RESUMEN
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.
Asunto(s)
Neoplasias del Sistema Nervioso Central/patología , FN-kappa B/metabolismo , 2-Metoxiestradiol/química , 2-Metoxiestradiol/metabolismo , 2-Metoxiestradiol/uso terapéutico , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/uso terapéutico , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Neoplasias del Sistema Nervioso Central/metabolismo , Niño , Glioma/metabolismo , Glioma/patología , Proteínas Hedgehog/antagonistas & inhibidores , Proteínas Hedgehog/metabolismo , Humanos , Meduloblastoma/metabolismo , Meduloblastoma/patología , FN-kappa B/antagonistas & inhibidores , Proteínas Wnt/antagonistas & inhibidores , Proteínas Wnt/metabolismoRESUMEN
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.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Glioblastoma/tratamiento farmacológico , Himecromona/farmacología , Animales , Apoptosis/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Neoplasias del Sistema Nervioso Central/metabolismo , Neoplasias del Sistema Nervioso Central/patología , Ensayos de Selección de Medicamentos Antitumorales , Glioblastoma/metabolismo , Glioblastoma/patología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Células Tumorales CultivadasRESUMEN
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.
Asunto(s)
Neoplasias Encefálicas/genética , Neoplasias del Sistema Nervioso Central/genética , MicroARNs/biosíntesis , Factores de Edad , Animales , Neoplasias Encefálicas/metabolismo , Neoplasias del Sistema Nervioso Central/metabolismo , Niño , Humanos , MicroARNs/genéticaRESUMEN
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.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Metabolómica/métodos , Neoplasias de Células Germinales y Embrionarias/metabolismo , Carcinogénesis , Diferenciación Celular , Neoplasias del Sistema Nervioso Central/metabolismo , Neoplasias del Sistema Nervioso Central/patología , Niño , Hepatoblastoma/metabolismo , Hepatoblastoma/patología , Humanos , Espectroscopía de Resonancia Magnética , Metaboloma , Neoplasias de Células Germinales y Embrionarias/patología , Proteómica , Retinoblastoma/metabolismo , Retinoblastoma/patología , Tumor de Wilms/metabolismo , Tumor de Wilms/patologíaRESUMEN
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.
Asunto(s)
Biomarcadores de Tumor , Neoplasias del Sistema Nervioso Central , Silenciador del Gen , MicroARNs , Neoplasias de Células Germinales y Embrionarias , Células Madre Neoplásicas , ARN Neoplásico , Animales , Biomarcadores de Tumor/antagonistas & inhibidores , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Línea Celular Tumoral , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Neoplasias del Sistema Nervioso Central/genética , Neoplasias del Sistema Nervioso Central/metabolismo , Neoplasias del Sistema Nervioso Central/patología , Células HEK293 , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , MicroARNs/antagonistas & inhibidores , MicroARNs/genética , MicroARNs/metabolismo , Neoplasias de Células Germinales y Embrionarias/tratamiento farmacológico , Neoplasias de Células Germinales y Embrionarias/genética , Neoplasias de Células Germinales y Embrionarias/metabolismo , Neoplasias de Células Germinales y Embrionarias/patología , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , ARN Neoplásico/antagonistas & inhibidores , ARN Neoplásico/genética , ARN Neoplásico/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
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.
Asunto(s)
Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Complejos de Coordinación/farmacología , Renio/farmacología , Transporte Biológico/efectos de los fármacos , Barrera Hematoencefálica/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/patología , Línea Celular Tumoral , Membrana Celular/efectos de los fármacos , Permeabilidad de la Membrana Celular/efectos de los fármacos , Neoplasias del Sistema Nervioso Central/metabolismo , Neoplasias del Sistema Nervioso Central/patología , Humanos , Selenio/farmacología , Distribución Tisular/efectos de los fármacosRESUMEN
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.
Asunto(s)
Biomarcadores de Tumor/biosíntesis , Neoplasias del Sistema Nervioso Central/epidemiología , Neoplasias del Sistema Nervioso Central/metabolismo , Regulación Neoplásica de la Expresión Génica , MicroARNs/biosíntesis , Adolescente , Biomarcadores de Tumor/genética , Neoplasias del Sistema Nervioso Central/genética , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , México/epidemiología , MicroARNs/genéticaRESUMEN
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.
Asunto(s)
Neoplasias del Sistema Nervioso Central/metabolismo , Receptores de Progesterona/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
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).
Asunto(s)
Humanos , Neoplasias del Sistema Nervioso Central/genética , Glioblastoma/genética , Proteínas Quinasas S6 Ribosómicas/genética , Plásmidos , Western Blotting , Neoplasias del Sistema Nervioso Central/metabolismo , Senescencia Celular , Glioblastoma/metabolismo , Proteínas Quinasas S6 Ribosómicas/metabolismo , ARN Interferente Pequeño , Proliferación Celular , Transcripción Reversa , Fosfohidrolasa PTEN/metabolismo , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
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.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Neoplasias del Sistema Nervioso Central/metabolismo , Proteínas de Homeodominio/metabolismo , Proteínas de Fusión Oncogénica/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Neoplasias del Sistema Nervioso Central/diagnóstico , Niño , Reordenamiento Génico , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Pronóstico , RecurrenciaRESUMEN
BACKGROUND: To describe a case series of nasal natural killer (NK)/T-cell lymphoma (NKTL) with orbital and central nervous system extension. METHODS: This is a retrospective study. The medical records of 9 patients with a diagnosis of NKTL were reviewed. All patients had a positive biopsy for CD3, CD56, T-cell-restricted intracellular antigen-1, and granzyme expression and CT imaging of nose, sinuses, orbits, and brain. Five patients were also examined with MRI. RESULTS: Orbital extension occurred in 6 patients. All had extraocular muscle enlargement and 5 showed signs of perineural spread. CONCLUSIONS: NKTL is a polymorphous disease. Extraocular muscle involvement and perineural spread are overlooked features that explain dissemination of the tumor to both the orbit and the central nervous system.
Asunto(s)
Neoplasias del Sistema Nervioso Central/patología , Células Asesinas Naturales/patología , Linfoma de Células T/patología , Neoplasias Orbitales/patología , Adolescente , Adulto , Biomarcadores de Tumor/metabolismo , Complejo CD3/metabolismo , Antígeno CD56/metabolismo , Neoplasias del Sistema Nervioso Central/diagnóstico por imagen , Neoplasias del Sistema Nervioso Central/metabolismo , Niño , Femenino , Granzimas/metabolismo , Humanos , Células Asesinas Naturales/metabolismo , Linfoma de Células T/diagnóstico por imagen , Linfoma de Células T/metabolismo , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Neoplasias Orbitales/diagnóstico por imagen , Neoplasias Orbitales/metabolismo , Proteínas de Unión al ARN/metabolismo , Estudios Retrospectivos , Tomografía Computarizada por Rayos X , Adulto JovenRESUMEN
AIMS: This study evaluated the salivary biochemical and immunological status of children with cancer undergoing to antineoplasic treatment in an attempt to identify alternatives for a less invasive and less painful monitoring of these patients. MATERIALS AND METHODS: Unstimulated whole saliva samples were obtained from 115 children without cancer (control) and 32 children with cancer (CA). Children with cancer were also evaluated after antineoplasic treatment (CAT, n = 17). The salivary concentrations of glucose, triglycerides, total cholesterol, alkaline phosphatase, gamma-glutamyltransferase (GGT), urea, insulin, thyroid-stimulating hormone (TSH), triiodothyronine (T3), levothyroxine (T4), and immunoglobulin A (IgA) were determined. RESULTS: Acute lymphocytic leukemia, acute myeloid leukemia, and Hodgkin's lymphoma were the most frequent cancers, although cases of non-Hodgkin's lymphoma, medulloblastoma, ependymoma, osteosarcoma, nephroblastoma, Ewing's sarcoma, and endodermal sinus tumor were also observed. The salivary concentration of cholesterol, triglycerides, or GGT did not differ between groups. Instead, the concentrations of alkaline phosphatase and T4 were higher in patients with cancer, irrespective of treatment. TSH levels were higher in the CA group and urea concentration was lower in the CAT group. T3 was undetectable in all groups. Antineoplasic treatment increased the glucose level and decreased the insulin concentration. Salivary concentration of total IgA was lower in children with cancer, irrespective of treatment. CONCLUSIONS: Cancer and antineoplasic treatment affected biochemical and immunological parameters in the saliva of children, shedding new light on the potential usefulness of saliva for monitoring children with cancer, especially to patients undergoing immunosuppressive therapy.
Asunto(s)
Estado de Salud , Neoplasias/terapia , Saliva/química , Proteínas y Péptidos Salivales/análisis , Proteínas y Péptidos Salivales/metabolismo , Biomarcadores/análisis , Glucemia/metabolismo , Estudios de Casos y Controles , Neoplasias del Sistema Nervioso Central/metabolismo , Neoplasias del Sistema Nervioso Central/terapia , Niño , Estudios de Cohortes , Femenino , Humanos , Inmunoglobulina A/metabolismo , Insulina/metabolismo , Leucemia/metabolismo , Leucemia/terapia , Linfoma/metabolismo , Linfoma/terapia , Masculino , Neoplasias/metabolismo , Estudios Prospectivos , Valores de Referencia , Saliva/metabolismo , Sarcoma/metabolismo , Sarcoma/terapia , Tirotropina/metabolismo , Tiroxina/metabolismo , Triyodotironina/metabolismo , Urea/metabolismo , gamma-Glutamiltransferasa/metabolismoRESUMEN
Some 20 years ago c-Fos was identified as a member of the AP-1 family of inducible transcription factors (Angel and Karin in Biochim Biophys Acta 1072:129-157, 1991). More recently, an additional activity was described for this protein: it associates to the endoplasmic reticulum and activates the biosynthesis of phospholipids (Bussolino et al. in FASEB J 15:556-558, 2001), (Gil et al. in Mol Biol Cell 15:1881-1894, 2004), the quantitatively most important components of cellular membranes. This latter activity of c-Fos determines the rate of membrane genesis and consequently of growth in differentiating PC12 cells (Gil et al. in Mol Biol Cell 15:1881-1894, 2004). In addition, it has been shown that c-Fos is over-expressed both in PNS and CNS tumors (Silvestre et al. in PLoS One 5(3):e9544, 2010). Herein, it is shown that c-Fos-activated phospholipid synthesis is required to support membrane genesis during the exacerbated growth characteristic of brain tumor cells. Specifically blocking c-Fos-activated phospholipid synthesis significantly reduces proliferation of tumor cells in culture. Blocking c-Fos expression also prevents tumor progression in mice intra-cranially xeno-grafted human brain tumor cells. In NPcis mice, an animal model of the human disease Neurofibromatosis Type I (Cichowski and Jacks in Cell 104:593-604, 2001), animals spontaneously develop tumors of the PNS and the CNS, provided they express c-Fos (Silvestre et al. in PLoS One 5(3):e9544, 2010). Treatment of PNS tumors with an antisense oligonucleotide that specifically blocks c-Fos expression also blocks tumor growth in vivo. These results disclose cytoplasmic c-Fos as a new target for effectively controlling brain tumor growth.
Asunto(s)
Proliferación Celular/efectos de los fármacos , Neoplasias del Sistema Nervioso Central/patología , Neoplasias del Sistema Nervioso Periférico/patología , Fosfolípidos/biosíntesis , Proteínas Proto-Oncogénicas c-fos/metabolismo , Animales , Línea Celular Tumoral , Sistema Nervioso Central/metabolismo , Neoplasias del Sistema Nervioso Central/metabolismo , Retículo Endoplásmico/metabolismo , Humanos , Ratones , Oligonucleótidos Antisentido/metabolismo , Células PC12 , Neoplasias del Sistema Nervioso Periférico/metabolismo , RatasAsunto(s)
Antígenos CD/metabolismo , Moléculas de Adhesión Celular/metabolismo , Neoplasias del Sistema Nervioso Central/metabolismo , Neoplasias del Sistema Nervioso Central/patología , Epéndimo/patología , Glioma/metabolismo , Glioma/patología , Antígeno 12E7 , Adulto , Biomarcadores de Tumor/metabolismo , Transformación Celular Neoplásica/patología , Neoplasias del Sistema Nervioso Central/diagnóstico , Diagnóstico Diferencial , Glioma/diagnóstico , Humanos , Imagen por Resonancia Magnética , Masculino , Tercer Ventrículo/cirugía , Resultado del TratamientoRESUMEN
BACKGROUND: We have previously shown that the transcription factor c-Fos is also capable of associating to endoplasmic reticulum membranes (ER) and activating phospholipid synthesis. Herein we examined phospholipid synthesis status in brain tumors from human patients and from NPcis mice, an animal model of the human disease Neurofibromatosis Type 1 (NF1). PRINCIPAL FINDINGS: In human samples, c-Fos expression was at the limit of detection in non-pathological specimens, but was abundantly expressed associated to ER membranes in tumor cells. This was also observed in CNS of adult tumor-bearing NPcis mice but not in NPcis fos(-/-) KO mice. A glioblastoma multiforme and a malignant PNS tumor from a NF1 patient (MPNST) showed a 2- and 4- fold c-Fos-dependent phospholipid synthesis activation, respectively. MPNST samples also showed increased cell proliferation rates and abundant c-Fos expression. CONCLUSIONS: Results highlight a role of cytoplasmic c-Fos as an activator of phospholipid synthesis in events demanding high rates of membrane biogenesis as occurs for the exacerbated growth of tumors cells. They also disclose this protein as a potential target for controlling tumor growth in the nervous system.
Asunto(s)
Neoplasias del Sistema Nervioso Central/patología , Citoplasma/metabolismo , Proteínas Proto-Oncogénicas c-fos/biosíntesis , Animales , Encéfalo/metabolismo , Encéfalo/patología , Proliferación Celular , Neoplasias del Sistema Nervioso Central/metabolismo , Modelos Animales de Enfermedad , Retículo Endoplásmico/metabolismo , Genotipo , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neurofibromatosis 1/metabolismo , FosforilaciónRESUMEN
PURPOSE: Oral temozolomide is approved in many countries for malignant glioma and for melanoma in some countries outside the USA. This study evaluated the exposure equivalence and safety of temozolomide by intravenous infusion and oral administration. METHODS: Subjects with primary central nervous system malignancies (excluding central nervous system lymphoma) received 200 mg/m(2) of oral temozolomide on days 1, 2 and 5. On days 3 and 4, subjects received 150 mg/m(2) temozolomide either as a 90-min intravenous infusion on one day or by oral administration on an alternate day. RESULTS: Ratio of log-transformed means (intravenous:oral) of area under the concentration-time curve and maximum concentration of drug after dosing for temozolomide and 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide (MTIC) met exposure equivalence criteria (90% confidence interval = 0.8-1.25). Treatment-emergent adverse events were consistent with those reported previously in subjects with recurrent glioma treated with oral temozolomide, except for mostly mild and transient injection site reactions with intravenous administration. CONCLUSIONS: This study demonstrated an exposure equivalence of a 90-min intravenous infusion of temozolomide and an equivalent oral dose.
Asunto(s)
Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Dacarbazina/análogos & derivados , Administración Oral , Adulto , Anemia/inducido químicamente , Antineoplásicos Alquilantes/administración & dosificación , Antineoplásicos Alquilantes/efectos adversos , Antineoplásicos Alquilantes/farmacocinética , Área Bajo la Curva , Neoplasias del Sistema Nervioso Central/metabolismo , Estreñimiento/inducido químicamente , Estudios Cruzados , Dacarbazina/administración & dosificación , Dacarbazina/farmacocinética , Esquema de Medicación , Femenino , Cefalea/inducido químicamente , Humanos , Infusiones Intravenosas , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Náusea/inducido químicamente , Temozolomida , Equivalencia Terapéutica , Factores de Tiempo , Vómitos/inducido químicamenteRESUMEN
The role of prolactin (PRL) in the CNS remains uncertain. We evaluated the presence of hyperprolactinemia, intracellular prolactin (ICP), and prolactin receptor (PRL-R) in primary CNS tumors, and their relationship with cellular replication with a prospective cross-sectional study of 82 consecutive patients with primary CNS tumors admitted for neurosurgical resection between October 2003 and September 2005. Patients submitted to a questionnaire, and venous blood samples were obtained for measurement of serum PRL and TSH. Immunohistochemical analyses were performed to evaluate the presence of ICP, PRL-R, and Ki-67. Serum PRL levels ranged from 2 to 70 ng/ml, and hyperprolactinemia was detected in 25 cases (30.5%). ICP was detected in 18 patients (21.9%), in whom PRL ranged from 2 to 32 ng/ml. A positive correlation was found between PRL levels and the presence of ICP (Student's t test, P = 0.022). The PRL-R was observed immunohistochemically in 32 cases (39%). The frequencies of hyperprolactinemia, ICP, and PRL-R were similar across the several histological types of CNS tumors. Ki-67 index was similar in all groups. Hyperprolactinemia and intracellular presence of PRL and PRL-R were common findings in this population, suggesting a role for PRL in CNS tumor genesis.