárias de Células Germinativas/metabolismo , Neoplasias Testiculares/metabolismo , Fatores de Transcrição/metabolismo , Hormônio Antimülleriano/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Inibinas/metabolismo , Masculino , Fatores de Processamento de RNA , Testículo/metabolismoRESUMO
Congenital diaphragmatic hernia (CDH) is an often fatal birth defect that is commonly associated with pulmonary hypoplasia and cardiac malformations. Some investigators hypothesize that this constellation of defects results from genetic or environmental triggers that disrupt mesenchymal cell function in not only the primordial diaphragm but also the thoracic organs. The alternative hypothesis is that the displacement of the abdominal viscera in the chest secondarily perturbs the development of the heart and lungs. Recently, loss-of-function mutations in the gene encoding FOG-2, a transcriptional co-regulator, have been linked to CDH and pulmonary hypoplasia in humans and mice. Here we show that mutagenesis of the gene for GATA-4, a transcription factor known to functionally interact with FOG-2, predisposes inbred mice to a similar set of birth defects. Analysis of wild-type mouse embryos demonstrated co-expression of Gata4 and Fog2 in mesenchymal cells of the developing diaphragm, lungs, and heart. A significant fraction of C57Bl/6 mice heterozygous for a Gata4 deletion mutation died within 1 day of birth. Developmental defects in the heterozygotes included midline diaphragmatic hernias, dilated distal airways, and cardiac malformations. Heterozygotes had any combination of these defects or none. In chimeric mice, Gata4(-/-) cells retained the capacity to contribute to cells in the diaphragmatic central tendon and lung mesenchyme, indicating that GATA-4 is not required for differentiation of these lineages. We conclude that GATA-4, like its co-regulator FOG-2, is required for proper mesenchymal cell function in the developing diaphragm, lungs, and heart.
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Fator de Transcrição GATA4/metabolismo , Hérnia Diafragmática/metabolismo , Hérnia Diafragmática/patologia , Pulmão/anormalidades , Pulmão/metabolismo , Células-Tronco Mesenquimais/metabolismo , Animais , Animais Recém-Nascidos , Diferenciação Celular , Fator de Transcrição GATA4/deficiência , Fator de Transcrição GATA4/genética , Deleção de Genes , Regulação da Expressão Gênica no Desenvolvimento , Hérnia Diafragmática/genética , Hérnias Diafragmáticas Congênitas , Heterozigoto , Pulmão/irrigação sanguínea , Pulmão/patologia , Células-Tronco Mesenquimais/citologia , Camundongos , Camundongos Endogâmicos C57BL , Mutação/genética , Fatores de Tempo , Transcrição Gênica/genéticaRESUMO
BACKGROUND: Of the thirteen active carbonic anhydrase (CA) isozymes, CA IX and XII have been linked to carcinogenesis. It has been suggested that these membrane-bound CAs participate in cancer cell invasion, which is facilitated by an acidic tumor cell environment. Since active cell migration is a characteristic feature of embryonic development, we set out to explore whether these isozymes are expressed in mouse embryos of different ages. The studies were focused on organogenesis stage. RESULTS: Immunohistochemistry demonstrated that both CA IX and XII are present in several tissues of the developing mouse embryo during organogenesis. Staining for CA IX revealed a relatively wide distribution pattern with moderate signals in the brain, lung, pancreas and liver and weak signals in the kidney and stomach. The expression pattern of CA XII in the embryonic tissues was also relatively broad, although the intensity of immunostaining was weak in most tissues. The CA XII-positive tissues included the brain, where the most prominent staining was seen in the choroid plexus, and the stomach, pancreas, liver and kidney. CONCLUSION: Membrane-bound CA isozymes IX and XII are expressed in various tissues during mouse organogenesis. These enzymes may regulate ion and pH homeostasis within the developing embryo.
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Anidrases Carbônicas/metabolismo , Desenvolvimento Embrionário , Animais , Anidrase Carbônica IX , Feminino , Expressão Gênica , Concentração de Íons de Hidrogênio , Masculino , Camundongos , Distribuição TecidualRESUMO
Ovarian germ cell tumors (GCTs) are histologically heterogeneous neoplasms originating from activated germ cells, the oocyte stem cells. These rare tumors often contain many different tissues mixed together, and malignant components are occasionally hidden within benign tissues thus complicating the diagnosis. The reasons for the variable differentiation of germ cells are still largely unknown. As transcription factors GATA-4 and GATA-6 as well as their downstream factors (e.g. HNF-4, BMP-2 and Ihh) are essential for normal yolk sac development, we studied their expression in 19 ovarian GCTs. Endodermal markers were expressed distinctively in different GCT types. The malignant endoderm in yolk sac tumors expressed all factors of endodermal development included in the study. Dysgerminomas, on the contrary, expressed only GATA-4 and, in a minority of cases, Ihh and BMP-2. The results suggest that GATA-4 and GATA-6 detected in the ovarian GCTs have retained their normal function. The fact that GATA-6 and HNF-4 are expressed exclusively in endodermal tissues indicates that these transcription factors play a role in the differentiation of germ cells towards the endodermal phenotype. Analysis of the nuclear transcription factors in tumor tissue could serve as a new informative diagnostic tool for ovarian GCTs.
Assuntos
Proteínas de Ligação a DNA/biossíntese , Neoplasias Embrionárias de Células Germinativas/genética , Neoplasias Embrionárias de Células Germinativas/fisiopatologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/fisiopatologia , Fatores de Transcrição/biossíntese , Adolescente , Adulto , Transformação Celular Neoplásica , Criança , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/fisiologia , Feminino , Fator de Transcrição GATA4 , Fator de Transcrição GATA6 , Perfilação da Expressão Gênica , Fator 4 Nuclear de Hepatócito , Humanos , Pessoa de Meia-Idade , Fenótipo , Fosfoproteínas/biossíntese , Fatores de Transcrição/genética , Fatores de Transcrição/fisiologiaRESUMO
In order to investigate the biologic activity of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on human erythropoiesis, glycophorin A (GPA)+ erythroid cells were generated in serum-free liquid phase from human cord blood (CB) CD34+ progenitor cells. The surface expression of TRAIL-R1 was weakly detectable in the early-intermediate phase of erythroid differentiation (days 4-6; dim-intermediate GPA expression), whereas a clear-cut expression of TRAIL-R2 was observed through the entire course of erythroid differentiation (up to days 12-14; bright GPA expression). On the other hand, surface TRAIL-R3 and -R4 were not detected at any culture time. Besides inducing a rapid but small increase of apoptotic cell death, which was abrogated by the pan-caspase inhibitor z-VAD-fmk, the addition of recombinant TRAIL at day 6 of culture inhibited the generation of morphologically mature erythroblasts. Among the intracellular pathways investigated, TRAIL significantly stimulated the extracellular signal-regulated kinase 1/2 (ERK1/2) but not the p38/mitogen-activated protein kinase (MAPK) or the c-Jun NH2-terminal kinase (JNK) pathway. Consistently with a key role of ERK1/2 in mediating the negative effects of TRAIL on erythroid maturation, PD98059, a pharmacologic inhibitor of the ERK pathway, but not z-VAD-fmk or SB203580, a pharmacologic inhibitor of p38/MAPK, reverted the antidifferentiative effect of TRAIL on CB-derived erythroblasts.