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/metabolismoRESUMO
Glioblastoma (GBM), the most frequent primary tumor of the central nervous system, has a median survival of 14.6 months. 4-Methylumbelliferone (4MU) is a coumarin derivative widely used as a hyaluronan synthesis inhibitor with proven antitumor activity and without toxic effects reported. We aim to evaluate the antitumor effect of 4MU alone or combined with temozolomide (TMZ) on a GBM cell line, its absence of toxicity on brain cells and its selectivity for tumor cells. The antitumor effect of 4MU alone or combined with TMZ was evaluated on GL26 cells by assessing the metabolic activity through the XTT assay, cell proliferation by BrdU incorporation assay, migration by the wound healing assay, cell death by fluorescein diacetate/propidium iodide (FDA/PI) staining, apoptosis by membrane asymmetry and DNA fragmentation and metalloproteinase activity by zymography. The levels of hyaluronan and its capacity to counteract the effects of 4MU and the expression of RHAMM and CD44 were also determined. The toxicity and selectivity of 4MU were determined by XTT assay and PI staining on normal brain primary cell culture (NBPC-GFP) and GL26/NBPC-GFP cocultures. The GL26 cells expressed RHAMM but not CD44 while synthetized hyaluronan. 4MU decreased hyaluronan synthesis, diminished proliferation and induced apoptosis while reducing cell migration and the activity of metalloproteinases, which was restored by addition of hyaluronic acid. Furthermore, 4MU sensitized GL26 cells to the TMZ effect and showed selective toxicity on tumor cells without exhibiting neurotoxic effects. We demonstrated for the first time the cytotoxic effect of 4MU on GBM cells, highlighting its potential usefulness to improve GBM treatment.
Assuntos
Antineoplásicos/farmacologia , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Himecromona/farmacologia , Animais , Apoptose/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias do Sistema Nervoso Central/metabolismo , Neoplasias do Sistema Nervoso Central/patologia , Ensaios de Seleção de Medicamentos Antitumorais , Glioblastoma/metabolismo , Glioblastoma/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Células Tumorais CultivadasRESUMO
Most childhood cancers occur as isolated cases and show very different biological behavior when compared with cancers in adults. There are some solid tumors that occur almost exclusively in children among which stand out the embryonal solid tumors. These cancers main types are neuroblastoma, nephroblastoma (Wilms tumors), retinoblastoma and hepatoblastomas and tumors of the central nervous system (CNS). Embryonal solid tumors represent a heterogeneous group of cancers supposedly derived from undifferentiated cells, with histological features that resemble tissues of origin during embryogenesis. This key observation suggests that tumorigenesis might begin during early fetal or child life due to the errors in growth or pathways differentiation. There are not many literature data on genomic, transcriptomic, epigenetic, proteomic, or metabolomic differences in these types of cancers when compared to the omics- used in adult cancer research. Still, metabolomics by nuclear magnetic resonance (NMR) in childhood embryonal solid tumors research can contribute greatly to understand better metabolic pathways alterations and biology of the embryonal solid tumors and potential to be used in clinical applications. Different types of samples, such as tissues, cells, biofluids, mostly blood plasma and serum, can be analyzed by NMR to detect and identify cancer metabolic signatures and validated biomarkers using enlarged group of samples. The literature search for biomarkers points to around 20-30 compounds that could be associated with pediatric cancer as well as metastasis.
Assuntos
Biomarcadores Tumorais/metabolismo , Metabolômica/métodos , Neoplasias Embrionárias de Células Germinativas/metabolismo , Carcinogênese , Diferenciação Celular , Neoplasias do Sistema Nervoso Central/metabolismo , Neoplasias do Sistema Nervoso Central/patologia , Criança , Hepatoblastoma/metabolismo , Hepatoblastoma/patologia , Humanos , Espectroscopia de Ressonância Magnética , Metaboloma , Neoplasias Embrionárias de Células Germinativas/patologia , Proteômica , Retinoblastoma/metabolismo , Retinoblastoma/patologia , Tumor de Wilms/metabolismo , Tumor de Wilms/patologiaRESUMO
Even though the treatment of childhood cancer has evolved significantly in recent decades, aggressive central nervous system (CNS) tumors are still a leading cause of morbidity and mortality in this population. Consequently, the identification of molecular targets that can be incorporated into diagnostic practice, effectively predict prognosis, follow treatment response, and materialize into potential targeted therapeutic approaches are still warranted. Since the first evidence of the participation of miRNAs in cancer development and progression 20 years ago, notable progress has been made in the basic understanding of the contribution of their dysregulation as epigenetic driver of tumorigenesis. Nevertheless, among the plethora of articles in the literature, microRNA profiling of pediatric tumors are scarce. This article gives an overview of the recent advances in the diagnostic/prognostic potential of miRNAs in a selection of pediatric CNS tumors: medulloblastoma, ependymoma, pilocytic astrocytoma, glioblastoma, diffuse intrinsic pontine glioma, atypical teratoid/rhabdoid tumors, and choroid plexus tumors.
Assuntos
Neoplasias Encefálicas/genética , Neoplasias do Sistema Nervoso Central/genética , MicroRNAs/biossíntese , Fatores Etários , Animais , Neoplasias Encefálicas/metabolismo , Neoplasias do Sistema Nervoso Central/metabolismo , Criança , Humanos , MicroRNAs/genéticaRESUMO
Aberrant expression of the pluripotency factor OCT4A in embryonal tumors of the central nervous system (CNS) is a key factor that contributes to tumor aggressiveness and correlates with poor patient survival. OCT4A overexpression has been shown to up-regulate miR-367, a microRNA (miRNA) that regulates pluripotency in embryonic stem cells and stem-like aggressive traits in cancer cells. Here, we show that (a) miR-367 is carried in microvesicles derived from embryonal CNS tumor cells expressing OCT4A; and (b) inhibition of miR-367 in these cells attenuates their aggressive traits. miR-367 silencing in OCT4A-overexpressing tumor cells significantly reduced their proliferative and invasive behavior, clonogenic activity, and tumorsphere generation capability. In vivo, targeting of miR-367 through direct injections of a specific inhibitor into the cerebrospinal fluid of Balb/C nude mice bearing OCT4A-overexpressing tumor xenografts inhibited tumor development and improved overall survival. miR-367 was also shown to target SUZ12, one of the core components of the polycomb repressive complex 2 known to be involved in epigenetic silencing of pluripotency-related genes, including POU5F1, which encodes OCT4A. Our findings reveal possible clinical applications of a cancer stemness pathway, highlighting miR-367 as a putative liquid biopsy biomarker that could be further explored to improve early diagnosis and prognosis prediction, and potentially serve as a therapeutic target in aggressive embryonal CNS tumors.
Assuntos
Biomarcadores Tumorais , Neoplasias do Sistema Nervoso Central , Inativação Gênica , MicroRNAs , Neoplasias Embrionárias de Células Germinativas , Células-Tronco Neoplásicas , RNA Neoplásico , Animais , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/genética , Neoplasias do Sistema Nervoso Central/metabolismo , Neoplasias do Sistema Nervoso Central/patologia , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , MicroRNAs/metabolismo , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Neoplasias Embrionárias de Células Germinativas/genética , Neoplasias Embrionárias de Células Germinativas/metabolismo , Neoplasias Embrionárias de Células Germinativas/patologia , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , RNA Neoplásico/antagonistas & inibidores , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Tumorigenic cell lines are more susceptible to [Re6Se8I6]3- cluster-induced death than normal cells, becoming a novel candidate for cancer treatment. Still, the feasibility of using this type of molecules in human patients remains unclear and further pharmacokinetics analysis is needed. Using coupled plasma optical emission spectroscopy, we determined the Re-cluster tissue content in injected mice, as a biodistribution measurement. Our results show that the Re-cluster successfully reaches different tissues, accumulating mainly in heart and liver. In order to dissect the mechanism underlying cluster biodistribution, we used three different experimental approaches. First, we evaluate the degree of lipophilicity by determining the octanol/water partition coefficient. The cluster mostly remained in the octanol fraction, with a coefficient of 1.86 ± 0.02, which indicates it could potentially cross cell membranes. Then, we measured the biological membrane penetration through a parallel artificial membrane permeability assays (PAMPA) assay. The Re-cluster crosses the artificial membrane, with a coefficient of 122 nm/s that is considered highly permeable. To evaluate a potential application of the Re-cluster in central nervous system (CNS) tumors, we analyzed the cluster's brain penetration by exposing cultured blood-brain-barrier (BBB) cells to increasing concentrations of the cluster. The Re-cluster effectively penetrates the BBB, reaching nearly 30% of the brain side after 24 h. Thus, our results indicate that the Re-cluster penetrates biological membranes reaching different target organs-most probably due to its lipophilic properties-becoming a promising anti-cancer drug with high potential for CNS cancer's diagnosis and treatment.
Assuntos
Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Complexos de Coordenação/farmacologia , Rênio/farmacologia , Transporte Biológico/efeitos dos fármacos , Barreira Hematoencefálica/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Linhagem Celular Tumoral , Membrana Celular/efeitos dos fármacos , Permeabilidade da Membrana Celular/efeitos dos fármacos , Neoplasias do Sistema Nervoso Central/metabolismo , Neoplasias do Sistema Nervoso Central/patologia , Humanos , Selênio/farmacologia , Distribuição Tecidual/efeitos dos fármacosRESUMO
PURPOSE: MicroRNAs were identified as molecules that participate in gene regulation; alterations in their expression characterize central nervous system (CNS). Information in pediatrics is scarce, so the objective of this work was to determine and then compare the patterns of expression of microRNAs in astrocytomas, ependymomas, and medulloblastomas, as well as in non-neoplastic brain. METHODS: Low-density arrays were utilized to evaluate 756 microRNAs in three samples of each type of tumor and non-neoplastic brain. The relative expression was calculated in order to identify the three microRNAs whose expression was modified notably. This was verified using RT-qPCR in more number of tumor samples. RESULTS: The microRNAs selected for testing were miR-100-5p, miR-195-5p, and miR-770-5p. A higher expression of miR-100-5p was observed in the astrocytomas and ependymomas compared to the medulloblastomas: on average 3.8 times (p < 0.05). MiR-770-5p was expressed less in medulloblastomas compared to astrocytomas four times (p = 0.0162). MiR-195-5p had a low expression in medulloblastomas compared to non-neoplastic cerebellum (p = 0.049). In all three tumor types, expression of miR-770-5p was lower than in non-neoplastic brain (p < 0.001). CONCLUSIONS: These microRNAs may represent potential markers in these tumors.
Assuntos
Biomarcadores Tumorais/biossíntese , Neoplasias do Sistema Nervoso Central/epidemiologia , Neoplasias do Sistema Nervoso Central/metabolismo , Regulação Neoplásica da Expressão Gênica , MicroRNAs/biossíntese , Adolescente , Biomarcadores Tumorais/genética , Neoplasias do Sistema Nervoso Central/genética , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , México/epidemiologia , MicroRNAs/genéticaRESUMO
INTRODUCTION: Immunostaining of progesterone receptors (PRs) has been described as a prognostic factor related to recurrences in meningiomas. However, its expression in other primary intracranial tumors has been poorly studied. In this paper, we compare the pattern of expression of the receptor in meningiomas with that of nonmeningothelial intracranial tumors to evaluate its value in the diagnosis of the former. MATERIALS AND METHODS: A total of 42 nonmeningothelial intracranial tumors (21 glioblastomas, 4 anaplastic oligodendrogliomas, 4 oligodendrogliomas, 1 pilomyxoid astrocytoma, 3 ependymomas, 8 schwannomas, 1 chordoid chordoma) and 32 meningiomas (1 rhabdoid, 1 papillary, 5 atypical, 7 with histologic features of more aggressive behavior, 1 microcyst, 8 meningothelial, 7 transitional, 2 fibroblastic) were studied for PR by immunohistochemistry. RESULTS: About 73.8% of the nonmeningothelial tumors and 100% of the meningiomas were positive for the receptor, the difference being statistically significant (P=0.0017). The mean percentage of positive tumor cells per high-power field was frequently higher than 30% in meningiomas and lower than 10% in nonmeningothelial tumors (P=0.0001). CONCLUSIONS: Although we detected that immunostaining for the PR is more frequently observed in meningiomas, we confirmed its expression in diverse nonmeningothelial primary intracranial tumors. Immunohistochemistry for PR would be useful in the diagnosis of meningioma only when its positivity shows a mean higher than 30% of the positive tumor cells per high-power field.
Assuntos
Neoplasias do Sistema Nervoso Central/metabolismo , Receptores de Progesterona/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Os astrocitomas são neoplasias primárias do Sistema Nervoso Central, graduadas de I a IV com base em critérios clínicos e histológicos. O astrocitoma de grau IV, também denominado glioblastoma, é o tipo mais comum e agressivo dos tumores gliais e apresenta baixa resposta a agentes quimioterápicos. Em glioblastomas, mutações e superexpressão dos receptores de fatores de crescimento podem levar à ativação desregulada da via das proteínas cinases ativadas por mitógenos (MAPK). A via de MAPK é ativadora direta da cinase RSK (do inglês, p90 ribosomal S6 kinase), que está envolvida com diversos processos celulares. Apesar dessa proteína ter sido estudada em diferentes tipos tumorais, sua participação em glioblastomas nunca foi avaliada. Dessa maneira, neste trabalho tivemos como objetivo analisar o envolvimento de RSK na tumorigênese em glioblastoma, e observar a participação dessa proteína em processos como proliferação e senescência celular. Observamos que a regulação dessa proteína ocorre principalmente a nível traducional em linhagens celulares de glioblastoma. Utilizando células nocaute para RSK1 e/ou 2 obtidas pela metodologia CRISPR/Cas9, pudemos constatar o envolvimento dessa proteína na proliferação celular. Além disso, a relação entre RSK e a senescência celular induzida pela perda de PTEN foi demonstrada em células não transformadas, utilizando siRNA e inibidores químicos de RSK. Pudemos também descrever que inibidores de RSK comumente utilizados na literatura possuem importantes efeitos inespecíficos que podem levar a interpretações errôneas sobre as funções de RSK. Adicionalmente, determinamos que o melhor alvo para acessar a atividade de RSK é a proteína TSC2 (Ser1798).
Astrocytomas are primary Central Nervous System tumors graded from I to IV based on histological and clinical criteria. The grade IV astrocytoma, also known as glioblastoma, is the most common and aggressive of glial tumors and presents low response to chemotherapeutic agents. In glioblastomas, mutations and overexpression of growth factor receptors can lead to the upregulated activation of the mitogen-activated protein kinases pathways (MAPK). MAPK pathway is the major activator of the p90 ribosomal S6 kinase (RSK), which is involved in many cellular processes. RSK involvement has been performed in several tumor types; however it has never been studied in glioblastomas. Thus, this work aimed to analyze the involvement of RSK in glioblastoma. Firstily, it was observed that the regulation of this protein occurs mainly at translational level or by pos-tranlstional control in glioblastoma cell lines. Using RSK1 and/or RSK2 knockout cells obtained by the CRISPR/Cas9 methodology, it was found the involvement of this protein on cell proliferation. Furthermore, the possible relationship between RSK and cellular senescence induced by PTEN loss has been demonstrated in untransformed cells by using siRNA and chemical RSK inhibitors. Additionally, it also was observed that RKS inhibitors commonly used in the literature have unspecific effects that can lead to wrongful conclusions about the true functions of RSKs. It was also demonstrated that the best target to access the RSK activity is the TSC2 protein (Ser1798).
Assuntos
Humanos , Neoplasias do Sistema Nervoso Central/genética , Glioblastoma/genética , Proteínas Quinases S6 Ribossômicas/genética , Plasmídeos , Western Blotting , Neoplasias do Sistema Nervoso Central/metabolismo , Senescência Celular , Glioblastoma/metabolismo , Proteínas Quinases S6 Ribossômicas/metabolismo , RNA Interferente Pequeno , Proliferação de Células , Transcrição Reversa , PTEN Fosfo-Hidrolase/metabolismo , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Acute lymphoblastic leukemia (ALL) is the most common cancer in children. The inclusion of molecular biology techniques in the diagnosis and prognostic stratification of these patients has allowed major treatment achievements in developed countries. One of the best studied gene rearrangements is E2A-PBX1, which predicts isolated central nervous system relapse in patients with ALL. However, further research on the search for new molecular markers related to prognosis of patients with childhood leukemia is required. Such studies need the integration of different disciplines, including epidemiology. Epidemiological studies are needed not only to accelerate the discovery of new molecular markers and new biological signals as to the etiology and pathophysiology of cancer, but also to evaluate the clinical impact of these findings in well-defined populations.
La leucemia linfoblástica aguda (LLA) es el cáncer más frecuente en niños. La inclusión de técnicas de biología molecular en el diagnóstico y la estratificación pronóstica de estos pacientes ha permitido que se logren avances importantes del tratamiento en países desarrollados. Uno de los rearreglos génicos más estudiados es el E2A-PBX1, el cual predice la recaída aislada al sistema nervioso central (SNC) en pacientes con LLA. Es necesaria una mayor investigación acerca de la búsqueda de nuevos marcadores moleculares relacionados con el pronóstico de los pacientes con leucemia infantil. Este tipo de estudios requieren de la integración de diferentes disciplinas del campo de la investigación, entre ellas la epidemiología. Los estudios epidemiológicos son necesarios no solo para acelerar los descubrimientos de nuevos marcadores moleculares y nuevas señales biológicas en cuanto a la etiología y la fisiopatología del cáncer, sino también para para evaluar el impacto clínico de esos descubrimientos en poblaciones bien definidas.