Biflavone Ginkgetin,a Novel Wnt Inhibitor,Suppresses the Growth of Medulloblastoma

Medulloblastoma(MB)is a form of malignant brain tumor that predominantly arises in infants and children,of which approximately 25%is due to upregulation of canonical Wnt pathway with mainly mutations in CTNNB1.Therefore,Wnt inhibitors could offer rational therapeutic strategies and chemoprevention for this malignant cancer.In our present study,we undertook a screening for antagonists of Wnt signaling from 600 natural compounds,and identified Ginkgetin,a biflavone isolated from Cephalotaxus fortunei var.alpina.Ginkgetin inhibited Wnt pathway with an IC50 value around 5.92 lM and structure–activity relationship analysis suggested the methoxy group in Ginkgetin as a functional group.Biflavone Ginkgetin showed obvious cytotoxicity in Daoy and D283 MB cells.Cell cycle analysis by flow cytometry showed that Ginkgetin induced efficiently G2/M phase arrest in Daoy cells.Further mechanism studies showed that Ginkgetin reduced the expression of Wnt target genes,including Axin2,cyclinD1 and survivin in MB cells.The phosphorylation level of b-catenin also decreased in a time-and concentration-dependent manner.Collectively,our data suggest that Ginkgetin is a novel inhibitor of Wnt signaling,and as such warrants further exploration as a promising antimedulloblastoma candidate.

Expressions of GSK-3beta,Beta-Catenin and PPAR-Gamma in Medulloblastoma

Objective： To investigate the expressions of GSK-3beta, Beta-catenin and PPAR-gamma, and their relationship in medulloblastoma, and to explore their value in clinic application. Methods： Immunohistochemical staining with SP method was conducted to determine the expressions of GSK-3beta, Beta-catenin and PPAR-gamma in 48 cases of medulloblastoma and 10 normal cerebellar tissues. Results： The rate of abnormal expressions of beta-catenin and PPAR-gamma in MB was higher than that in normal. Conversely, GSK-3beta in MB was lower than that in the normal （P〈0.05）. Furthermore, in medulloblastoma, beta-catenin and GSK-3beta showed a negative correlation, PPAR-gamma and beta-catenin had a positive correlation. Conclusion： Abnormal expression of beta-catenin plays a crucial role in the development of medulloblastoma. Meanwhile, PPAR-gamma and GSK-3beta which are tightly related with beta-catenin are both involved in the genesis and development of medulloblastoma.

The miR-183～96～182 cluster promotes tumorigenesis in a mouse model of medulloblastoma

Medulloblastoma is the most common malignant pediatric brain tumor. Some are thought to originate from cerebellar granule neuron progenitors （CGNPs） that fail to undergo normal cell cycle exit and differentiation. The contribution of microRNAs to the initiation and progression of medulloblastoma remains poorly understood. Increased expression of the miR-183-96-182 cluster of microRNAs has been noted in several aggressive sub- groups. We identified that expression of miR-183-96-182 was higher in medulloblastomas with Pten gene loss in the background of the activated sonic hedgehog （Shh） signaling pathway. Ectopic miR-183-96-182 expression in CGNPs synergized with exogenous Shh to increase proliferation and its role depended on hedgehog signaling ac- tivation. Our findings suggest a new microRNA cluster, the miR-183-96-182, functionally collaborates with the Shh signaling pathway in the development of medulloblastomas in mice.

1H magnetic resonance spectroscopy and diffusion weighted imaging findings of medulloblastoma in 3.0T MRI A retrospective analysis of 17 cases

1H magnetic resonance spectroscopy and diffusion weighted imaging features of the cerebellar vermis in 17 medulloblastoma patients were retrospectively analyzed, and 17 healthy volunteers were selected as controls. 1H magnetic resonance spectroscopy showed that in all 17 medulloblastoma patients, N-acetyl aspartate and creatine peaks were significantly decreased, the choline peak was significantly increased, and there was evidence of a myo-inositol peak. Further, 11 patients showed a low taurine peak at 3.4 ppm, five patients showed a lipid peak at 0.9-1.3 ppm, and three patients showed a negative lactic acid peak at 1.33 ppm. Compared with the control group, the ratios of N-acetyl aspartate/choline and N-acetyl aspartate/creatine were significantly decreased, and the ratio of choline/creatine was increased, in medulloblastoma patients. Diffusion weighted imaging displayed hyperintensity and decreased apparent diffusion coefficient in medulloblastoma patients. These findings indicate that 1H magnetic resonance spectroscopy and diffusion weighted imaging are useful for qualitative diagnosis of medulloblastoma.

Expressions of Beta-Catenin,SUFU and VEGFR-2 Proteins in Medulloblastoma

Objective： to investigate the expressions of beta-catenin, SUFU and VEGFR-2 proteins in medulloblastoma. Methods： Immunohistochemical staining with SP method was conducted to determine the expressions of beta-catenin, SUFU and VEGFR-2 in 33 cases of medulloblastoma and 10 normal cerebellar tissues. Results： the abnormal expression rates of beta-catenin and VEGFR-2 in medulloblastoma were significantly higher than that in normal tissue. While the positive expression of SUFU gene in medulloblastoma was significantly lower than that in 10 normal cerebellar tissues, A significant negative correlation was found between beta-catenin and SUFU proteins and a positive correlation between beta-catenin and VEGFR-2 was found in medulloblastoma. Conclusion： Beta-catenin, VEGFR-2 and SUFU have important effects on the pathogenesis and development of medulloblastoma.

Relationship between Expression of beta-catenin and VEGFs(VEGFA,VEGF-C),VEGF Receptors-2(VEGFR-2)in Medulloblastoma

Objective： To investigate the expression of beta-catenin and VEGFs （VEGF-A, VEGF-C） and VEGF receptor-2 （VEGFR-2） protein in medulloblastoma. Methods： Immunohistochemical staining with SP method was conducted to determine the expression of beta-catenin and VEGFs （VEGF-A, VEGF-C） and VEGFR-2 in 33 cases of medulloblastoma and 10 normal cerebellar tissues. Results： The expression rate of beta-catenin, and VEGFs （VEGF-A, VEGF-C） and VEGFR-2 in medulloblastoma were significantly higher than that in normal tissue. A significant positive correlation was found between beta-catenin and VEGFs （VEGF-A, VEGF-C） and VEGFR-2 protein in medulloblastoma. Conclusion： There was a correlation between beta-catenin and VEGFs （VEGF-A, VEGF-C） and VEGFR-2 in medulloblastoma, which may play a role in the pathogenesis and development of medulloblastoma.

Adult Medulloblastoma Associated with Syringomyelia:A Case Report

The association between cerebellar medulloblastoma and syringomyelia is uncommon and only found in pediatric patients.To date,adult medulloblastoma associated with syringomyelia has not been reported in the literature.Paroxysmal bradycardia is an uncommon clinical manifestation in posterior fossa tumors and likely to be vagally mediated via brainstem preganglionic cardiac motor neurons.This report introduces the diagnosis and treatment of a case of adult medulloblastoma associated with syringomyelia, which presented with paroxysmal bradycardia.

Intramedullary Metastasis of Medulloblastoma: A Case Report

Medulloblastoma (MB) is a malignant brain tumor with a usual potential for leptomeningeal spread. Intramedullary metastases of MB are rare and there are very few cases reported in the literature. Here, we report the case of an 18-year-old man with intramedullary spinal cord metastasis of MB occurring 9 years after the first diagnosis. The patient presented a 2-month history of progressive weakness in both lower limbs associated with urinary incontinence. Magnetic resonance imaging (MRI) demonstrated a large intramedullary spinal cord tumor extending from T10 to L1. The patient underwent surgical decompression and adjuvant therapy. Histological examination confirmed the diagnosis of classic MB metastasis. Postoperatively, the neurological status was stationary. Intramedullary metastasis of medulloblastoma is rare and difficult to manage with a poor prognosis. Comprehensive studies on the medulloblastoma dissemination mechanisms and clinical trials are needed to assess combined therapeutic approaches on metastases of MB.

An adult case of medulloblastoma in the cerebellopontine angle extending to the supratentorial area

Medulloblastoma is an undifferentiated embryonic neuroepithelial tumor. It is a rare tumor in the central nervous system, with an even rarer occurrence during adulthood. It may develop at an atypical and uncommon site, such as the cerebellopontine angle （CPA）, and such tumors rarely present with supratentorial extension. The present study reports an adult case of medulloblastoma in the CPA extending to the supratentorial area. The patient presented with complaints of headache, vertigo, hearing difficulty in the left ear, nausea/vomiting, and unsteady gait. Disequilibrium began 4 weeks earlier. Examination revealed normal cranial nerves, and computed tomography showed a hyperdense lesion, with a heterogeneously enhancing mass, in the left CPA region. The patient underwent a nearly total excision of the lesion in the CPA region. Histopathological examination confirmed medulloblastoma, WHO grade IV. Postoperatively, the patient received radiotherapy and remained asymptomatic for 30 months. However, he received two more surgeries for relapse and progression of medulloblastoma and eventually died. A CPA medulloblastoma with supratentorial extension is relatively rare in the clinic.

Gene expression by simian virus 40 large Tantigen-induced medulloblastomas in mice

Signaling pathways known to have components with mutations in human medulloblastoma include sonic hedgehog, Wnt/beta-catenin and insulin-like growth factor. Microarray analysis was applied to examine the gene expression changes in medulloblastomas of pTet-on/pTRE-SV40Tag transgenic mice. Altogether, 14 112 genes were detectable, including 152 genes with significantly different expression levels. These genes were associated with immunity, the cell cycle, signal transduction, cytoskeleton and metabolism. To further confirm the microarray data, real-time polymerase chain reactions were used to examine the expression changes of genes related to sonic hedgehog, Wnt/beta-catenin and insulin-like growth factor signal pathways. Immunohistochemistry detected insulin receptor substrate-1 in the nuclei of brain tumor tissue cells from pTet-on/pTRE-SV40Tag transgenic mice, suggesting that SV40 large T antigen may activate the insulin-like growth factor signal pathway to promote tumorigenesis.

The role of microRNAs during the genesis of medulloblastomas induced by the hedgehog pathway

Constitutive hedgehog （Hh） signaling is associated with the genesis of medulloblastomas （MB）. The objective of this study is to identify special microRNAs （miRNAs） regulated by the Hh pathway, and to clarify the role of miRNAs during the genesis of MB induced by sustained Hh activation. In the primary screening, we used stemloop RT-PCR to test the expression of 90 different miRNAs in the wildtype （WT） and Ptc-/- MEF cell lines. In the secondary screening, the miRNAs screened from the first screening were validated in the Sufu-/- MEF cell lines. We then verified the expression of miRNAs both in the normal cerebellar tissues and the MB induced by activated Hh pathway, and examined the expression of the other 21 miRNA members of the miR-154 cluster in the MB and normal cerebellum. In the first screening, 13 miRNAs showed significant differential expression in WT and Ptc-/- MEF cell lines, while 10 of them had significant difference in the Sufu-/- MEF cell line. Compared to the normal mouse cerebellum, only 2 miRNAs in 15 miRNAs were differentially expressed between the MB and normal cerebellar tissues. Among 21 members of the miR-154 cluster, 6 miRNAs were downregulated in the MB. Our study demonstrated that miR-154 may be regulated by the Hh pathway, and the activation of the Hh pathway led to the downregulation of the miR-154 cluster, resulting in the genesis of MB.

Concurrent chemotherapy and reduced - dose cranial spinal irradiation followed by conformal posterior fossa tumor bed boost for average - risk medulloblastoma: efficacy and patterns of failure

PURPOSE:To review the efficacy and patterns of failure in average-risk medulloblastoma patients treated withconcurrent chemotherapy and reduced-dose cranial spinal irradiation and a conformal tumor bed boost.METH-ODS AND MATERIALS:Thirty-three patients with average risk(defined as<==1.5 cm(2)of residual tumorafter resection,age>3 years,and no involvement of the cerebrospinal fluid or spine)medulloblastoma werediagnosed at our institution between January 1994 and December 2001.They were enrolled in an institutional

A molecular fingerprint for medulloblastoma

Medulloblastoma is the most common malignant pediatric brain tumor. In mice, Ptcl haploinsufficiency and disruption of DNA repair (DNA ligase IV inactivation) or cell cycle regulation (Kipl, Ink4d, or Inkd.c inactivation), in conjunction with p53 dysfunction, predispose to medulloblastoma. To identify genes important for this tumor, we evaluated gene expression profiles in medulloblastomas from these mice. Unexpectedly, medulloblastoma

PROMOTION OF IN VITRO GROWTH OF HUMAN MEDULLOBLASTOMA CELLS BY EXOGENEOUS IL－6

In vivo and in vitro expression of IL-6 and its signal transducer genes, IM-6R and gp130, in human medulloblastoma cells were investigated by the approaches of molecular biologr and cellular immunology.The results revealed that 12 out of 13 samples examined were found to express IL-6R and gp 130, but none of them showcd IL-6 expression. Thcn, the Potential effccts of cxogenous IL-6 on the proliferation of medulloblastoma cell line, Med-3 were evaluated, which showed that IL-6could enhance cell outgrowth dramatically. Our data thus for the first t'me demonstrate the important role of IL-6as paracrine growth factor in the proliferat'on of medulloblastoma cells.

Metabolic determinants of stemness in medulloblastoma

Medulloblastomas(MBs)are the most prevalent brain tumours in children.They are classified as grade IV,the highest in malignancy,with about 30%metastatic tumours at the time of diagnosis.Cancer stem cells(CSCs)are a small subset of tumour cells that can initiate and support tumour growth.In MB,CSCs contribute to tumour initiation,metastasis,and therapy resistance.Metabolic differences among the different MB groups have started to emerge.Sonic hedgehog tumours show enriched lipid and nucleic acid metabolism pathways,whereas Group 3 MBs upregulate glycolysis,gluconeogenesis,glutamine anabolism,and glutathione-mediated anti-oxidant pathways.Such differences impact the clinical behaviour of MB tumours and can be exploited therapeutically.In this review,we summarise the existing knowledge about metabolic rewiring in MB,with a particular focus on MB-CSCs.Finally,we highlight some of the emerging metabolism-based therapeutic strategies for MB.

The Expression of PI3K, AKT, β-Catenin and VEGFR2 in Medulloblastoma

Medulloblastoma (MB) is common tumor of the central nervous system in children. It’s reported that PI3K/AKT and Wnt signal pathway have important roles in MB. This study aims to investigate the expression of PI3K, AKT, Β-catenin and VEGFR-2 in MB to find a new pathway for MB. A total of 33 MB and 17 control brain cases were retrospectively evaluate d for PI3K, AKT, β-catenin and VEGFR-2 expression by immunohistochemical staining, and the relationship with clinical feature were analyzed. The positive rate of PI3K, AKT, β-catenin and VEGFR-2 in 33 MB were significantly greater than those in control group

Analysis of the personalized treatment and the relevant prognostic factors in children with medulloblastoma

Purpose:The present study summarized cases of children(n=32)with medulloblastoma(MB)who were treated using stratified therapy based on risk grading and also discussed the factors affecting prognosis.Methods:According to the risk stratification criteria,the cases were divided into the following four risk groups:low,standard,high,and very high.The 5-year overall survival(OS)and progression-free survival(PFS)rates were summarized.Further,the effects on the prognosis of tumor size,tumor stage,degree of resection,treatment mode,metastatic recurrence,molecular typing,and risk stratification were analyzed.Results:In the present study,following surgery,3 cases abandoned radiotherapy(RT)and chemotherapy(CHT),7 cases(<3 years of age)received only CHT,and 22 cases received combined RT and CHT.Total and near-total tumor resections were performed in 29 cases(90.6%).Subtotal resections were performed in 3 cases,and there were no surgery-related deaths.The average follow-up duration was 47 months.The average 5-year PFS and OS rates were 57.3%±7.2%and 68.7%±8.6%,respectively.The OS and PFS rates were significantly correlated with tumor-risk stratification,molecular staging,tumor stage,treatment mode,and recurrence after surgery(p<0.01).The degree of tumor resection,pathological type,and the presence of preoperative implantation were secondary factors affecting the prognosis(p<0.05).Age was correlated with the PFS rate.There was no correlation between age/tumor location/tumor size and prognosis(p>0.05).Favorable prognostic factors in the low-and standard-risk groups were stage M0,wingless-type MB,postoperative RT combined with CHT,no postoperative recurrence,age≥3 years,and total tumor resection.Conclusions:Personalized treatment strategies based on the risk stratification of MB and postoperative stratified comprehensive treatment could help improve the prognosis for MB.

Nrf-2 and HO-1 Expression in Medulloblastoma: A Clinicopathological Analysis

Medulloblastoma (MB) is one of the most common malignant tumors with poor survival in children. Nuclear factor erythroid 2-related factor2 (Nrf-2) and heme oxygenase-1 (HO-1) have been considered to play major roles in the pathogenesis of many tumors. There is no report about clinicopathological significance of Nrf-2 and HO-1 expression in medulloblastoma. In the present study, to explore the expression and potential function of Nrf-2 and HO-1 in MBs, immunohistochemistry was used to examine the Nrf-2 and HO-1 expression in 41 MBs and 27 control tissues adjacent to the tumor. The results showed that in the cases of MB, the positive expression rates of Nrf-2 and HO-1 (82.9% and 78.0%) were significantly increased compared with that (37.0% and 29.6%) in peritumoral control brain tissues. The difference was statistically significant (P 0.05). The abnormal expression of Nrf-2 and HO-1 in MB suggest that the Nrf-2/HO-1 pathway plays an important role in the formation and development of MB and may be a potential therapeutic target for MB.

Magnetic Resonance Spectroscopy and Prognostic Analysis of Molecular Subtypes of Medulloblastoma

Aim: The aim of this study was to investigate whether magnetic resonance spectrum (MRS) and MR imaging features can be used for non-invasive medulloblastoma subgrouping, and analyse patient characteristics and prognosis of molecular subtypes of medulloblastoma. Material and Methods: 32 patients with medulloblastoma underwent MRI prior to surgical resection, 16 of them underwent MRS. MR imaging features and metabolites measured by MRS were analysed to distinguish molecular subtypes of medulloblastoma. Patient demographics, histopathological types, and prognosis of different molecular subtypes were analysed and compared respectively. Results: MRS and MR imaging features differed from different individuals, but without statistical significance that involves acquiring non-quantitative MR imaging features and NAA/Cr, Cho/Cr, Lip/Cr, Glu and Gln/Cr ratio, to be used to determine molecular subtypes. There was no significant difference of the three molecular subtypes in age, gender and pathological type. The 5-year event-free survival (EFS) of SHH, WNT and non SHH/WNT subtype respectively were 75%, 57.1%, 38.1%, with no significant difference (p = 0.382). 5-year EFS of non SHH/WNT subtype was significantly higher in ≤3 years old group than >3 years old group (p = 0.047). Conclusion: MRS and MR imaging features can’t be used to determine molecular subtypes based on our small sample study. There was no significant difference of the prognosis in the three molecular subtypes. The prognosis of ≤3 years old group of non SHH/WNT subtype is better than >3 years old group.

Microvesicles in Gliomas and Medulloblastomas: An Overview

Microvesicles (MVs) or shedding membrane vesicles have recently been described as a novel model of intercellular communication. Previously, MVs were considered as unnecessary or secreted cellular debris, but MVs have lately been described as having roles in a variety of biological functions, such as cell homeostasis and the cellular processes involved in the oncogenesis of many types of tumors. Carrying several key molecules that contribute to tumor development and progression, similar to mRNAs, microRNAs and other non-coding RNAs, DNA and even small proteins, MVs can be considered as a ubiquitous form of novel cell communication that is present in most somatic cells. Although tumor-derived MVs have been demonstrated in different types of cancers, the literature data on MVs in primary central nervous system (CNS) tumors are relatively scarce. In this review, we address the involvement of MVs in diffuse astrocytomas, particularly glioblastomas, as well as oligodendrogliomas and medulloblastomas. We placed particular focus on the cellular crosstalk between tumor and “normal” cells, the putative mechanisms how the tumor microenvironment is modulated and the spread of aggressive phenotypes. Additionally, a better understanding of the participation of tumor-derived MVs in the regulation of key cancer pathways will offer new insights into tumor pathogenesis and the mechanisms of multidrug resistance, and may help to develop new strategies for novel therapies against these infiltrative CNS tumors.