Metabolism and Brain Cancer

Cellular energy metabolism is one of the main processes affected during the transition from normal to cancer cells, and it is a crucial determinant of cell proliferation or cell death. As a support for rapid proliferation, cancer cells choose to use glycolysis even in the presence of oxygen (Warburg effect) to fuel macromolecules for the synthesis of nucleotides, fatty acids, and amino acids for the accelerated mitosis, rather than fuel the tricarboxylic acid cycle and oxidative phosphorylation. Mitochondria biogenesis is also reprogrammed in cancer cells, and the destiny of those cells is determined by the balance between energy and macromolecule supplies, and the efficiency of buffering of the cumulative radical oxygen species. In glioblastoma, the most frequent and malignant adult brain tumor, a metabolic shift toward aerobic glycolysis is observed, with regulation by well known genes as integrants of oncogenic pathways such as phosphoinositide 3-kinase/protein kinase, MYC, and hypoxia regulated gene as hypoxia induced factor 1. The expression profile of a set of genes coding for glycolysis and the tricarboxylic acid cycle in glioblastoma cases confirms this metabolic switch. An understanding of how the main metabolic pathways are modified by cancer cells and the interactions between oncogenes and tumor suppressor genes with these pathways may enlighten new strategies in cancer therapy. In the present review, the main metabolic pathways are compared in normal and cancer cells, and key regulations by the main oncogenes and tumor suppressor genes are discussed. Potential therapeutic targets of the cancer energetic metabolism are enumerated, highlighting the astrocytomas, the most common brain cancer

Polimorfismo no gene de metilenetetrahidrofolato redutase não está relacionado com o risco de doença cerebrovascular isquêmica em uma população brasileira

OBJETIVO: Os dados são conflitantes em relação a risco de acidente cerebrovascular associado a polimorfismo do gene 5,10-metilenetetrahidrofolato redutase C677T, o qual predispõe a hiperhomocisteinemia. Um estudo de meta-análise sugere que o genotipo 5,10-metilenetetrahidrofolato redutase 677TT poderia ter uma pequena influência em determinar susceptibilidade a acidente cerebrovascular. MÉTODOS: Analisamos este polimorfismo em indivíduos brasileiros com acidente cerebrovascular isquêmico, baseando-se em um estudo de caso-controle. RESULTADOS: Comparamos os genótipos 5,10-metilenetetrahidrofolato redutase em grupos de indivíduos com acidente cerebrovascular isquêmico (n=127) e controle normal (n=126), e encontramos Odds Ratio de 1,97 (IC 95% 0,84 - 4,64) em uma análise multivariada, na qual os resultados foram ajustados a características clínicas basais dos indivíduos estudados. DISCUSSÃO: Nossos estudos indicam que o genótipo 5,10-metilenetetrahidrofolato redutase C677T não é um fator de risco para acidente cerebrovascular isquêmico entre indivíduos brasileiros.PURPOSE: Data are conflicting concerning the risk for ischemic stroke associated with a common polymorphism in the gene encoding 5,10-methylenetetrahydrofolate reductase C677T, which predisposes carriers to hyperhomocysteinemia. A meta-analysis study suggested that the 5,10-methylenetetrahydrofolate reductase 677TT genotype might have a small influence in determining susceptibility to ischemic stroke. METHODS: We analyzed the 5,10-methylenetetrahydrofolate reductase 677TT genotype polymorphism in Brazilian subjects with ischemic stroke, using a case-control design. RESULTS: We compared 5,10-methylenetetrahydrofolate reductase genotypes in groups of subjects presenting ischemic stroke (n = 127) and normal control (n = 126) and found an odds ratio of 1.97 (95% CI, 0.84-4.64) in a multivariate analysis in which results were adjusted to baseline clinical characteristics of study participants. CONCLUSION: We found that the homozygous 5,10-methylenetetrahydrofolate reductase C677T genotype was not a risk factor for ischemic stroke in these Brazilian subjects

Xenograft Transplantation of Human Malignant Astrocytoma Cells Into Immunodeficient Rats: An Experimental Model of Glioblastoma

INTRODUCTION: Astrocytic gliomas are the most common intracranial central nervous system neoplasias, accounting for about 60% of all primary central nervous system tumors. Despite advances in the treatment of gliomas, no effective therapeutic approach is yet available; hence, the search for a more realistic model to generate more effective therapies is essential. OBJECTIVE: To develop an experimental malignant astrocytoma model with the characteristics of the human tumor. METHOD: Primary cells from subcutaneous xenograft tumors produced with malignant astrocytoma U87MG cells were inoculated intracerebrally by stereotaxis into immunosuppressed (athymic) Rowett rats. RESULTS: All four injected animals developed non-infiltrative tumors, although other glioblastoma characteristics, such as necrosis, pseudopalisading cells and intense mitotic activity, were observed. CONCLUSION: A malignant astrocytoma intracerebral xenograft model with poorly invasive behavior was achieved in athymic Rowett rats. Tumor invasiveness in an experimental animal model may depend on a combination of several factors, including the cell line used to induce tumor formation, the rat strains and the status of the animal's immune system

Factors associated with serum CA19-9 levels among healthy children: a cross-sectional study

Abstract\ud \ud \ud \ud Background\ud CA19-9 is a tumor marker mainly used for biliary tract, pancreas and colorectum. Since the marker applies usually for adults, the normal range of serum CA19-9 among children has been rarely reported. This is the first study reporting the distribution of serum CA19-9 levels among cancer-free children as well as their parents, taking into account the Lewis and secretor gene polymorphism and physical growth.\ud \ud \ud \ud Methods\ud Study subjects were 972 apparently healthy Japanese Brazilians including 476 children aged from 1 to 19 years.\ud \ud \ud \ud Results\ud The comparisons in five-year age groups demonstrated that the mean values of serum CA19-9 was lower in the boys than in the girls, and higher in younger age groups; 22.5 U/ml for 1–4 year-old (n=13), 17.4 U/ml for 5–9 year-old (n=36), 15.5 U/ml for 10–14 year-old (n=96) and 10.2 U/ml for 15–19 year-old (n=74) in boys, and 25.3 U/ml (n=11), 27.1 U/ml (n=50), 17.7 U/ml (n=105) and 13.5 U/ml (n=59) in girls, respectively. The difference in those geometric means was statistically significant among four age groups (p=0.006, ANOVA adjusted for sex). After Lewis and secretor genotypes, which are definitive factors of serum CA19-9, were taken into account, geometric mean of serum CA19-9 was associated with any of BMI (p<0.001), height (p<0.001) and weight (p<0.001) among children excluding those with le/le genotype. The associations were still significant when age was adjusted.\ud \ud \ud \ud Conclusions\ud Serum CA19-9 values were higher among children than among adults, and influenced by sex, height, weight, and BMI even after the adjustment for age as well as Le and Se genotypes.This study was supported in part by a Grant-in-Aid for Scientific Research on Special Priority Areas of Cancer from the Japanese Ministry of Education, Culture, Sports, Science, and Technology. We are grateful to Ms. Yoko Mitsuda and Ms. Keiko Shibata for their technical assistance

Selection of suitable housekeeping genes for expression analysis in glioblastoma using quantitative RT-PCR

Background: Considering the broad variation in the expression of housekeeping genes among tissues and experimental situations, studies using quantitative RT-PCR require strict definition of adequate endogenous controls. for glioblastoma, the most common type of tumor in the central nervous system, there was no previous report regarding this issue.Results: Here we show that amongst seven frequently used housekeeping genes TBP and HPRT1 are adequate references for glioblastoma gene expression analysis. Evaluation of the expression levels of 12 target genes utilizing different endogenous controls revealed that the normalization method applied might introduce errors in the estimation of relative quantities. Genes presenting expression levels which do not significantly differ between tumor and normal tissues can be considered either increased or decreased if unsuitable reference genes are applied. Most importantly, genes showing significant differences in expression levels between tumor and normal tissues can be missed. We also demonstrated that the Holliday Junction Recognizing Protein, a novel DNA repair protein over expressed in lung cancer, is extremely over-expressed in glioblastoma, with a median change of about 134 fold.Conclusion: Altogether, our data show the relevance of previous validation of candidate control genes for each experimental model and indicate TBP plus HPRT1 as suitable references for studies on glioblastoma gene expression.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)FAEPA-FMRUniv São Paulo, Fac Med, Dept Surg & Anat, BR-14049090 Ribeirao Preto, SP, BrazilUniv São Paulo, Fac Med, Dept Cellular & Mol Biol, BR-14049090 Ribeirao Preto, SP, BrazilUniv São Paulo, Fac Med, Dept Pathol, BR-14049090 Ribeirao Preto, SP, BrazilUniversidade Federal de São Paulo, Dept Neurol & Neurosurg, BR-04023900 São Paulo, BrazilUniv São Paulo, Sch Med, Dept Neurol, BR-01246903 São Paulo, BrazilUniv São Paulo, Fac Med, Dept Pediat, BR-14049090 Ribeirao Preto, SP, BrazilUniversidade Federal de São Paulo, Dept Neurol & Neurosurg, BR-04023900 São Paulo, BrazilFAPESP: 04/12133-6FAPESP: 06/57602-9CNPq: 485342/2006Web of Scienc

Correlation of MGMT promoter methylation status with gene and protein expression levels in glioblastoma

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% of glioblastoma by methylation-specific PCR and 38.8% 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

IDH1 mutations in a Brazilian series of Glioblastoma

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Albert Einstein Jewish HospitalUniversidade de São Paulo Faculdade de Medicina Department of NeurologyUniversidade de São Paulo Faculdade de Medicina Department of PathologyCancer Institute of São PauloFundação Pio XII Barretos Cancer HospitalFederal University of São Paulo School of Medicine Department of NeurologyFederal University of São Paulo School of Medicine Department of PathologyNove de Julho HospitalAlbert Einstein Jewish HospitalUNIFESP, EPM, Department of NeurologyUNIFESP, EPM, Department of PathologyFAPESP: 04/12133-6SciEL

Frequent ATRX, CIC, FUBP1 and IDH1 mutations refine the classification of malignant gliomas

Mutations in the critical chromatin modifier ATRX and mutations in CIC and FUBP1, which are potent regulators of cell growth, have been discovered in specific subtypes of gliomas, the most common type of primary malignant brain tumors. However, the frequency of these mutations in many subtypes of gliomas, and their association with clinical features of the patients, is poorly understood. Here we analyzed these loci in 363 brain tumors. ATRX is frequently mutated in grade II-III astrocytomas (71%), oligoastrocytomas (68%), and secondary glioblastomas (57%), and ATRX mutations are associated with IDH1 mutations and with an alternative lengthening of telomeres phenotype. CIC and FUBP1 mutations occurred frequently in oligodendrogliomas (46% and 24%, respectively) but rarely in astrocytomas or oligoastrocytomas (&lt;10%). This analysis allowed us to define two highly recurrent genetic signatures in gliomas: IDH1/ATRX (I-A) and IDH1/CIC/FUBP1 (I-CF). Patients with I-CF gliomas had a significantly longer median overall survival (96 months) than patients with I-A gliomas (51 months) and patients with gliomas that did not harbor either signature (13 months). The genetic signatures distinguished clinically distinct groups of oligoastrocytoma patients, which usually present a diagnostic challenge, and were associated with differences in clinical outcome even among individual tumor types. In addition to providing new clues about the genetic alterations underlying gliomas, the results have immediate clinical implications, providing a tripartite genetic signature that can serve as a useful adjunct to conventional glioma classification that may aid in prognosis, treatment selection, and therapeutic trial design.American Cancer Society [RSG-10-126-01-CCE]American Cancer SocietyNCINCI [5R01-CA140316]Pediatric Brain Tumor Foundation Institute GrantPediatric Brain Tumor Foundation Institute GrantSoutheastern Brain Tumor Foundation GrantSoutheastern Brain Tumor Foundation GrantVoices Against Brain Cancer Foundation GrantVoices Against Brain Cancer Foundation GrantJames S. McDonnell Foundation GrantJames S. McDonnell Foundation GrantV FoundationV FoundationAccelerate Brain Cancer Cure Foundation GrantAccelerate Brain Cancer Cure Foundation GrantNIHNIH [5P50 NS20023, 5P50 CA108785, CA057345, CA129825, R37 011898]Sanofi-AventisSanofiAventi

Activation of Neural and Pluripotent Stem Cell Signatures Correlates with Increased Malignancy in Human Glioma

The presence of stem cell characteristics in glioma cells raises the possibility that mechanisms promoting the maintenance and self-renewal of tissue specific stem cells have a similar function in tumor cells. Here we characterized human gliomas of various malignancy grades for the expression of stem cell regulatory proteins. We show that cells in high grade glioma co-express an array of markers defining neural stem cells (NSCs) and that these proteins can fulfill similar functions in tumor cells as in NSCs. However, in contrast to NSCs glioma cells co-express neural proteins together with pluripotent stem cell markers, including the transcription factors Oct4, Sox2, Nanog and Klf4. In line with this finding, in high grade gliomas mesodermal- and endodermal-specific transcription factors were detected together with neural proteins, a combination of lineage markers not normally present in the central nervous system. Persistent presence of pluripotent stem cell traits could only be detected in solid tumors, and observations based on in vitro studies and xenograft transplantations in mice imply that this presence is dependent on the combined activity of intrinsic and extrinsic regulatory cues. Together these results demonstrate a general deregulated expression of neural and pluripotent stem cell traits in malignant human gliomas, and indicate that stem cell regulatory factors may provide significant targets for therapeutic strategies