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1.
Int J Mol Sci ; 22(19)2021 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-34638718

RESUMO

Despite the considerable advances in diagnostic methods in medicine, central nervous system (CNS) tumors, particularly the most common ones-gliomas-remain incurable, with similar incidence rates and mortality. A growing body of literature has revealed that degradation of the extracellular matrix by matrix metalloproteinases (MMPs) might be involved in the pathogenesis of CNS tumors. However, the subfamily of MMPs, known as disintegrin and metalloproteinase (ADAM) proteins are unique due to both adhesive and proteolytic activities. The objective of our review is to present the role of ADAMs in CNS tumors, particularly their involvement in the development of malignant gliomas. Moreover, we focus on the diagnostic and prognostic significance of selected ADAMs in patients with these neoplasms. It has been proven that ADAM12, ADAMTS4 and 5 are implicated in the proliferation and invasion of glioma cells. In addition, ADAM8 and ADAM19 are correlated with the invasive activity of glioma cells and unfavorable survival, while ADAM9, -10 and -17 are associated with tumor grade and histological type of gliomas and can be used as prognostic factors. In conclusion, several ADAMs might serve as potential diagnostic and prognostic biomarkers as well as therapeutic targets for malignant CNS tumors. However, future research on ADAMs biology should be performed to elucidate new strategies for tumor diagnosis and treatment of patients with these malignancies.


Assuntos
Proteínas ADAM/metabolismo , Biomarcadores Tumorais/metabolismo , Proliferação de Células , Neoplasias do Sistema Nervoso Central , Glioma , Proteínas de Neoplasias/metabolismo , Animais , Neoplasias do Sistema Nervoso Central/diagnóstico , Neoplasias do Sistema Nervoso Central/enzimologia , Neoplasias do Sistema Nervoso Central/patologia , Neoplasias do Sistema Nervoso Central/terapia , Glioma/diagnóstico , Glioma/enzimologia , Glioma/patologia , Glioma/terapia , Humanos , Gradação de Tumores , Invasividade Neoplásica
2.
Cell Mol Life Sci ; 78(17-18): 6161-6200, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34333711

RESUMO

Despite advances in the understanding of the molecular mechanisms underlying the basic biology and pathogenesis of pediatric central nervous system (CNS) malignancies, patients still have an extremely unfavorable prognosis. Over the years, a plethora of natural and synthetic compounds has emerged for the pharmacologic intervention of the NF-kB pathway, one of the most frequently dysregulated signaling cascades in human cancer with key roles in cell growth, survival, and therapy resistance. Here, we provide a review about the state-of-the-art concerning the dysregulation of this hub transcription factor in the most prevalent pediatric CNS tumors: glioma, medulloblastoma, and ependymoma. Moreover, we compile the available literature on the anti-proliferative effects of varied NF-kB inhibitors acting alone or in combination with other therapies in vitro, in vivo, and clinical trials. As the wealth of basic research data continues to accumulate, recognizing NF-kB as a therapeutic target may provide important insights to treat these diseases, hopefully contributing to increase cure rates and lower side effects related to therapy.


Assuntos
Neoplasias do Sistema Nervoso Central/patologia , NF-kappa B/metabolismo , 2-Metoxiestradiol/química , 2-Metoxiestradiol/metabolismo , 2-Metoxiestradiol/uso terapêutico , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/uso terapêutico , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/metabolismo , Criança , Glioma/metabolismo , Glioma/patologia , Proteínas Hedgehog/antagonistas & inibidores , Proteínas Hedgehog/metabolismo , Humanos , Meduloblastoma/metabolismo , Meduloblastoma/patologia , NF-kappa B/antagonistas & inibidores , Proteínas Wnt/antagonistas & inibidores , Proteínas Wnt/metabolismo
3.
Exp Cell Res ; 406(2): 112760, 2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34339674

RESUMO

The activity of the most complex system, the central nervous system (CNS) is profoundly regulated by a huge number of membrane-associated proteins (MAP). A minor change stimulates immense chemical changes and the elicited response is organized by MAP, which acts as a receptor of that chemical or channel enabling the flow of ions. Slight changes in the activity or expression of these MAPs lead to severe consequences such as cognitive disorders, memory loss, or cancer. CNS tumors are heterogeneous in nature and hard-to-treat due to random mutations in MAPs; like as overexpression of EGFRvIII/TGFßR/VEGFR, change in adhesion molecules α5ß3 integrin/SEMA3A, imbalance in ion channel proteins, etc. Extensive research is under process for developing new therapeutic approaches using these proteins such as targeted cytotoxic radiotherapy, drug-delivery, and prodrug activation, blocking of receptors like GluA1, developing viral vector against cell surface receptor. The combinatorial approach of these strategies along with the conventional one might be more potential. Henceforth, our review focuses on in-depth analysis regarding MAPs aiming for a better understanding for developing an efficient therapeutic approach for targeting CNS tumors.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Proteínas de Membrana/antagonistas & inibidores , Terapia de Alvo Molecular , Animais , Neoplasias do Sistema Nervoso Central/metabolismo , Neoplasias do Sistema Nervoso Central/patologia , Humanos
4.
Acta Cytol ; 65(6): 529-540, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34311461

RESUMO

INTRODUCTION: Extraneural/-cranial metastases (ENM) of primary central nervous system (CNS) tumors are rare and may be diagnostically challenging. We describe the cytomorphological and pertinent clinical features of ENM in a case series assessed by fine-needle aspiration (FNA). A search of the laboratory information systems of 2 tertiary care centers in Toronto (2000-2015) was performed. Cases with direct extracranial/-spinal extension of CNS neoplasms were excluded. Microscopic slides of FNA and surgical specimens were reviewed. Demographic and clinicopathological data were retrieved. CASE PRESENTATION: Six cases were identified with the original diagnoses of glioblastoma, glioblastoma with primitive neuroectodermal tumor-like components, anaplastic ependymoma, myxopapillary ependymoma, atypical meningioma, and hemangiopericytoma. Median patient age at first diagnosis was 44 years (range 22-56). The time interval between initial diagnosis and first metastatic disease manifestation was 3 months to 19 years. All FNA diagnoses were rendered correctly. In 4 cases, immunohistochemistry was used to support the diagnosis. All cases had prior surgical intervention at the primary tumor site. In 4 cases, the ENM location was the ipsilateral parotid or buccal area. Two primary tumors in midline location developed ENM in the scapular area. DISCUSSION/CONCLUSION: ENM are a rare manifestation of a range of different primary CNS tumors and may involve the ipsilateral head and neck mimicking clinically a salivary gland neoplasm. FNA can rapidly discriminate ENM from other, potentially more indolent conditions. Awareness of the clinical history is paramount to avoid diagnostic confusion.


Assuntos
Neoplasias do Sistema Nervoso Central/patologia , Neoplasias de Tecido Nervoso/secundário , Adulto , Biomarcadores Tumorais/análise , Biópsia por Agulha Fina , Neoplasias do Sistema Nervoso Central/química , Neoplasias do Sistema Nervoso Central/terapia , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Neoplasias de Tecido Nervoso/química , Neoplasias de Tecido Nervoso/terapia , Ontário , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Resultado do Tratamento , Adulto Jovem
5.
Brain Tumor Pathol ; 38(3): 173-182, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34255226

RESUMO

Primary central nervous system lymphoma (PCNSL) is a highly aggressive, extra-nodal non-Hodgkin lymphoma that is confined to the central nervous system (CNS) and the eyes. Most PCNSLs arise in immunocompetent older patients and less frequently in immunocompromised patients with Epstein-Barr virus infection. Although a patient's initial response to chemotherapy and radiation therapy is favorable, the clinical outcome of PCNSL remains poor compared to that of systemic lymphoma. Radiation-induced neurotoxicity is also a critical problem for patients with PCNSL. Therefore, a novel therapeutic strategy is required to overcome these challenges. Recent studies have largely uncovered the genomic landscape and associated histopathological features of PCNSL. Based on this background, novel therapeutic agents, such as Bruton's tyrosine kinase inhibitors and immune checkpoint inhibitors, have been introduced for patients with PCNSL. Here, we provide an overview of the updated histopathological and genomic characterization of PCNSL and summarize the current therapeutic strategies. We also review current preclinical PCNSL models for translational research.


Assuntos
Neoplasias do Sistema Nervoso Central/genética , Neoplasias do Sistema Nervoso Central/patologia , Linfoma não Hodgkin/genética , Linfoma não Hodgkin/patologia , Adulto , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Terapia Baseada em Transplante de Células e Tecidos , Neoplasias do Sistema Nervoso Central/epidemiologia , Neoplasias do Sistema Nervoso Central/terapia , Inibidores Enzimáticos/uso terapêutico , Neoplasias Oculares/genética , Neoplasias Oculares/patologia , Neoplasias Oculares/terapia , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Linfoma não Hodgkin/epidemiologia , Linfoma não Hodgkin/terapia , Camundongos , Terapia de Alvo Molecular , Pesquisa Médica Translacional , Adulto Jovem
6.
J Clin Neurosci ; 89: 381-388, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34083111

RESUMO

Primary central nervous system lymphoma (PCNSL) is a rare and aggressive form of extra-nodal non-Hodgkin's lymphoma. Corticosteroids cause transient regression of PCNSL at the radiological and histological level. A growing number of case reports describe histologically confirmed neuroinflammation (sentinel lesions) heralding the development of PCNSL. We present two further cases of sentinel lesions contextualised by a review of past literature. Our aims are to collate existing knowledge on sentinel lesions in PCNSL and explore their pathophysiological significance. Two cases were identified (n = 2) from a cohort of 104 patients with PCNSL referred to a tertiary neurosurgery centre. A literature search identified previously reported cases (n = 14). Median age was 57.5 (range; 26-72); pre-biopsy corticosteroid administration was reported in 50% of cases (n = 8); mean time between biopsies was 10 months (range; 3-60). Common MRI features were homogenous enhancement (10;71.4%) and T2-hyperintensity (11;100%). Histochemical analysis of sentinel lesion biopsy revealed inflammatory CD3/4/5/8-positive T-cells (14; 100%), demyelination (13; 81.3%), rare/scattered CD20-postive B-cells (11;78.6%) and CD68-positive macrophages (10;71.4%). Repeat biopsy confirmed PCNSL in all cases. Waxing and waning CNS inflammation has been identified in 16 patients ultimately diagnosed with PCNSL. Neuro-specialists should be aware of this atypical presentation and maintain a high index of suspicion for lymphoma despite histopathology negative for lymphoma when clinical or radiological features indicate PCNSL.


Assuntos
Neoplasias do Sistema Nervoso Central/patologia , Linfoma não Hodgkin/patologia , Corticosteroides/uso terapêutico , Adulto , Idoso , Anti-Inflamatórios/uso terapêutico , Biópsia , Neoplasias do Sistema Nervoso Central/sangue , Neoplasias do Sistema Nervoso Central/diagnóstico por imagem , Feminino , Humanos , Inflamação/sangue , Inflamação/tratamento farmacológico , Inflamação/patologia , Linfoma não Hodgkin/sangue , Linfoma não Hodgkin/diagnóstico por imagem , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Radiografia , Linfócitos T/metabolismo , Linfócitos T/patologia
7.
PLoS Pathog ; 17(6): e1009618, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34106998

RESUMO

Subpopulations of B-lymphocytes traffic to different sites and organs to provide diverse and tissue-specific functions. Here, we provide evidence that epigenetic differences confer a neuroinvasive phenotype. An EBV+ B cell lymphoma cell line (M14) with low frequency trafficking to the CNS was neuroadapted to generate a highly neuroinvasive B-cell population (MUN14). MUN14 B cells efficiently infiltrated the CNS within one week and produced neurological pathologies. We compared the gene expression profiles of viral and cellular genes using RNA-Seq and identified one viral (EBNA1) and several cellular gene candidates, including secreted phosphoprotein 1/osteopontin (SPP1/OPN), neuron navigator 3 (NAV3), CXCR4, and germinal center-associated signaling and motility protein (GCSAM) that were selectively upregulated in MUN14. ATAC-Seq and ChIP-qPCR revealed that these gene expression changes correlated with epigenetic changes at gene regulatory elements. The neuroinvasive phenotype could be attenuated with a neutralizing antibody to OPN, confirming the functional role of this protein in trafficking EBV+ B cells to the CNS. These studies indicate that B-cell trafficking to the CNS can be acquired by epigenetic adaptations and provide a new model to study B-cell neuroinvasion associated CNS lymphoma and autoimmune disease of the CNS, including multiple sclerosis (MS).


Assuntos
Linfócitos B/patologia , Linfócitos B/virologia , Neoplasias do Sistema Nervoso Central/virologia , Epigênese Genética , Infecções por Vírus Epstein-Barr/patologia , Animais , Linfócitos B/metabolismo , Transformação Celular Viral/fisiologia , Neoplasias do Sistema Nervoso Central/metabolismo , Neoplasias do Sistema Nervoso Central/patologia , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/metabolismo , Herpesvirus Humano 4 , Linfoma/metabolismo , Linfoma/patologia , Linfoma/virologia , Camundongos , Osteopontina/metabolismo
8.
Front Immunol ; 12: 634031, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34163465

RESUMO

Although there are several immunotherapy approaches for the treatment of Central Nervous System (CNS) tumors under evaluation, currently none of these approaches have received approval from the regulatory agencies. CNS tumors, especially glioblastomas, are tumors characterized by highly immunosuppressive tumor microenvironment, limiting the possibility of effectively eliciting an immune response. Moreover, the peculiar anatomic location of these tumors poses relevant challenges in terms of safety, since uncontrolled hyper inflammation could lead to cerebral edema and cranial hypertension. The most promising strategies of immunotherapy in neuro-oncology consist of the use of autologous T cells redirected against tumor cells through chimeric antigen receptor (CAR) constructs or genetically modified T-cell receptors. Trials based on native or genetically engineered oncolytic viruses and on vaccination with tumor-associated antigen peptides are also under evaluation. Despite some sporadic complete remissions achieved in clinical trials, the outcome of patients with CNS tumors treated with different immunotherapeutic approaches remains poor. Based on the lessons learned from these unsatisfactory experiences, novel immune-therapy approaches aimed at overcoming the profound immunosuppressive microenvironment of these diseases are bringing new hope to reach the cure for CNS tumors.


Assuntos
Neoplasias do Sistema Nervoso Central/terapia , Imunoterapia/tendências , Oncologia/tendências , Terapia Viral Oncolítica/tendências , Animais , Vacinas Anticâncer/uso terapêutico , Neoplasias do Sistema Nervoso Central/imunologia , Neoplasias do Sistema Nervoso Central/patologia , Difusão de Inovações , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia Adotiva/tendências , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologia , Linfócitos T/transplante , Resultado do Tratamento , Microambiente Tumoral
9.
PLoS One ; 16(6): e0251272, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34166375

RESUMO

Dysregulation of cell morphology and cell-cell interaction results in cancer cell growth, migration, invasion, and metastasis. Besides, a balance between the extracellular matrix (ECM) and matrix metalloprotease (MMP) is required for cancer cell morphology and angiogenesis. Here, we determined gene signatures associated with the morphology and microenvironment of primary central nervous system lymphoma (PCNSL) to enable prognosis prediction. Next-generation sequencing (NGS) on 31 PCNSL samples revealed gene signatures as follows: ACTA2, ACTR10, CAPG, CORO1C, KRT17, and PALLD in cytoskeleton, CDH5, CLSTN1, ITGA10, ITGAX, ITGB7, ITGA8, FAT4, ITGAE, CDH10, ITGAM, ITGB6, and CDH18 in adhesion, COL8A2, FBN1, LAMB3, and LAMA2 in ECM, ADAM22, ADAM28, MMP11, and MMP24 in MMP. Prognosis prediction formulas with the gene expression values and the Cox regression model clearly divided survival curves of the subgroups in each status. Furthermore, collagen genes contributed to gene network formation in glasso, suggesting that the ECM balance controls the PCNSL microenvironment. Finally, the comprehensive balance of morphology and microenvironment enabled prognosis prediction by a combinatorial expression of 8 representative genes, including KRT17, CDH10, CDH18, COL8A2, ADAM22, ADAM28, MMP11, and MMP24. Besides, these genes could also diagnose PCNSL cell types with MTX resistances in vitro. These results would not only facilitate the understanding of biology of PCNSL but also consider targeting pathways for anti-cancer treatment in personalized precision medicine in PCNSL.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias do Sistema Nervoso Central/mortalidade , Linfoma não Hodgkin/mortalidade , Microambiente Tumoral , Neoplasias do Sistema Nervoso Central/genética , Neoplasias do Sistema Nervoso Central/patologia , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Linfoma não Hodgkin/genética , Linfoma não Hodgkin/patologia , Prognóstico , Taxa de Sobrevida , Células Tumorais Cultivadas
10.
BMC Cancer ; 21(1): 754, 2021 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-34187419

RESUMO

BACKGROUND: Corticosteroid therapy (CST) prior to biopsy may hinder histopathological diagnosis in primary central nervous system lymphoma (PCNSL). Therefore, preoperative CST in patients with suspected PCNSL should be avoided if clinically possible. The aim of this study was thus to analyze the difference in the rate of diagnostic surgeries in PCNSL patients with and without preoperative CST. METHODS: A multicenter retrospective study including all immunocompetent patients diagnosed with PCNSL between 1/2004 and 9/2018 at four neurosurgical centers in Austria was conducted and the results were compared to literature. RESULTS: A total of 143 patients were included in this study. All patients showed visible contrast enhancement on preoperative MRI. There was no statistically significant difference in the rate of diagnostic surgeries with and without preoperative CST with 97.1% (68/70) and 97.3% (71/73), respectively (p = 1.0). Tapering and pause of CST did not influence the diagnostic rate. Including our study, there are 788 PCNSL patients described in literature with an odds ratio for inconclusive surgeries after CST of 3.3 (CI 1.7-6.4). CONCLUSIONS: Preoperative CST should be avoided as it seems to diminish the diagnostic rate of biopsy in PCNSL patients. Yet, if CST has been administered preoperatively and there is still a contrast enhancing lesion to target for biopsy, surgeons should try to keep the diagnostic delay to a minimum as the likelihood for acquiring diagnostic tissue seems sufficiently high.


Assuntos
Corticosteroides/uso terapêutico , Corticosteroides/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Sistema Nervoso Central/patologia , Feminino , Humanos , Linfoma/patologia , Masculino , Pessoa de Meia-Idade , Período Pré-Operatório , Estudos Retrospectivos , Adulto Jovem
11.
Medwave ; 21(2): e8138, 2021 Mar 26.
Artigo em Espanhol | MEDLINE | ID: mdl-33830973

RESUMO

Introduction: Lymphomatosis cerebri is a rare form of primary central nervous system lymphoma characterized by an atypical clinical presentation and neuroimaging, with a poor short-term prognosis. Case Report: A 51-year-old woman began with clinical manifestations characterized by rapidly progressing cognitive impairment associated with a behavioral disorder, myoclonus, and gait disturbance. The brain magnetic resonance image showed extensive signaling in the bilateral periventricular white matter. The 18F-FDG PET-CT showed severe dorsolateral neocortical hypometabolism in the absence of focal hypermetabolic lesion, a metabolic pattern indicative of cerebri lymphomatosis. A brain biopsy confirmed the diagnosis. The patient started chemotherapy achieving complete remission. Eighteen months after diagnosis, the patient had improved clinically and neuroimaging. Conclusion: This is the first report in Peru of an entity that should be considered in rapidly progressive dementia and leukoencephalopathy cases. Timely diagnosis and appropriate chemotherapy management can increase patient survival.


Assuntos
Neoplasias Encefálicas/patologia , Encéfalo/diagnóstico por imagem , Neoplasias do Sistema Nervoso Central/complicações , Demência/diagnóstico , Demência/etiologia , Leucoencefalopatias/etiologia , Linfoma/complicações , Biópsia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/patologia , Demência/patologia , Feminino , Humanos , Leucoencefalopatias/diagnóstico , Linfoma/patologia , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada
12.
Biol Chem ; 402(7): 839-848, 2021 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-33894112

RESUMO

Glioblastoma (GBM) is the most common and fatal type of primary malignant tumours in the central nervous system. Cytokines such as interleukins (ILs) play an important role in GBM progression. Our present study found that IL-24 is down-regulated in GBM cells. Recombinant IL-24 (rIL-24) can suppress the in vitro migration and invasion of GBM cells while increase its chemo-sensitivity to temozolomide (TMZ) treatment. rIL-24 negatively regulates the expression of Zeb1, one well known transcription factors of epithelial to mesenchymal transition (EMT) of cancer cells. Over expression of Zeb1 can attenuate IL-24-suppressed malignancy of GBM cells. Mechanistically, IL-24 decreases the protein stability of Zeb1 while has no effect on its mRNA stability. It is due to that IL-24 can increase the expression of FBXO45, which can destabilize Zeb1 in cancer cells. Collectively, we reveal that IL-24 can suppress the malignancy of GBM cells via decreasing the expression of Zeb1. It suggests that targeted activation of IL-24 signals might be a potential therapy approach for GBM treatment.


Assuntos
Neoplasias do Sistema Nervoso Central/metabolismo , Glioblastoma/metabolismo , Interleucinas/metabolismo , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo , Células Cultivadas , Neoplasias do Sistema Nervoso Central/patologia , Glioblastoma/patologia , Humanos , Interleucinas/genética , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética
13.
Int J Mol Sci ; 22(8)2021 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-33920124

RESUMO

Central nervous system tumor with BCL6-corepressor internal tandem duplication (CNS-BCOR ITD) is a malignant entity characterized by recurrent alterations in exon 15 encoding the essential binding domain for the polycomb repressive complex (PRC). In contrast to deletion or truncating mutations seen in other tumors, BCOR expression is upregulated in CNS-BCOR ITD, and a distinct oncogenic mechanism has been suggested. However, the effects of this change on the biology of neuroepithelial cells is poorly understood. In this study, we introduced either wildtype BCOR or BCOR-ITD into human and murine neural stem cells and analyzed them with quantitative RT-PCR and RNA-sequencing, as well as growth, clonogenicity, and invasion assays. In human cells, BCOR-ITD promoted derepression of PRC2-target genes compared to wildtype BCOR. A similar effect was found in clinical specimens from previous studies. However, no growth advantage was seen in the human neural stem cells expressing BCOR-ITD, and long-term models could not be established. In the murine cells, both wildtype BCOR and BCOR-ITD overexpression affected cellular differentiation and histone methylation, but only BCOR-ITD increased cellular growth, invasion, and migration. BCOR-ITD overexpression drives transcriptional changes, possibly due to altered PRC function, and contributes to the oncogenic transformation of neural precursors.


Assuntos
Proliferação de Células/genética , Neoplasias do Sistema Nervoso Central/genética , Proteínas do Grupo Polycomb/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Repressoras/genética , Animais , Linhagem Celular Tumoral , Neoplasias do Sistema Nervoso Central/patologia , Duplicação Gênica/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Camundongos , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/patologia , Sequências de Repetição em Tandem/genética
14.
Theranostics ; 11(8): 3565-3579, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33664848

RESUMO

Rationale: Primary central nervous system diffuse large B-cell lymphoma (PCNSL) is a rare and aggressive entity that resides in an immune-privileged site. The tumor microenvironment (TME) and the disruption of the immune surveillance influence lymphoma pathogenesis and immunotherapy resistance. Despite growing knowledge on heterogeneous therapeutic responses, no comprehensive description of the PCNSL TME is available. We hence investigated the immune subtypes of PCNSL and their association with molecular signaling and survival. Methods: Analysis of PCNSL transcriptomes (sequencing, n = 20; microarrays, n = 34). Integrated correlation analysis and signaling pathway topology enabled us to infer intercellular interactions. Immunohistopathology and digital imaging were used to validate bioinformatic results. Results: Transcriptomics revealed three immune subtypes: immune-rich, poor, and intermediate. The immune-rich subtype was associated to better survival and characterized by hyper-activation of STAT3 signaling and inflammatory signaling, e.g., IFNγ and TNF-α, resembling the hot subtype described in primary testicular lymphoma and solid cancer. WNT/ß-catenin, HIPPO, and NOTCH signaling were hyper-activated in the immune-poor subtype. HLA down-modulation was clearly associated with a low or intermediate immune infiltration and the absence of T-cell activation. Moreover, HLA class I down-regulation was also correlated with worse survival with implications on immune-intermediate PCNSL that frequently feature reduced HLA expression. A ligand-receptor intercellular network revealed high expression of two immune checkpoints, i.e., CTLA-4/CD86 and TIM-3/LAGLS9. TIM-3 and galectin-9 proteins were clearly upregulated in PCNSL. Conclusion: Altogether, our study reveals that patient stratification according to immune subtypes, HLA status, and immune checkpoint molecule quantification should be considered prior to immune checkpoint inhibitor therapy. Moreover, TIM-3 protein should be considered an axis for future therapeutic development.


Assuntos
Neoplasias do Sistema Nervoso Central/imunologia , Linfoma Difuso de Grandes Células B/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Sistema Nervoso Central/metabolismo , Neoplasias do Sistema Nervoso Central/patologia , Estudos de Coortes , Regulação para Baixo , Feminino , Perfilação da Expressão Gênica , Antígenos HLA/genética , Humanos , Estimativa de Kaplan-Meier , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Medicina de Precisão , Prognóstico , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
15.
J Cancer Res Clin Oncol ; 147(6): 1713-1723, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33651140

RESUMO

BACKGROUND: Gliomas are highly aggressive and lack of efficient targeted therapy. YAP, as a Hippo pathway downstream effector, plays a key role in promoting tumor development through the interaction with transcription factor TEAD on the NH3-terminal proline-rich domain. Therefore, targeting TEAD-interacting domain of YAP may provide a novel approach for the treatment of gliomas. MATERIALS AND METHODS: We generated a truncated YAP protein which includes the TEAD-binding domain (YAPBD), and supposed YAPBD can interact with endogenous TEAD but lost the function to activate YAP target gene expressions. The association of YAP expression with the malignant characters of glioma tissues were determined by immunohistochemistry. TEAD-binding capacity of YAPBD was determined by co-immunoprecipitation. The cell proliferation and migration were determined by MTT assay, xenograft assay, wound healing assay and transwell assay, respectively. YAP target genes were detected by Western blot. RESULTS: YAP was highly expressed in glioma tissues and associated with tumor malignancy. YAPBD could block the TEAD-YAP complex formation by competing with YAP binding to TEAD. YAPBD could inhibit glioma cell growth both in vitro and in vivo, through the induction of cell cycle arrest and apoptosis. The cell cycle-related gene cyclin D1 and c-myc, and anti-apoptotic gene Bcl-2, Bcl-xL and survivin were inhibited after YAPBD overexpression. Furthermore, YAPBD also decreased cell migration and invasion, and repressed epithelial-mesenchymal transition. CONCLUSION: YAPBD can block glioma cell survival and repress YAP-dependent gene expressions, indicating gene therapy which targets TEAD-YAP complex would be a potential and significant novel approach for human malignant gliomas.


Assuntos
Proteínas de Ciclo Celular/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Sistema Nervoso Central/patologia , Glioma/patologia , Proteínas Recombinantes/farmacologia , Fatores de Transcrição/farmacologia , Animais , Ligação Competitiva , Proteínas de Ciclo Celular/química , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Neoplasias do Sistema Nervoso Central/diagnóstico , Neoplasias do Sistema Nervoso Central/genética , Códon sem Sentido/genética , Estudos de Coortes , Proteínas de Ligação a DNA/metabolismo , Regulação Neoplásica da Expressão Gênica , Glioma/diagnóstico , Glioma/genética , Humanos , Camundongos , Camundongos Nus , Proteínas Nucleares/metabolismo , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas/genética , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Fatores de Transcrição/química , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Cancer Lett ; 509: 121-129, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33766752

RESUMO

Primary central nervous system lymphoma (PCNSL) is an aggressive cancer typically confined to the brain, eyes, leptomeninges and spinal cord, without evidence of systemic involvement. PCNSL remains a challenge for scientists and clinicians due to insufficient biological knowledge, a lack of appropriate animal models and validated diagnostic biomarkers. We summarize recent findings on genomic, transcriptomic and epigenetic alterations identified in PCNSL. These findings help to define pathobiology of the disease and delineate defects in B cell differentiation. Evidence from genomic and transcriptomic studies helps to separate PCNSL from other hematological malignancies, improves diagnostics and reveals new therapeutic targets for treatment. Discovery of the CNS lymphatic system may be instrumental in better understanding the origin of the disease. We critically assess the attempts to model PCNSL in rodents, and conclude that there is a lack of a genetic/transgenic model that adequately mimics pathogenesis of the disease. Contribution of the tumor microenvironment in tumorigenesis and aggressiveness of PCNSL remains understudied. Assessing heterogeneity of immune infiltrates, cytokine profiling and molecular markers, may improve diagnostics and put forward new therapeutic strategies.


Assuntos
Neoplasias do Sistema Nervoso Central/patologia , Linfoma/patologia , Células-Tronco Neoplásicas/patologia , Microambiente Tumoral , Animais , Apoptose , Diferenciação Celular , Proliferação de Células , Neoplasias do Sistema Nervoso Central/genética , Neoplasias do Sistema Nervoso Central/imunologia , Neoplasias do Sistema Nervoso Central/metabolismo , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Humanos , Linfoma/genética , Linfoma/imunologia , Linfoma/metabolismo , Células-Tronco Neoplásicas/imunologia , Células-Tronco Neoplásicas/metabolismo , Fenótipo , Transdução de Sinais
17.
Mol Diagn Ther ; 25(2): 207-229, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33646562

RESUMO

Cerebrospinal fluid (CSF) is a clear and paucicellular fluid that circulates within the ventricular system and the subarachnoid space of the central nervous system (CNS), and diverse CNS disorders can impact its composition, volume, and flow. As conventional CSF testing suffers from suboptimal sensitivity, this review aimed to evaluate the role of next-generation sequencing (NGS) in the work-up of infectious, neoplastic, neuroimmunological, and neurodegenerative CNS diseases. Metagenomic NGS showed improved sensitivity-compared to traditional methods-to detect bacterial, viral, parasitic, and fungal infections, while the overall performance was maximized in some studies when all diagnostic modalities were used. In patients with primary CNS cancer, NGS findings in the CSF were largely concordant with the molecular signatures derived from tissue-based molecular analysis; of interest, additional mutations were identified in the CSF in some glioma studies, reflecting intratumoral heterogeneity. In patients with metastasis to the CNS, NGS facilitated diagnosis, prognosis, therapeutic management, and monitoring, exhibiting higher sensitivity than neuroimaging, cytology, and plasma-based molecular analysis. Although evidence is still rudimentary, NGS could enhance the diagnosis and pathogenetic understanding of multiple sclerosis in addition to Alzheimer and Parkinson disease. To conclude, NGS has shown potential to aid the research, facilitate the diagnostic approach, and improve the management outcomes of all the aforementioned CNS diseases. However, to establish its role in clinical practice, the clinical validity and utility of each NGS protocol should be determined. Lastly, as most evidence has been derived from small and retrospective studies, results from randomized control trials could be of significant value.


Assuntos
Doenças do Sistema Nervoso Central/genética , Neoplasias do Sistema Nervoso Central/genética , Doenças do Sistema Imunitário/genética , Doenças Neurodegenerativas/genética , Sistema Nervoso Central/patologia , Doenças do Sistema Nervoso Central/imunologia , Doenças do Sistema Nervoso Central/patologia , Neoplasias do Sistema Nervoso Central/imunologia , Neoplasias do Sistema Nervoso Central/patologia , Humanos , Doenças do Sistema Imunitário/imunologia , Doenças do Sistema Imunitário/patologia , Mutação/genética , Doenças Neurodegenerativas/imunologia , Doenças Neurodegenerativas/patologia
18.
Int J Cancer ; 149(1): 158-168, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33634856

RESUMO

Asparaginase (Asp) is one of the most important drugs for treating acute lymphoblastic leukemia (ALL). However, off-protocol Asp administration (OPAA) or hypersensitivity may disturb its pharmacokinetic profile. In this retrospective study, we sought to determine whether OPAA and hypersensitivity to Escherichia coli asparaginase (E coli Asp) impaired extramedullary relapse prevention in a pediatric ALL cohort treated according to SCMC-ALL-2005 protocol from 2005 to 2014 at the Shanghai Children's Medical Center (SCMC). In total, 676 patients were enrolled in this study, including 369 with OPAA and 60 exhibiting hypersensitivity to E coli Asp. At the end of the most recent follow-up, 58 patients had extramedullary relapse. The 5-year cumulative extramedullary relapse incidence in patients with OPAA was 11.01%, whereas that in patients without OPAA was 5.28% (P = .0036). Moreover, the 5-year cumulative extramedullary relapse incidence in patients that exhibited hypersensitivity to E coli Asp was 16.48%, whereas that in patients without hypersensitivity was 7.59% (P = .0195). Concerning the relapse site, OPAA not only increased central nervous system (CNS) relapse but testicular relapse as well. Based on Fine and Gray multivariate analysis, OPAA and hypersensitivity to Asp were independent risk factors for extramedullary relapse. In conclusion, to prevent extramedullary relapse of ALL, adequate duration to administrate Asp was more important than the total dosage, and more attention should be paid to Asp inadequate due to hypersensitivity.


Assuntos
Asparaginase/administração & dosagem , Linfócitos B/efeitos dos fármacos , Neoplasias do Sistema Nervoso Central/prevenção & controle , Recidiva Local de Neoplasia/prevenção & controle , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Neoplasias Testiculares/prevenção & controle , Adolescente , Neoplasias do Sistema Nervoso Central/patologia , Criança , Pré-Escolar , China , Escherichia coli/enzimologia , Feminino , Seguimentos , Humanos , Lactente , Masculino , Recidiva Local de Neoplasia/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Prognóstico , Estudos Retrospectivos , Neoplasias Testiculares/patologia
19.
BMC Cancer ; 21(1): 183, 2021 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-33618687

RESUMO

BACKGROUD: Establishing diagnostic and prognostic biomarkers of primary central nervous system lymphoma (PCNSL) is a challenge. This study evaluated the value of dynamic interleukin (IL)-10 cerebrospinal fluid (CSF) concentrations for prognosis and relapse prediction in PCNSL. METHODS: Consecutive 40 patients newly diagnosed with PCNSL between April 2015 and April 2019 were recruited, and serial CSF specimens were collected by lumbar punctures (LP) or by Ommaya reservoir at diagnosis, treatment, and follow-up phase. RESULTS: We confirmed that an elevated IL-10 cutoff value of 8.2 pg/mL for the diagnosis value of PCNSL showed a sensitivity of 85%. A persistent detectable CSF IL-10 level at the end of treatment was associated with poor progression-free survival (PFS) (836 vs. 481 days, p = 0.049). Within a median follow-up of 13.6 (2-55) months, 24 patients relapsed. IL-10 relapse was defined as a positive conversion in patients with undetectable IL-10 or an increased concentration compared to the last test in patients with sustained IL-10. IL-10 relapse was detected a median of 67 days (28-402 days) earlier than disease relapse in 10/16 patients. CONCLUSION: This study highlights a new perspective that CSF IL-10 relapse could be a surrogate marker for disease relapse and detected earlier than conventional magnetic resonance imaging (MRI) scan. Further evaluation of IL-10 monitoring in PCNSL follow-up is warranted.


Assuntos
Neoplasias do Sistema Nervoso Central/líquido cefalorraquidiano , Interleucina-10/líquido cefalorraquidiano , Linfoma de Células B/líquido cefalorraquidiano , Recidiva Local de Neoplasia/líquido cefalorraquidiano , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/líquido cefalorraquidiano , Neoplasias do Sistema Nervoso Central/diagnóstico por imagem , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/patologia , Feminino , Humanos , Linfoma de Células B/diagnóstico por imagem , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/patologia , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico por imagem , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Prognóstico , Taxa de Sobrevida
20.
Acta Neuropathol Commun ; 9(1): 20, 2021 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-33536079

RESUMO

Primitive neuroectodermal tumors of the central nervous system (CNS-PNETs) are highly malignant neoplasms posing diagnostic challenge due to a lack of defining molecular markers. CNS neuroblastoma with forkhead box R2 (FOXR2) activation (CNS_NBL) emerged as a distinct pediatric brain tumor entity from a pool previously diagnosed as primitive neuroectodermal tumors of the central nervous system (CNS-PNETs). Current standard of identifying CNS_NBL relies on molecular analysis. We set out to establish immunohistochemical markers allowing safely distinguishing CNS_NBL from morphological mimics. To this aim we analyzed a series of 84 brain tumors institutionally diagnosed as CNS-PNET. As expected, epigenetic analysis revealed different methylation groups corresponding to the (1) CNS-NBL (24%), (2) glioblastoma IDH wild-type subclass H3.3 G34 (26%), (3) glioblastoma IDH wild-type subclass MYCN (21%) and (4) ependymoma with RELA_C11orf95 fusion (29%) entities. Transcriptome analysis of this series revealed a set of differentially expressed genes distinguishing CNS_NBL from its mimics. Based on RNA-sequencing data we established SOX10 and ANKRD55 expression as genes discriminating CNS_NBL from other tumors exhibiting CNS-PNET. Immunohistochemical detection of combined expression of SOX10 and ANKRD55 clearly identifies CNS_NBL discriminating them to other hemispheric CNS neoplasms harboring "PNET-like" microscopic appearance. Owing the rarity of CNS_NBL, a confirmation of the elaborated diagnostic IHC algorithm will be necessary in prospective patient series.


Assuntos
Biomarcadores Tumorais/genética , Proteínas de Transporte/genética , Neoplasias do Sistema Nervoso Central , Fatores de Transcrição Forkhead/genética , Neuroblastoma , Tumores Neuroectodérmicos Primitivos/diagnóstico , Tumores Neuroectodérmicos Primitivos/genética , Fatores de Transcrição SOXE/genética , Adolescente , Neoplasias do Sistema Nervoso Central/classificação , Neoplasias do Sistema Nervoso Central/diagnóstico , Neoplasias do Sistema Nervoso Central/genética , Neoplasias do Sistema Nervoso Central/patologia , Criança , Pré-Escolar , Metilação de DNA/genética , Feminino , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Masculino , Neuroblastoma/diagnóstico , Neuroblastoma/genética , Neuroblastoma/patologia , Tumores Neuroectodérmicos Primitivos/classificação , Tumores Neuroectodérmicos Primitivos/patologia
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