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1.
Frontiers of Medicine ; (4): 551-561, 2021.
Article in English | WPRIM | ID: wpr-888745

ABSTRACT

Glioma is the most common lethal tumor of the human brain. The median survival of patients with primary World Health Organization grade IV glioma is only 14.6 months. The World Health Organization classification of tumors of the central nervous system categorized gliomas into lower-grade gliomas and glioblastomas. Unlike primary glioblastoma that usually develop de novo in the elderly, secondary glioblastoma enriched with an isocitrate dehydrogenase mutant typically progresses from lower-grade glioma within 5-10 years from the time of diagnosis. Based on various evolutional trajectories brought on by clonal and subclonal alterations, the evolution patterns of glioma vary according to different theories. Some important features distinguish the normal brain from other tissues, e.g., the composition of the microenvironment around the tumor cells, the presence of the blood-brain barrier, and others. The underlying mechanism of glioma recurrence and evolution patterns of glioma are different from those of other types of cancer. Several studies correlated tumor recurrence with tumor heterogeneity and the immune microenvironment. However, the detailed reasons for the progression and recurrence of glioma remain controversial. In this review, we introduce the different mechanisms involved in glioma progression, including tumor heterogeneity, the tumor microenvironment and drug resistance, and their pre-clinical implements in clinical trials. This review aimed to provide new insights into further clinical strategies for the treatment of patients with recurrent and secondary glioma.


Subject(s)
Aged , Brain Neoplasms/genetics , Drug Resistance , Glioblastoma , Glioma/genetics , Humans , Mutation , Neoplasm Recurrence, Local/drug therapy , Tumor Microenvironment
2.
Braz. j. med. biol. res ; 54(7): e10612, 2021. tab, graf
Article in English | LILACS | ID: biblio-1249314

ABSTRACT

Genomic studies have provided insights into molecular subgroups and oncogenic drivers of pediatric brain tumors (PBT) that may lead to novel therapeutic strategies. Participants of the cohort Pediatric Brain Tumor Atlas: CBTTC (CBTTC cohort), were randomly divided into training and validation cohorts. In the training cohort, Kaplan-Meier analysis and univariate Cox regression model were applied to preliminary screening of prognostic genes. The LASSO Cox regression model was implemented to build a multi-gene signature, which was then validated in the validation and CBTTC cohorts through Kaplan-Meier, Cox, and receiver operating characteristic curve (ROC) analyses. Also, gene set enrichment analysis (GSEA) and immune infiltrating analyses were conducted to understand function annotation and the role of the signature in the tumor microenvironment. An eight-gene signature was built, which was examined by Kaplan-Meier analysis, revealing that a significant overall survival difference was seen, either in the training or validation cohorts. The eight-gene signature was further proven to be independent of other clinic-pathologic parameters via the Cox regression analyses. Moreover, ROC analysis demonstrated that this signature owned a better predictive power of PBT prognosis. Furthermore, GSEA and immune infiltrating analyses showed that the signature had close interactions with immune-related pathways and was closely related to CD8 T cells and monocytes in the tumor environment. Identifying the eight-gene signature (CBX7, JADE2, IGF2BP3, OR2W6P, PRAME, TICRR, KIF4A, and PIMREG) could accurately identify patients' prognosis and the signature had close interactions with the immunodominant tumor environment, which may provide insight into personalized prognosis prediction and new therapies for PBT patients.


Subject(s)
Humans , Child , Brain Neoplasms/genetics , Gene Expression Profiling , Prognosis , Gene Expression Regulation, Neoplastic , Cell Cycle Proteins , Kaplan-Meier Estimate , Tumor Microenvironment , Polycomb Repressive Complex 1
3.
Arq. neuropsiquiatr ; 78(1): 34-38, Jan. 2020. graf
Article in English | LILACS | ID: biblio-1088980

ABSTRACT

Abstract Brain tumors are one of the most common causes of cancer-related deaths around the world. Angiogenesis is critical in high-grade malignant gliomas, such as glioblastoma multiforme. Objective: The aim of this study is to comparatively analyze the angiogenesis-related genes, namely VEGFA, VEGFB, KDR, CXCL8, CXCR1 and CXCR2 in LGG vs. GBM to identify molecular distinctions using datasets available on The Cancer Genome Atlas (TCGA). Methods: DNA sequencing and mRNA expression data for 514 brain lower grade glioma (LGG) and 592 glioblastoma multiforme (GBM) patients were acquired from The Cancer Genome Atlas (TCGA), and the genetic alterations and expression levels of the selected genes were analyzed. Results: We identified six distinct KDR mutations in the LGG patients and 18 distinct KDR mutations in the GBM patients, including missense and nonsense mutations, frame shift deletion and altered splice region. Furthermore, VEGFA and CXCL8 were significantly overexpressed within GBM patients. Conclusions: VEGFA and CXCL8 are important factors for angiogenesis, which are suggested to have significant roles during tumorigenesis. Our results provide further evidence that VEGFA and CXCL8 could induce angiogenesis and promote LGG to progress into GBM. These findings could be useful in developing novel targeted therapeutics approaches in the future.


Resumo Os tumores cerebrais são uma das causas mais comuns de mortes relacionadas ao câncer em todo o mundo. A angiogênese tem caráter crítico em gliomas malignos de alto grau, como o glioblastoma multiforme. Objetivo: O objetivo deste estudo foi analisar comparativamente os genes relacionados à angiogênese, VEGFA, VEGFB, KDR, CXCL8, CXCR1 e CXCR2 em GBG vs. GBM para identificar distinções moleculares usando conjuntos de dados disponíveis no The Cancer Genome Atlas (TCGA). Métodos: Os dados de sequenciamento de DNA e expressão de mRNA para 514 pacientes com glioma cerebral de baixo grau (GBG) e 592 pacientes com glioblastoma multiforme (GBM) foram adquiridos do TCGA e as alterações genéticas e os níveis de expressão dos genes selecionados foram analisados. Resultados: Identificamos seis mutações KDR distintas nos pacientes GBG e 18 mutações KDR distintas nos pacientes GBM, incluindo mutações missense e nonsense, exclusão de mudança de quadro e região de emenda alterada. Além disso, VEGFA e CXCL8 foram significativamente super-expressos nos pacientes com GBM. Conclusões: VEGFA e CXCL8 são fatores importantes para a angiogênese, os quais parecem ter um papel significativo durante a tumorigênese. Nossos resultados fornecem evidências adicionais de que o VEGFA e o CXCL8 podem induzir a angiogênese e promover o GBG a progredir no GBM. Esses achados podem ser úteis no desenvolvimento de novas abordagens terapêuticas direcionadas no futuro.


Subject(s)
Humans , Brain Neoplasms/genetics , Glioblastoma/genetics , Carcinogenesis/genetics , Glioma/genetics , Neovascularization, Pathologic/genetics , Reference Values , Gene Expression , Interleukin-8/analysis , Point Mutation/genetics , Glioblastoma/pathology , Receptors, Interleukin-8A/analysis , Receptors, Interleukin-8B/analysis , Vascular Endothelial Growth Factor Receptor-2/analysis , Vascular Endothelial Growth Factor A/analysis , Vascular Endothelial Growth Factor B/analysis , Glioma/pathology
4.
Rev. méd. Chile ; 147(11): 1487-1490, nov. 2019. graf
Article in Spanish | LILACS | ID: biblio-1094178

ABSTRACT

The 2016 WHO Classification of Tumours of the Central Nervous System incorporates a new diagnostic entity: the mutant diffuse midline glioma H3K27, a tumor with a characteristic location and special molecular biology. We report the case of a 51-year-old male patient with progressive diplopia. The imaging study showed a mesencephalic tumor; the stereotacic biopsy disclosed an Anaplastic Astrocytoma Isocitrate dehydrogenase (IDH) wild type. The molecular study concludes H3K27 mutation. The patient was treated with radiotherapy with concurrent and adjuvant chemotherapy (temozolomide) with partial recovery of the diplopia.


Subject(s)
Humans , Male , Middle Aged , Brain Neoplasms/genetics , Histones/genetics , Glioma/genetics , Mutation/genetics , Brain Neoplasms/pathology , Brain Neoplasms/diagnostic imaging , Magnetic Resonance Imaging , Biomarkers, Tumor , Genetic Markers , Neuroimaging , Glioma/pathology , Glioma/diagnostic imaging
5.
Arq. neuropsiquiatr ; 76(6): 393-398, June 2018. tab, graf
Article in English | LILACS | ID: biblio-950553

ABSTRACT

ABSTRACT Background Glioma, the most common primary malignant brain tumor in adults, is highly aggressive and associated with a poor prognosis. The objectives of this study were to evaluate the association of genetic polymorphisms related to angiogenesis and apoptosis with gliomas, as well as comorbidities, lifestyle, clinical profile, survival and response to treatment (temozolomide [TMZ] and radiotherapy [RT]) in patients with the disease. Methods In a total of 303 individuals, genotypes were performed by real-time PCR, and clinical data, lifestyle and comorbidities were obtained from medical records and questionnaires. The significance level was set at 5%. Results Smoking, alcohol consumption, systemic arterial hypertension, diabetes mellitus and body mass index prevailed among patients, compared to controls (p < 0.05). The heterozygous genotype rs1468727 (T/C) and the homozygous genotype rs2010963 (G/G) (p > 0.05) were observed in both groups. Lifestyle and comorbidities showed independent risk factors for the disease (p < 0.0001, p = 0.0069, p = 0.0394, respectively). Patients with low-grade gliomas had a survival rate of 80.0 ± 1.7% in three years. For the combination of TMZ+RT, survival was 78.7 ± 7.6% in 20 months, compared to TMZ only (21.9 ± 5.1%, p = 0.8711). Conclusions Genetic variants were not associated with gliomas. Specific lifestyle habits and comorbidities stood out as independent risk factors for the disease. Low-grade gliomas showed an increase in patient survival with TMZ+RT treatment.


RESUMO Introdução Glioma, tumor cerebral maligno, é altamente agressivo e associado a mau prognóstico. Os objetivos deste estudo foram avaliar a associação de polimorfismos genéticos relacionados a angiogênese e apoptose em pacientes com glioma, bem como suas comorbidades, hábitos de vida, perfil clínico, sobrevida e resposta ao tratamento (temozolomida [TMZ] e radioterapia [RT]). Métodos 303 indivíduos foram genotipados por PCR em tempo real, e foram coletados dados clínicos, hábitos de vida e comorbidades. Admitiu-se nível de significância para valor p < 0,05. Resultados Tabagismo, elitismo, hipertensão arterial sistêmica, diabetes mellitus e índice de massa corporal prevaleceram entre os pacientes, comprados aos controles (p < 0,05). O genótipo heterozigoto rs1468727 (T/C) e homozigoto rs2010963 (G/G) (p > 0,05) foram observados em ambos os grupos. Tabagismo, elitismo, hipertensão arterial sistêmica, diabetes mellitus e índice de massa corporal apresentaram fatores de risco independentes para a doença (p < 0.0001, p = 0.0069, p = 0.0394, respectivamente). Os pacientes com gliomas de baixo grau apresentaram sobrevida de 80,0 ± 1,7% em três anos. Para a combinação de RT e TMZ, a sobrevida foi de 78,7±7,6% em 20 meses, em comparação com TMZ (21,9 ± 5,1%, p = 0,8711). Conclusões As variantes genéticas não estiveram associadas aos gliomas. Hábitos de vida e comorbidades específicas destacaram-se como fatores de risco independentes para a doença. O tratamento com TMZ + RT mostrou aumento na sobrevida dos pacientes.


Subject(s)
Humans , Male , Female , Infant , Child, Preschool , Child , Adolescent , Adult , Middle Aged , Aged , Aged, 80 and over , Young Adult , Polymorphism, Genetic/genetics , Brain Neoplasms/genetics , Apoptosis/genetics , Glioma/genetics , Brain Neoplasms/pathology , Brain Neoplasms/therapy , Combined Modality Therapy , Antineoplastic Agents, Alkylating/administration & dosage , Dacarbazine/administration & dosage , Dacarbazine/analogs & derivatives , Kaplan-Meier Estimate , Real-Time Polymerase Chain Reaction , Temozolomide , Genotype , Glioma/pathology , Glioma/therapy , Life Style , Neovascularization, Pathologic
6.
Rev. méd. Chile ; 146(1): 7-14, ene. 2018. tab, graf
Article in Spanish | LILACS | ID: biblio-902616

ABSTRACT

Background: Patients with Glioblastoma multiforme (GBM) have a five years survival of less than 5%, but the response to chemotherapy with alkylating agents can vary depending on the methylation status of O6-methylguanine-DNA-methyltransferase (MGMT). Genetic testing has limitations for routine use, while immunohistochemistry (IHC) offers a fast and affordable technique but with heterogeneous results in the literature. Aim: To evaluate MGMT expression by IHC in tumor tissue of Chilean patients with GBM. Material and Methods: Tumor samples of 29 patients with a pathological diagnosis of GBM were studied. We performed IHC staining and manual analysis of positive and negative cells for MGMT expression. A cut-off of at least 10% of cells expressing MGMT was used. Demographic and clinical features of patients were obtained from clinical records. Results: The median number of cells counted per case was 692 (interquartile range [IQR] 492-928). Fifteen cases (52%) were positive for MGMT expression. Median overall survival was 5.3 months (IQR 3.4-12-8). The effect of MGMT expression on the therapeutic response was not studied since only 3 patients received chemotherapy. Conclusions: Our results are similar to international reports, but we were not able to determine the association between MGMT expression and therapeutic response.


Subject(s)
Humans , Male , Female , Adult , Middle Aged , Aged , Brain Neoplasms/enzymology , Biomarkers, Tumor/metabolism , Glioblastoma/enzymology , O(6)-Methylguanine-DNA Methyltransferase/metabolism , Prognosis , Brain Neoplasms/genetics , Immunohistochemistry , Biomarkers, Tumor , Gene Expression Regulation, Neoplastic , Chile , Survival Rate , Retrospective Studies , Glioblastoma/genetics , O(6)-Methylguanine-DNA Methyltransferase/genetics
7.
Arq. neuropsiquiatr ; 75(12): 875-880, Dec. 2017. graf
Article in English | LILACS | ID: biblio-888280

ABSTRACT

ABSTRACT Glioblastoma (GBM) is the most malignant glioma and represents 29% of all brain tumors. Tumorigenesis is intimately connected with characteristics acquired in the physiologic pathway of cellular death. Objective: In the present study, the expression of anti-apoptotic (XIAP and Bcl-2) and apoptotic (cytochrome C, caspase 9, APAF-1), caspase 3 and the Smac/DIABLO genes related to the apoptosis pathway were evaluated in 30 samples of glioblastoma. Methods: The gene expression was evaluated in 30 glioblastomas (WHO grade IV) and compared to 10 white matter control samples with real-time PCR. Results and Conclusion: There were higher expressions of XIAP (p = 0.0032) and Bcl-2 (p = 0.0351) in the glioblastoma samples compared to the control samples of normal brain. These results raise the question of whether Bcl-2 and XIAP genes can be responsible for the inhibition of programmed cell death in glioblastomas. Moreover, they provide additional information capable of allowing the development of new target therapy strategies.


RESUMO O glioblastoma (GBM) é o glioma mais maligno e representa 29% de todos os tumores cerebrais. A tumorigênese está intimamente ligada à características adquiridas na via fisiológica de morte celular. Objetivo: Avaliar a expressão de genes anti-apoptóticos (XIAP e Bcl-2) e apoptóticos (citocromo C, a caspase 9, APAF-1), caspase 3 e SMAC/DIABLO, relacionados à apoptose, em 30 amostras de tecido de pacientes com glioblastoma. Métodos: A expressão gênica foi avaliada em trinta glioblastomas e comparada a dez amostras controles de substância branca por PCR em tempo real. Resultados e Conclusão: Houve maior nível de expressão de XIAP (p = 0,0032) e Bcl-2 (p = 0,0351) em comparação com as amostras controle, de cérebro normal. Estes resultados levantam a questão de que os genes Bcl-2 e XIAP podem ser responsáveis pela inibição da morte celular programada em glioblastomas, além disso, proporcionam informação adicional capaz de permitir o desenvolvimento de novas estratégias de terapia alvo.


Subject(s)
Humans , Male , Female , Middle Aged , Brain Neoplasms/metabolism , Gene Expression Regulation, Neoplastic , Apoptosis , Glioblastoma/metabolism , Proto-Oncogene Proteins c-bcl-2/metabolism , X-Linked Inhibitor of Apoptosis Protein/metabolism , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Glioblastoma/genetics , Glioblastoma/pathology , Proto-Oncogene Proteins c-bcl-2/genetics , Cell Line, Tumor , X-Linked Inhibitor of Apoptosis Protein/genetics , Real-Time Polymerase Chain Reaction
8.
An. bras. dermatol ; 91(5,supl.1): 98-100, Sept.-Oct. 2016. tab, graf
Article in English | LILACS | ID: biblio-837940

ABSTRACT

Abstract The occurrence of multiple primary melanomas in a single individual is rare. Most commonly, malignant melanocytic lesions subsequent to the initial diagnosis of melanoma are secondary cutaneous metastases. We report a patient with gastrointestinal bleeding from gastric metastasis of cutaneous melanoma. During clinical evaluation and staging, we discovered a brain metastasis associated with 3 synchronous primary cutaneous melanomas. We suggest the research on the mutation in the cyclin-dependent kinase inhibitor 2A (CDKN2A) (INK4a) in such cases. We also emphasize the importance of clinical examination and dermoscopy of the entire tegument, even after a malignant melanocytic lesion is identified.


Subject(s)
Humans , Aged , Skin Neoplasms/pathology , Stomach Neoplasms/secondary , Brain Neoplasms/secondary , Melanoma/secondary , Neoplasms, Multiple Primary/pathology , Skin Neoplasms/genetics , Stomach Neoplasms/genetics , Biopsy , Brain Neoplasms/genetics , Dermoscopy , Cyclin-Dependent Kinase Inhibitor p18/genetics , Melanoma/genetics , Mutation , Neoplasms, Multiple Primary/genetics
9.
Biol. Res ; 49: 1-10, 2016. ilus, graf
Article in English | LILACS | ID: biblio-950860

ABSTRACT

BACKGROUND: Glioblastoma is one of the most aggressive cancers of the brain. Malignant traits of glioblastoma cells include elevated migration, proliferation and survival capabilities. Galectins are unconventionally secreted glycan-binding proteins that modulate processes of cell adhesion, migration, proliferation and apoptosis by interacting with beta-galactosides of cell surface glycoproteins and the extracellular matrix. Galectin-8 is one of the galectins highly expressed in glioblastoma cells. It has a unique selectivity for terminally sialylated glycans recently found enhanced in these highly malignant cells. A previous study in glioblastoma cell lines reported that Gal-8 coating a plastic surface stimulates two-dimensional motility. Because in other cells Gal-8 arrests proliferation and induces apoptosis, here we extend its study by analyzing all of these processes in a U87 glioblastoma cell mode.l METHODS: We used immunoblot and RT-PCR for Gal-8 expression analysis, recombinant Gal-8 produced in a bacteria system for Gal-8 treatment of the cells, and shRNA in lentivirus transduction for Gal-8 silencing. Cell migration as assessed in transwell filters. Cell proliferation, cell cycle and apoptosis were analyzed by FACS. RESULTS: Gal-8 as a soluble stimulus triggered chemotactic migration of U87 cells across the polycarbonate filter of transwell chambers, almost as intensively as fetal bovine serum. Unexpectedly, Gal-8 also enhanced U87 cell growth. Co-incubation of Gal-8 with lactose, which blocks galectin-glycan interactions, abrogated both effects. Immunoblot showed Gal-8 in conditioned media reflecting its secretion. U87 cells transduced with silencing shRNA in a lentiviral vector expressed and secreted 30-40 % of their normal Gal-8 levels. These cells maintained their migratory capabilities, but decreased their proliferation rate and underwent higher levels of apoptosis, as revealed by flow cytometry analysis of cell cycle, CFSE and activated caspase-3 staining. Proliferation seemed to be more sensitive than migration to Gal-8 expression levels. CONCLUSIONS: Gal-8, either secreted or exogenously enriched in the media, and acting through extracellular glycan interactions, constitutes a strong stimulus of directional migration in glioblastoma U87 cells and for the first time emerges as a factor that promotes proliferation and prevents apoptosis in cancerous cells. These properties could potentially contribute to the exaggerated malignancy of glioblastoma cells.


Subject(s)
Humans , Animals , Cattle , Brain Neoplasms/pathology , Glioblastoma/pathology , Galectins/physiology , Time Factors , Brain Neoplasms/genetics , Tumor Cells, Cultured , Cell Movement/physiology , Apoptosis/physiology , Glioblastoma/genetics , Reverse Transcriptase Polymerase Chain Reaction , Galectins/analysis , Galectins/pharmacology , Galectin 1/analysis , Galectin 1/physiology , Galectin 3/analysis , Galectin 3/physiology , Cell Line, Tumor , Cell Proliferation/physiology , Flow Cytometry/methods
10.
JABHS-Journal of the Arab Board of Health Specializations. 2013; 14 (3): 11-17
in English, Arabic | IMEMR | ID: emr-139587

ABSTRACT

The aim of this study was to evaluate the frequency of immunohistochemical [IHC] expression of p53 protein in different types of glioma in Mosul city, and to correlate p53 expression with the histological types and grades of gliomas, and compare the results of this study with those of others. This study was performed on 50 cases of glioma. Samples were obtained in a prospective and retrospective fashion [cross-sectional study]. The samples were collected during the period extending from October 2010 to May 2011. All cases were obtained from Al-Jamhuri Teaching Hospital in Mosul city, Northen Iraq and some private laboratories. Typing and grading of the glioma were done according to World Health Organization [WHO] classification system. P53 expression was assessed immunohistochemically. Fifty cases of gliomas were collected; they included 37 cases of astrocytoms, 8 ependymoma 4 oligodendrogliomas and 1 oligoastrocytoma. p53 expression was detected in 25 cases ofglioma [50%]. The positive cases included 59.45% ofastrocytomas, 50% of oligodendrogliomas, and one case of oligoastrocytoma which was positive also. On the other hand, all of the ependymomas were negative for p53 protein. p53 was significantly related to the grades of glioma, but not significantly related to the type ofglioma. P53 expression was expressed in 50% of gliomas in Mosul city. P53 expression is common among high grade astrocytomas and mixed gliomas, less among oligodendrogliomas, and lacking in cases of ependymomas. Statistically, p53 expression was not significantly correlated with the type of glioma. p53 index is directly correlated with the grade of glioma, and so it is of prognostic value


Subject(s)
Humans , Glioma/genetics , Astrocytoma/genetics , Gene Expression , Base Sequence , Brain Neoplasms/genetics , Mutation , Glioblastoma/genetics , DNA, Neoplasm , Genes, p53
11.
Article in English | WPRIM | ID: wpr-131294

ABSTRACT

Malignant glioma is the most frequent type in brain tumors. The prognosis of this tumor has not been significantly improved for the past decades and the average survival of patients is less than one year. Thus, an effective novel therapy is urgently needed. TNF-related apoptosis inducing ligand (TRAIL), known to have tumor cell-specific killing activity, has been investigated as a novel therapeutic for cancers. We have developed Ad-stTRAIL, an adenovirus delivering secretable trimeric TRAIL for gene therapy and demonstrated the potential to treat malignant gliomas. Currently, this Ad-stTRAIL gene therapy is under phase I clinical trial for malignant gliomas. Here, we report preclinical studies for Ad-stTRAIL carried out using rats. We delivered Ad-stTRAIL intracranially and determined its pharmacokinetics and biodistribution. Most Ad-stTRAIL remained in the delivered site and the relatively low number of viral genomes was detected in the opposite site of brain and cerebrospinal fluid. Similarly, only small portion of the viral particles injected was found in the blood plasma and major organs and tissues, probably due to the brain-blood barrier. Multiple administrations did not lead to accumulation of Ad-stTRAIL at the injection site and organs. Repeated delivery of Ad-stTRAIL did not show any serious side effects. Our data indicate that intracranially delivered Ad-stTRAIL is a safe approach, demonstrating the potential as a novel therapy for treating gliomas.


Subject(s)
Adenoviridae/genetics , Animals , Blood-Brain Barrier , Brain/drug effects , Brain Neoplasms/genetics , Clinical Trials, Phase I as Topic , DNA, Viral/metabolism , Disease Models, Animal , Drug Delivery Systems , Drug Evaluation, Preclinical , Genetic Therapy , Glioma/genetics , Humans , Liver/drug effects , Protein Multimerization/genetics , Rats , Spleen/drug effects , TNF-Related Apoptosis-Inducing Ligand/genetics
12.
Article in English | WPRIM | ID: wpr-131291

ABSTRACT

Malignant glioma is the most frequent type in brain tumors. The prognosis of this tumor has not been significantly improved for the past decades and the average survival of patients is less than one year. Thus, an effective novel therapy is urgently needed. TNF-related apoptosis inducing ligand (TRAIL), known to have tumor cell-specific killing activity, has been investigated as a novel therapeutic for cancers. We have developed Ad-stTRAIL, an adenovirus delivering secretable trimeric TRAIL for gene therapy and demonstrated the potential to treat malignant gliomas. Currently, this Ad-stTRAIL gene therapy is under phase I clinical trial for malignant gliomas. Here, we report preclinical studies for Ad-stTRAIL carried out using rats. We delivered Ad-stTRAIL intracranially and determined its pharmacokinetics and biodistribution. Most Ad-stTRAIL remained in the delivered site and the relatively low number of viral genomes was detected in the opposite site of brain and cerebrospinal fluid. Similarly, only small portion of the viral particles injected was found in the blood plasma and major organs and tissues, probably due to the brain-blood barrier. Multiple administrations did not lead to accumulation of Ad-stTRAIL at the injection site and organs. Repeated delivery of Ad-stTRAIL did not show any serious side effects. Our data indicate that intracranially delivered Ad-stTRAIL is a safe approach, demonstrating the potential as a novel therapy for treating gliomas.


Subject(s)
Adenoviridae/genetics , Animals , Blood-Brain Barrier , Brain/drug effects , Brain Neoplasms/genetics , Clinical Trials, Phase I as Topic , DNA, Viral/metabolism , Disease Models, Animal , Drug Delivery Systems , Drug Evaluation, Preclinical , Genetic Therapy , Glioma/genetics , Humans , Liver/drug effects , Protein Multimerization/genetics , Rats , Spleen/drug effects , TNF-Related Apoptosis-Inducing Ligand/genetics
14.
Clinics ; 66(10): 1747-1755, 2011. ilus, graf, tab
Article in English | LILACS | ID: lil-601909

ABSTRACT

OBJECTIVES: 1) To correlate the methylation status of the O6-methylguanine-DNA-methyltransferase (MGMT) promoter to its gene and protein expression levels in glioblastoma and 2) to determine the most reliable method for using MGMT to predict the response to adjuvant therapy in patients with glioblastoma. BACKGROUND: The MGMT gene is epigenetically silenced by promoter hypermethylation in gliomas, and this modification has emerged as a relevant predictor of therapeutic response. METHODS: Fifty-one cases of glioblastoma were analyzed for MGMT promoter methylation by methylation-specific PCR and pyrosequencing, gene expression by real time polymerase chain reaction, and protein expression by immunohistochemistry. RESULTS: MGMT promoter methylation was found in 43.1 percent of glioblastoma by methylation-specific PCR and 38.8 percent by pyrosequencing. A low level of MGMT gene expression was correlated with positive MGMT promoter methylation (p = 0.001). However, no correlation was found between promoter methylation and MGMT protein expression (p = 0.297). The mean survival time of glioblastoma patients submitted to adjuvant therapy was significantly higher among patients with MGMT promoter methylation (log rank = 0.025 by methylation-specific PCR and 0.004 by pyrosequencing), and methylation was an independent predictive factor that was associated with improved prognosis by multivariate analysis. DISCUSSION AND CONCLUSION: MGMT promoter methylation status was a more reliable predictor of susceptibility to adjuvant therapy and prognosis of glioblastoma than were MGMT protein or gene expression levels. Methylation-specific polymerase chain reaction and pyrosequencing methods were both sensitive methods for determining MGMT promoter methylation status using DNA extracted from frozen tissue.


Subject(s)
Adolescent , Adult , Aged , Female , Humans , Male , Middle Aged , Brain Neoplasms/genetics , DNA Modification Methylases/genetics , DNA Repair Enzymes/genetics , Glioblastoma/genetics , Promoter Regions, Genetic/genetics , Tumor Suppressor Proteins/genetics , Brain Neoplasms/metabolism , DNA Methylation , DNA Modification Methylases/metabolism , DNA Repair Enzymes/metabolism , Gene Expression , Glioblastoma/metabolism , Immunohistochemistry , Kaplan-Meier Estimate , Polymerase Chain Reaction , Predictive Value of Tests , Prognosis , Statistics, Nonparametric , Time Factors , Tumor Suppressor Proteins/metabolism
15.
Yonsei Medical Journal ; : 633-640, 2010.
Article in English | WPRIM | ID: wpr-46868

ABSTRACT

At this time, brain tumor stem cells remain a controversial hypothesis while malignant brain tumors continue to present a dire prognosis of severe morbidity and mortality. Yet, brain tumor stem cells may represent an essential cellular target for glioma therapy as they are postulated to be the tumorigenic cells responsible for recurrence. Targeting oncogenic pathways that are essential to the survival and growth of brain tumor stem cells represents a promising area for developing therapeutics. However, due to the multiple oncogenic pathways involved in glioma, it is necessary to determine which pathways are the essential targets for therapy. Furthermore, research still needs to comprehend the morphogenic processes of cell populations involved in tumor formation. Here, we review research and discuss perspectives on models of glioma in order to delineate the current issues in defining brain tumor stem cells as therapeutic targets in models of glioma.


Subject(s)
Phosphatidylinositol 3-Kinase/genetics , Animals , Brain Neoplasms/genetics , Glioma/genetics , Humans , Neoplastic Stem Cells/metabolism , Receptors, Notch/genetics , Signal Transduction/genetics
16.
Säo Paulo med. j ; 127(5): 288-294, Sept. 2009. ilus, tab
Article in English | LILACS | ID: lil-538382

ABSTRACT

Context and objective: Genetic investigation of central nervous system (CNS) tumors provides valuable information about the genes regulating proliferation, differentiation, angiogenesis, migration and apoptosis in the CNS. The aim of our study was to determine the prevalence of genetic polymorphisms (codon 31 and 3' untranslated region, 3'UTR) and protein expression of the cyclin-dependent kinase inhibitor 1A (CDKN1A) gene in patients with and without CNS tumors. Design and setting: Analytical cross-sectional study with a control group, at the Molecular Biology Laboratory, Pediatric Oncology Department, Hospital das Clínicas de Ribeirão Preto. Methods: 41 patients with CNS tumors and a control group of 161 subjects without cancer and paires for sex, age and ethnicity were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Protein analysis was performed on 36 patients with CNS tumors, using the Western Blotting technique. Results: The frequencies of the heterozygote (Ser/Arg) and polymorphic homozygote (Arg/Arg) genotypes of codon 31 in the control subjects were 28.0 percent and 1.2 percent, respectively. However, the 3'UTR site presented frequencies of 24.2 percent (C/T) and 0.6 percent (T/T). These frequencies were not statistically different (P > 0.05) from those seen in the patients with CNS tumors (19.4 percent and 0.0 percent, codon 31; 15.8 percent and 2.6 percent, 3'UTR site). Regarding the protein expression in ependymomas, 66.67 percent did not express the protein CDKN1A. The results for medulloblastomas and astrocytomas were similar: neither of them expressed the protein (57.14 percent and 61.54 percent, respectively). Conclusion: No significant differences in protein expression patterns or polymorphisms of CDKN1A in relation to the three types of CNS tumors were observed among Brazilian subjects.


Contexto e objetivo: A investigação genética dos tumores do sistema nervoso central (SNC) provê valiosa informação sobre os genes que regulam a proliferação, diferenciação, angiogênese, migração e apoptose. O objetivo deste estudo é determinar a prevalência entre os polimorfismos genéticos (códon 31 e da região 3' não traduzida, 3'UTR) e a expressão protéica do gene inibidor de quinase dependente de ciclina 1A (CDKN1A) em pacientes com e sem tumor do SNC. Tipo de estudo e local: Estudo transversal analítico com grupo controle, desenvolvido no Laboratório de Biologia Molecular do Departamento de Oncologia Pediátrica do Hospital das Clínicas de Ribeirão Preto. Métodos: 41 pacientes com tumor do SNC e um grupo controle de 161 indivíduos sem câncer pareados por idade, sexo e etnia foram genotipados mediante uma reação de polimorfismo no comprimento de fragmentos de restrição (RFLP). A análise das proteínas foi realizada em 36 pacientes com tumor de SNC mediante Western Blotting. Resultados: A frequência do genótipo heterozigoto (Ser/Arg) e do homozigoto polimórfico (Arg/Arg) do códon 31 nos controles foi 28,0 por cento e 1,2 por cento, respectivamente. Entretanto, o sítio 3'UTR apresentou uma frequência de 24,2 por cento (C/T) e 0,6 por cento (T/T). Estas frequências não são significativamente diferentes (P > 0,05) daquelas observadas no grupo dos pacientes com tumor de SNC (19,4 por cento e 0,0 por cento, códon 31; 15,8 por cento e 2,6 por cento, sítio 3'UTR). Com respeito à expressão protéica, nos ependimomas, 66,67 por cento não expressaram a proteína CDKN1A. Estes resultados foram similares entre os meduloblastomas e os astrocitomas, os quais não expressaram a proteína com 57,14 por cento e 61,54 por cento, respectivamente. Conclusão: Não foram encontradas diferenças significativas entre o padrão de expressão protéica, polimorfismos de CDKN1A e os três tipos de tumores de SNC em indivíduos brasileiros.


Subject(s)
Adolescent , Child , Child, Preschool , Female , Humans , Infant , Male , Young Adult , Brain Neoplasms/genetics , /genetics , Neoplasm Proteins/genetics , Polymorphism, Genetic/genetics , /genetics , Brain Neoplasms/metabolism , Codon/genetics , /metabolism , Epidemiologic Methods , Neoplasm Proteins/metabolism , Young Adult
17.
Indian J Cancer ; 2009 Apr-Jun; 46(2): 108-19
Article in English | IMSEAR | ID: sea-50507

ABSTRACT

In recent years, there has been a marked improvement in our understanding of molecular genetics of gliomas. These advancements offer hope for development of tailored therapies targeting a tumor's unique molecular profile, and may also translate into improved classification and identification of newer prognostic markers. This review focuses on the neuropathological features of different types of glial neoplasms according to the World Health Organization classification, and the recent advances in their molecular biology with emphasis on the genetic mechanisms underlying tumor progression, diagnostic and prognostic markers and potential therapeutic targets.


Subject(s)
Astrocytoma/genetics , Astrocytoma/pathology , Brain Neoplasms/classification , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Gene Deletion , Glioma/classification , Glioma/genetics , Glioma/pathology , Humans , Oligodendroglioma/genetics , Oligodendroglioma/pathology , Prognosis
18.
Indian J Cancer ; 2009 Apr-Jun; 46(2): 88-95
Article in English | IMSEAR | ID: sea-50345

ABSTRACT

Primary malignant brain tumors account for only 2% of all adult cancers but they cause a disproportionately high cancer-related disability and death. Survival of malignant glioma patients has changed only modestly over the past three decades despite the emergence of new treatment strategies for these tumors. In this review, we describe the standard treatment modalities for malignant glioma, which include surgery, radiation therapy and chemotherapy, as well as the status of novel therapies that have been developed to target various aspects of glioma cell biology. We also address this issue of drug delivery as a factor limiting the efficacy of systemic administration of therapeutics and attempts to overcome this barrier. Further progress towards a cure for malignant gliomas will require a greater understanding of the underlying mechanisms driving the growth, and resistance to therapy, of these challenging tumors.


Subject(s)
Astrocytoma/genetics , Astrocytoma/pathology , Brain Neoplasms/classification , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Gene Deletion , Glioma/classification , Glioma/genetics , Glioma/pathology , Humans , Oligodendroglioma/genetics , Oligodendroglioma/pathology , Prognosis
19.
Neurol India ; 2008 Oct-Dec; 56(4): 456-62
Article in English | IMSEAR | ID: sea-121664

ABSTRACT

AIMS: The involvement of various growth factors, growth factor receptors and proliferative markers in the molecular pathogenesis of astrocytic neoplasms are being studied extensively. Epidermal Growth Factor Receptor (EGFR) gene overexpression occurs in nearly 50% of cases of glioblastoma. Since EGFR and proliferating cell nuclear antigen (PCNA) are involved in mitogenic signal transduction and cellular proliferation pathway, we have studied the correlation between the expression of EGFR and PCNA labeling index in astrocytic tumors. MATERIALS AND METHODS: We investigated the immunohistochemical expression of EGFR and PCNA using the appropriate monoclonal antibodies in 40 cases of astrocytic tumors of which 21 cases were glioblastoma, eight cases were Grade III or anaplastic astrocytomas and six cases were Grade II or diffuse astrocytomas and five cases were Grade I or pilocytic astrocytomas. RESULTS: Both the EGFR expression and PCNA labeling index increase with increasing grades of astrocytomas with a significantly high percentage of cells showing positive staining for both EGFR and PCNA in GBM and Grade III astrocytomas compared to Grade II astrocytomas. The expression levels of both EGFR and PCNA were low in Grade I or pilocytic astrocytomas. CONCLUSIONS: A significant correlation was found between EGFR overexpression and PCNA labeling index in Grade III and Grade II astrocytomas and glioblastoma. These suggest that the tumor proliferation, at least in higher grades of astrocytomas is dependent in some measure on EGF and EGFR-related signaling pathways.


Subject(s)
Adult , Aged , Astrocytoma/genetics , Brain Neoplasms/genetics , Female , Humans , Immunohistochemistry , Male , Middle Aged , Proliferating Cell Nuclear Antigen/genetics , ErbB Receptors/genetics
20.
Yonsei Medical Journal ; : 301-310, 2008.
Article in English | WPRIM | ID: wpr-30670

ABSTRACT

PURPOSE: This investigation is intended to obtain differentially expressed genes related to human malignant glioma using Subtractive hybridization. MATERIALS AND METHODS: Subtractive hybridization is potentially faster methods for identifying differentially expressed genes associated with a particular disease state. We identified 7 over-expressed genes which were not homologous to any of the known genes in the Genbank(TM) database. RESULTS: Using semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR), the mRNA expression levels of these 7 genes were higher in human glioblastomas tissue than in non-tumor brain tissue. In order to learn more about the expression profile of these genes, RT-PCR was performed using various commercially available human carcinoma cell lines. Some of these new genes were over-expressed in human glioma cell line, but not the expressed in other human cancer cell line. CONCLUSION: Theses cloned new genes may play a role in brain tumorigenesis. Further studies including verification of oncogene, cancer protein, and glioblastoma induction in animal model are needed.


Subject(s)
Aged , Brain Neoplasms/genetics , Cell Line, Tumor , Female , Gene Expression Regulation, Neoplastic , Glioma/genetics , Humans , Male , Middle Aged , RNA, Messenger/genetics , Reverse Transcriptase Polymerase Chain Reaction , Up-Regulation/genetics
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