Oligodendrogliomas are the second most common malignant brain tumor in adults and exhibit characteristic losses of chromosomes 1p and 19q. To identify the molecular genetic basis for this alteration, ...we performed exomic sequencing of seven tumors. Among other changes, we found that the CIC gene (homolog of the Drosophila gene capicua) on chromosome 19q was somatically mutated in six cases and that the FUBP1 gene encoding far-upstream element (FUSE) binding protein on chromosome 1p was somatically mutated in two tumors. Examination of 27 additional oligodendrogliomas revealed 12 and 3 more tumors with mutations of CIC and FUBP1, respectively, 58% of which were predicted to result in truncations of the encoded proteins. These results suggest a critical role for these genes in the biology and pathology of oligodendrocytes.
Metabolism and Brain Cancer Marie, Suely Kazue Nagahashi; Shinjo, Sueli Mieko Oba
Clinics (São Paulo, Brazil),
01/2011, Letnik:
66, Številka:
Suppl 1
Journal Article
Recenzirano
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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.
Introduction
In a recent study, we have shown that atorvastatin is clinically safe for dermatomyositis (DM) and antisynthetase syndrome (ASS) patients with dyslipidemia. Herein, we showed in an ...unprecedented way, the safety of atorvastatin on the muscular tissues of these patients.
Methods
Transcriptome analysis was performed on samples of the vastus lateralis muscle obtained at baseline and after 12 weeks of atorvastatin (20 mg/day) intervention in DM or ASS patients with dyslipidemia 6DM and 5ASS received atorvastatin, and 2DM and 3ASS received placebo. The results were analyzed considering differences in expression fold change before and after treatment. Histological and histochemical analyses were also performed.
Results
In both groups, no significant changes were observed in genes related to the mitochondrial, oxidative, insulin, lipid, and fibrogenic pathways. Histological analysis showed a slight variability in the fiber size that was preserved after the intervention. In addition, the mosaic of muscle fibers was preserved in the internal architecture of the fibers and all histological regions. No fiber necrosis or atrophy, focal failures, subsarcolemmal accumulation, lipids, areas of fibrosis, or alterations in mitochondrial activity were observed. All muscle fibers were labeled for MHC I.
Conclusion
Atorvastatin did not promote significant changes in the expression of genes related to mitochondrial, oxidative, insulin, lipid, and fibrogenic pathways in the muscle tissues of DM and ASS patients with dyslipidemia. Atorvastatin did not also promote histological and histochemical changes in muscle tissues. Our results reinforce the safety of the administration of atorvastatin to treat dyslipidemia in patients with DM and ASS.
Glioblastoma (GBM), the most frequent and aggressive brain tumor, is characterized by marked angiogenesis directly related to invasiveness and poor prognosis. Hypoxia is considered to be an important ...stimulus for angiogenesis by inducing hypoxia‐inducible factor 1‐alpha (HIF‐1α) overexpression that activates platelet‐derived growth factor (PDGF) and VEGF. The aim of this study is to analyze the expression of PDGF‐C, VEGF in endothelial and tumor cells of GBM and their relation to HIF‐1α expression. Two hundred and eight GBM cases were studied by tissue microarray immunohistochemical preparation. Expression of HIF‐1α, VEGF and PDGF‐C was observed in 184 (88.5%), 131 (63%) and 160 (76.9%) tumor cases, respectively. The numbers of vessels were quantified by CD34, PDGF‐C, VEGF and CD105 staining, and were in median 20, 16, 5 and 6, respectively. The GBMs that showed positive or negative expression for HIF‐1α showed a median vascular density of 30 and 14, respectively, for CD34 (P < 0.015). Positive expression for HIF‐1α was correlated with VEGF and PDGF‐C expression in tumors (P < 0.001). There was a significant correlation between VEGF and PDGF‐C expression in the cytoplasm of GBM tumor cells (P < 0.0001). We showed that VEGF expression in tumor cells was correlated with its expression in blood vessels (P < 0.0001). Endothelial cells with PDGF‐C and VEGF positive expression were also positive for CD105 and their nuclei for Ki‐67, confirming the neoangiogenic and proliferative influence of VEGF and PDGF‐C. VEGF nuclear staining in tumor cells (P = 0.002) as well as nuclear staining for HIF‐1α and VEGF (P = 0.005) correlated with survival. In summary, our present findings of the concomitant upregulation of PDGF‐C with VEGF in GBM tumor cells and vessels further reinforce the benefit of using combined anti‐angiogenic approaches to potentially improve the therapeutic response for GBM.
Toll-like receptors (TLRs) are the first to identify disturbances in the immune system, recognizing pathogens such as bacteria, fungi, and viruses. Since the inflammation process plays an important ...role in several diseases, TLRs have been considered potential therapeutic targets, including treatment for cancer. However, TLRs' role in cancer remains ambiguous. This study aims to analyze the expression levels of plasmatic cell membrane TLRs (TLR1, TLR2, TLR4, TLR5, and TLR6) in human astrocytomas the most prevalent tumors of CNS different grades (II-IV). We demonstrated that TLR expressions were higher in astrocytoma samples compared to non-neoplastic brain tissue. The gene and protein expressions were observed in GBM cell lines U87MG and A172, proving their presence in the tumor cells. Associated expressions between the known heterodimers TLR1-TLR2 were found in all astrocytoma grades. In GBMs, the mesenchymal subtype showed higher levels of TLR expressions in relation to classical and proneural subtypes. A strong association of TLRs with the activation of cell cycle process and signaling through canonical, inflammasome and ripoptosome pathways was observed by in silico analysis, further highlighting TLRs as interesting targets for cancer treatment.
Tumor cell infiltrative ability into surrounding brain tissue is a characteristic of diffusely infiltrative astrocytoma and is strongly associated with extracellular matrix (ECM) stiffness. Collagens ...are the most abundant ECM scaffolding proteins and contribute to matrix organization and stiffness. LOX family members, copper-dependent amine oxidases, participate in the collagen and elastin crosslinking that determine ECM tensile strength. Common IDH mutations in lower-grade gliomas (LGG) impact prognosis and have been associated with ECM stiffness. We analyzed the expression levels of LOX family members and matrisome-associated genes in astrocytoma stratified by malignancy grade and IDH mutation status. A progressive increase in expression of all five LOX family members according to malignancy grade was found. LOX, LOXL1, and LOXL3 expression correlated with matrisome gene expressions. LOXL1 correlations were detected in LGG with IDH mutation (IDHmut), LOXL3 correlations in LGG with IDH wild type (IDHwt) and strong LOX correlations in glioblastoma (GBM) were found. These increasing correlations may explain the increment of ECM stiffness and tumor aggressiveness from LGG-IDHmut and LGG-IDHwt through to GBM. The expression of the mechanosensitive transcription factor, β-catenin, also increased with malignancy grade and was correlated with LOXL1 and LOXL3 expression, suggesting involvement of this factor in the outside–in signaling pathway.
Glioblastoma (GBM) is an aggressive brain tumor that exhibits resistance to current treatment, making the identification of novel therapeutic targets essential. In this context, cellular prion ...protein (PrP
) stands out as a potential candidate for new therapies. Encoded by the PRNP gene, PrP
can present increased expression levels in GBM, impacting cell proliferation, growth, migration, invasion and stemness. Nevertheless, the exact molecular mechanisms through which PRNP/PrP
modulates key aspects of GBM biology remain elusive.
To elucidate the implications of PRNP/PrP
in the biology of this cancer, we analyzed publicly available RNA sequencing (RNA-seq) data of patient-derived GBMs from four independent studies. First, we ranked samples profiled by bulk RNA-seq as PRNP
and PRNP
and compared their transcriptomic landscape. Then, we analyzed PRNP
and PRNP
GBM cells profiled by single-cell RNA-seq to further understand the molecular context within which PRNP/PrP
might function in this tumor. We explored an additional proteomics dataset, applying similar comparative approaches, to corroborate our findings.
Functional profiling revealed that vesicular dynamics signatures are strongly correlated with PRNP/PrP
levels in GBM. We found a panel of 73 genes, enriched in vesicle-related pathways, whose expression levels are increased in PRNP
/PRNP
cells across all RNA-seq datasets. Vesicle-associated genes, ANXA1, RAB31, DSTN and SYPL1, were found to be upregulated in vitro in an in-house collection of patient-derived GBM. Moreover, proteome analysis of patient-derived samples reinforces the findings of enhanced vesicle biogenesis, processing and trafficking in PRNP
/PRNP
GBM cells.
Together, our findings shed light on a novel role for PrP
as a potential modulator of vesicle biology in GBM, which is pivotal for intercellular communication and cancer maintenance. We also introduce GBMdiscovery, a novel user-friendly tool that allows the investigation of specific genes in GBM biology.
Glioblastoma (GBM) is the most aggressive type of brain tumor, with an overall survival of 17 months under the current standard of care therapy. CD99, an over-expressed transmembrane protein in ...several malignancies, has been considered a potential target for immunotherapy. To further understand this potentiality, we analyzed the differential expression of its two isoforms in human astrocytoma specimens, and the CD99 involved signaling pathways in glioma model U87MG cell line. CD99 was also analyzed in GBM molecular subtypes. Whole transcriptomes by RNA-Seq of
-siRNA, and functional in vitro assays in
-shRNA, that are found in U87MG cells, were performed. Astrocytoma of different malignant grades and U87MG cells only expressed CD99 isoform 1, which was higher in mesenchymal and classical than in proneural GBM subtypes. Genes related to actin dynamics, predominantly to focal adhesion, and lamellipodia/filopodia formation were down-regulated in the transcriptome analysis, when
was silenced. A decrease in tumor cell migration/invasion, and dysfunction of focal adhesion, were observed in functional assays. In addition, a striking morphological change was detected in
-silenced U87MG cells, further corroborating CD99 involvement in actin cytoskeleton rearrangement. Inhibiting the overexpressed CD99 may improve resectability and decrease the recurrence rate of GBM by decreasing tumor cells migration and invasion.
Altered Telomeres in Tumors with ATRX and DAXX Mutations Heaphy, Christopher M.; de Wilde, Roeland F.; Jiao, Yuchen ...
Science (American Association for the Advancement of Science),
07/2011, Letnik:
333, Številka:
6041
Journal Article
Recenzirano
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The proteins encoded by ATRX and DAXX participate in chromatin remodeling at telomeres and other genomic sites. Because inactivating mutations of these genes are common in human pancreatic ...neuroendocrine tumors (PanNETs), we examined the telomere status of these tumors. We found that 61% of PanNETs displayed abnormal telomeres that are characteristic of a telomerase-independent telomere maintenance mechanism termed ALT (alternative lengthening of telomeres). All of the PanNETs exhibiting these abnormal telomeres had ATRX or DAXX mutations or loss of nuclear ATRX or DAXX protein. ATRX mutations also correlate with abnormal telomeres in tumors of the central nervous system. These data suggest that an alternative telomere maintenance function may operate in human tumors with alterations in the ATRX or DAXX genes.
Molecular alterations in meningiomas: Literature review Pereira, Benedito Jamilson Araújo; Oba-Shinjo, Sueli Mieko; de Almeida, Antônio Nogueira ...
Clinical neurology and neurosurgery,
January 2019, 2019-01-00, 20190101, Letnik:
176
Journal Article
Recenzirano
•Analysis of exome, methylome and epigenetic aspects allow researchers to unveil a approach for patients with meningiomas.•Mechanisms underlying tumorigenesis pathways, personalized managment ...(chemotherapy/radiotherapy) to refractory meningiomas.•The factors that drive meningioma development will lead to the classification according to its signature alterations.
Meningiomas, tumors that originate from meningothelial cells, account for approximately 30% of all new diagnoses of central nervous system neoplasms. According to the 2016 WHO classification of central nervous system tumors meningiomas are classified into three grades: I, II, and III.
Past studies have shown that the risk of meningiomas recurrence is strongly correlated with the molecular profile of the tumor. Extensive whole-exome or whole-genome sequencing has provided a large body of information about the mutational landscape of meningiomas. However, such a stratification of meningiomas based on mutational analysis alone has been proven not to satisfy the clinical need for distinction between patients who need (or do not need) an adjuvant treatment.
Combined analysis of exome, transcriptome, methylome and future approaches for epigenetic aspects in meningiomas may allow researchers to unveil a more comprehensive understanding of tumor progression mechanisms and, consequently, a more personalized clinical approach for patients with meningioma.
A better understanding of the genetics and clinical behavior of high-grade meningiomas is mandatory in order to better design future clinical trials. By studying the mechanisms underlying these new tumorigenesis pathways, we should be able to offer personalized chemotherapy to patients with surgery and radiation-refractory meningiomas in the near future. The purpose of this article is to accurately bring the compilation of this information, for a greater understanding of the subject.
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