Science.gov

Sample records for glioblastoma brain cancer

  1. Cancer stem cells in glioblastoma

    PubMed Central

    Lathia, Justin D.; Mack, Stephen C.; Mulkearns-Hubert, Erin E.; Valentim, Claudia L.L.; Rich, Jeremy N.

    2015-01-01

    Tissues with defined cellular hierarchies in development and homeostasis give rise to tumors with cellular hierarchies, suggesting that tumors recapitulate specific tissues and mimic their origins. Glioblastoma (GBM) is the most prevalent and malignant primary brain tumor and contains self-renewing, tumorigenic cancer stem cells (CSCs) that contribute to tumor initiation and therapeutic resistance. As normal stem and progenitor cells participate in tissue development and repair, these developmental programs re-emerge in CSCs to support the development and progressive growth of tumors. Elucidation of the molecular mechanisms that govern CSCs has informed the development of novel targeted therapeutics for GBM and other brain cancers. CSCs are not self-autonomous units; rather, they function within an ecological system, both actively remodeling the microenvironment and receiving critical maintenance cues from their niches. To fulfill the future goal of developing novel therapies to collapse CSC dynamics, drawing parallels to other normal and pathological states that are highly interactive with their microenvironments and that use developmental signaling pathways will be beneficial. PMID:26109046

  2. Effective treatment of glioblastoma requires crossing the blood-brain barrier and targeting tumors including cancer stem cells: The promise of nanomedicine.

    PubMed

    Kim, Sang-Soo; Harford, Joe B; Pirollo, Kathleen F; Chang, Esther H

    2015-12-18

    Glioblastoma multiforme (GBM) is the most aggressive and lethal type of brain tumor. Both therapeutic resistance and restricted permeation of drugs across the blood-brain barrier (BBB) play a major role in the poor prognosis of GBM patients. Accumulated evidence suggests that in many human cancers, including GBM, therapeutic resistance can be attributed to a small fraction of cancer cells known as cancer stem cells (CSCs). CSCs have been shown to have stem cell-like properties that enable them to evade traditional cytotoxic therapies, and so new CSC-directed anti-cancer therapies are needed. Nanoparticles have been designed to selectively deliver payloads to relevant target cells in the body, and there is considerable interest in the use of nanoparticles for CSC-directed anti-cancer therapies. Recent advances in the field of nanomedicine offer new possibilities for overcoming CSC-mediated therapeutic resistance and thus significantly improving management of GBM. In this review, we will examine the current nanomedicine approaches for targeting CSCs and their therapeutic implications. The inhibitory effect of various nanoparticle-based drug delivery system towards CSCs in GBM tumors is the primary focus of this review. Copyright © 2015 Elsevier Inc. All rights reserved.

  3. Glioblastoma.

    PubMed

    Wirsching, Hans-Georg; Galanis, Evanthia; Weller, Michael

    2016-01-01

    Glioblastoma is the most common and aggressive primary brain tumor in adults. Defining histopathologic features are necrosis and endothelial proliferation, resulting in the assignment of grade IV, the highest grade in the World Health Organization (WHO) classification of brain tumors. The classic clinical term "secondary glioblastoma" refers to a minority of glioblastomas that evolve from previously diagnosed WHO grade II or grade III gliomas. Specific point mutations of the genes encoding isocitrate dehydrogenase (IDH) 1 or 2 appear to define molecularly these tumors that are associated with younger age and more favorable outcome; the vast majority of glioblastomas are IDH wild-type. Typical molecular changes in glioblastoma include mutations in genes regulating receptor tyrosine kinase (RTK)/rat sarcoma (RAS)/phosphoinositide 3-kinase (PI3K), p53, and retinoblastoma protein (RB) signaling. Standard treatment of glioblastoma includes surgery, radiotherapy, and alkylating chemotherapy. Promoter methylation of the gene encoding the DNA repair protein, O(6)-methylguanyl DNA methyltransferase (MGMT), predicts benefit from alkylating chemotherapy with temozolomide and guides choice of first-line treatment in elderly patients. Current developments focus on targeting the molecular characteristics that drive the malignant phenotype, including altered signal transduction and angiogenesis, and more recently, various approaches of immunotherapy.

  4. Aptamer for imaging and therapeutic targeting of brain tumor glioblastoma.

    PubMed

    Delač, Mateja; Motaln, Helena; Ulrich, Henning; Lah, Tamara T

    2015-09-01

    Aptamers are short single-stranded nucleic acids (RNA or ssDNA), identified by an in vitro selection process, denominated SELEX, from a partially random oligonucleotide library. They bind to a molecular target, a protein or other complex macromolecular structures of interest with high affinity and specificity, comparable to those of antibodies. Recently, aptamer selection protocols were developed for targeting living cells, including tumors. Chemical modifications of the aptamers and modalities of their detection and delivery systems are already available with high selectivity and targeting ability for the desired cancer cell type, making them promising for diagnosis and therapy. Glioblastoma multiformae represents the most malignant and fatal stage of glioma, and is also the most frequent brain tumor. Glioblastoma-specific aptamers were developed by either targeting the whole cell surface or known glioma biomarkers. These aptamers may gain importance for imaging, tumor cell isolation from biopsies and drug delivery. In biomedical imaging techniques, aptamers coupled with radionuclide or fluorescent labels, bioconjugates and nanoparticles offer an advanced, noninvasive manner for defining the glioblastoma tissue border. Though single modality aptamer imaging probes have some limitations, these are overcome by the use of multimodal probes. Due to selectivity and chemical characteristics, aptamers can be coupled to functionalized nanoparticles and loaded with a drug, appeared promising for in vivo targeting of glioblastoma. Finally, aptamers are effective mediators for gene silencing when coupled to small interfering RNA and a viral vector, thus providing a novel tool with enhanced targeting capability in drug delivery, designed for tailored treatment of glioblastoma patients.

  5. Development of Glioblastoma after Treatment of Brain Abscess.

    PubMed

    Matsumoto, Hiroaki; Minami, Hiroaki; Tominaga, Shogo; Yoshida, Yasuhisa

    2016-04-01

    Abscess formation within a glioblastoma has been reported rarely. In the few reported cases, after aspiration to treat a presumed abscess, lesions recurred over a short period and, consequently, glioblastoma was recognized. We present a case of a glioblastoma that developed 1.5 years after successful treatment of a brain abscess. A latency of 1.5 years before symptom development seems overly long, even if the glioblastoma was present at the time of the initial brain abscess. Hence, we consider this a possible de novo glioblastoma arising from glial scar tissue. We also discuss possible mechanisms underlying malignant transformation. A 78-year-old man was admitted to our hospital with progressive gait disturbance caused by a brain abscess. Aspiration of the cyst and systematic antibiotic therapy cured the abscess. However, 1.5 years later, the patient presented to our hospital with generalized convulsions due to recurrence of the cystic lesion. He underwent craniotomy for removal of the cystic lesion, which was found to be a glioblastoma rather than a recurrent brain abscess. Glial scar tissue was detected in the cyst wall. Development of glioblastoma after treatment of a brain abscess is rare; the pathogenesis is open to speculation. Based on the clinical course, the pathologic findings, and comparison with previous reports, de novo glioblastoma arising from glial scar tissue may be the most likely explanation of the current case. If so, to our knowledge, this is the first report of this condition. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. Cancer stem cell contribution to glioblastoma invasiveness

    PubMed Central

    2013-01-01

    Glioblastoma (GBM) is the most aggressive and lethal brain tumor in adults. Its invasive nature currently represents the most challenging hurdle to surgical resection. The mechanism adopted by GBM cells to carry out their invasive strategy is an intricate program that recalls what takes place in embryonic cells during development and in carcinoma cells during metastasis formation, the so-called epithelial-to-mesenchymal transition. GBM cells undergo a series of molecular and conformational changes shifting the tumor toward mesenchymal traits, including extracellular matrix remodeling, cytoskeletal re-patterning, and stem-like trait acquisition. A deeper understanding of the mechanisms driving the whole infiltrative process represents the first step toward successful treatment of this pathology. Here, we review recent findings demonstrating the invasive nature of GBM cancer stem cells, together with novel candidate molecules associated with both cancer stem cell biology and GBM invasion, like doublecortin and microRNAs. These findings may affect the design of effective therapies currently not considered for GBM invasive progression. PMID:23510696

  7. Cancer Stem Cell Hierarchy in Glioblastoma Multiforme

    PubMed Central

    Bradshaw, Amy; Wickremsekera, Agadha; Tan, Swee T.; Peng, Lifeng; Davis, Paul F.; Itinteang, Tinte

    2016-01-01

    Glioblastoma multiforme (GBM), an aggressive tumor that typically exhibits treatment failure with high mortality rates, is associated with the presence of cancer stem cells (CSCs) within the tumor. CSCs possess the ability for perpetual self-renewal and proliferation, producing downstream progenitor cells that drive tumor growth. Studies of many cancer types have identified CSCs using specific markers, but it is still unclear as to where in the stem cell hierarchy these markers fall. This is compounded further by the presence of multiple GBM and glioblastoma cancer stem cell subtypes, making investigation and establishment of a universal treatment difficult. This review examines the current knowledge on the CSC markers SALL4, OCT-4, SOX2, STAT3, NANOG, c-Myc, KLF4, CD133, CD44, nestin, and glial fibrillary acidic protein, specifically focusing on their use and validity in GBM research and how they may be utilized for investigations into GBM’s cancer biology. PMID:27148537

  8. Targeting Aggressive Cancer Stem Cells in Glioblastoma

    PubMed Central

    Seymour, Tracy; Nowak, Anna; Kakulas, Foteini

    2015-01-01

    Glioblastoma (GBM) is the most common and fatal type of primary brain tumor. Gliosarcoma (GSM) is a rarer and more aggressive variant of GBM that has recently been considered a potentially different disease. Current clinical treatment for both GBM and GSM includes maximal surgical resection followed by post-operative radiotherapy and concomitant and adjuvant chemotherapy. Despite recent advances in treating other solid tumors, treatment for GBM and GSM still remains palliative, with a very poor prognosis and a median survival rate of 12–15 months. Treatment failure is a result of a number of causes, including resistance to radiotherapy and chemotherapy. Recent research has applied the cancer stem cells theory of carcinogenesis to these tumors, suggesting the existence of a small subpopulation of glioma stem-like cells (GSCs) within these tumors. GSCs are thought to contribute to tumor progression, treatment resistance, and tumor recapitulation post-treatment and have become the focus of novel therapy strategies. Their isolation and investigation suggest that GSCs share critical signaling pathways with normal embryonic and somatic stem cells, but with distinct alterations. Research must focus on identifying these variations as they may present novel therapeutic targets. Targeting pluripotency transcription factors, SOX2, OCT4, and Nanog homeobox, demonstrates promising therapeutic potential that if applied in isolation or together with current treatments may improve overall survival, reduce tumor relapse, and achieve a cure for these patients. PMID:26258069

  9. Side population in human glioblastoma is non-tumorigenic and characterizes brain endothelial cells

    PubMed Central

    Golebiewska, Anna; Bougnaud, Sébastien; Stieber, Daniel; Brons, Nicolaas H. C.; Vallar, Laurent; Hertel, Frank; Klink, Barbara; Schröck, Evelin; Bjerkvig, Rolf

    2013-01-01

    The identification and significance of cancer stem-like cells in malignant gliomas remains controversial. It has been proposed that cancer stem-like cells display increased drug resistance, through the expression of ATP-binding cassette transporters that detoxify cells by effluxing exogenous compounds. Here, we investigated the ‘side population’ phenotype based on efflux properties of ATP-binding cassette transporters in freshly isolated human glioblastoma samples and intracranial xenografts derived thereof. Using fluorescence in situ hybridization analysis on sorted cells obtained from glioblastoma biopsies, as well as human tumour xenografts developed in immunodeficient enhanced green fluorescence protein-expressing mice that allow an unequivocal tumour-stroma discrimination, we show that side population cells in human glioblastoma are non-neoplastic and exclusively stroma-derived. Tumour cells were consistently devoid of efflux properties regardless of their genetic background, tumour ploidy or stem cell associated marker expression. Using multi-parameter flow cytometry we identified the stromal side population in human glioblastoma to be brain-derived endothelial cells with a minor contribution of astrocytes. In contrast with their foetal counterpart, neural stem/progenitor cells in the adult brain did not display the side population phenotype. Of note, we show that CD133-positive cells often associated with cancer stem-like cells in glioblastoma biopsies, do not represent a homogenous cell population and include CD31-positive endothelial cells. Interestingly, treatment of brain tumours with the anti-angiogenic agent bevacizumab reduced total vessel density, but did not affect the efflux properties of endothelial cells. In conclusion our findings contribute to an unbiased identification of cancer stem-like cells and stromal cells in brain neoplasms, and provide novel insight into the complex issue of drug delivery to the brain. Since efflux properties of

  10. Intracellular Progesterone Receptor Mediates the Increase in Glioblastoma Growth Induced by Progesterone in the Rat Brain.

    PubMed

    Germán-Castelán, Liliana; Manjarrez-Marmolejo, Joaquín; González-Arenas, Aliesha; Camacho-Arroyo, Ignacio

    2016-08-01

    Progesterone (P) is a steroid hormone involved in the development of several types of cancer including astrocytomas, the most common and malignant brain tumors. We undertook this study to investigate the effects of P on the growth and infiltration of a tumor caused by the xenotransplant of U87 cells derived from a human astrocytoma grade IV (glioblastoma) in the cerebral cortex of male rats and the participation of intracellular progesterone receptor (PR) on these effects. Eight weeks after the implantation of U87 cells in the cerebral cortex, we administered phosphorothioated antisense oligodeoxynucleotides (ODNs) to silence the expression of PR. This treatment lasted 15 days and was administered at the site of glioblastoma cells implantation using Alzet osmotic pumps. Vehicle (propylene glycol) or P4 (400 μg/100 g) was subcutaneously injected for 14 days starting 1 day after the beginning of ODN administration. We observed that P significantly increased glioblastoma tumor area and infiltration length as compared with vehicle, whereas PR antisense ODNs blocked these effects. P, through the interaction with PR, increases the area and infiltration of a brain tumor formed from the xenotransplant of human glioblastoma-derived U87 cells in the cerebral cortex of the rat. Copyright © 2016 IMSS. Published by Elsevier Inc. All rights reserved.

  11. Yes-associated protein 1 is widely expressed in human brain tumors and promotes glioblastoma growth.

    PubMed

    Orr, Brent A; Bai, Haibo; Odia, Yazmin; Jain, Deepali; Anders, Robert A; Eberhart, Charles G

    2011-07-01

    The hippo pathway and its downstream mediator yes-associated protein 1 (YAP1) regulate mammalian organ size in part through modulating progenitor cell numbers. YAP1 has also been implicated as an oncogene in multiple human cancers. Currently, little is known about the expression of YAP1 either in normal human brain tissue or in central nervous system neoplasms. We used immunohistochemistry to evaluate nuclear YAP1 expression in the fetal and normal adult human brains and in 264 brain tumors. YAP1 was expressed in fetal and adult brain regions known to harbor neural progenitor cells, but there was little YAP1 immunoreactivity in the adult cerebral cortex. YAP1 protein was also readily detected in the nuclei of human brain tumors. In medulloblastoma, the expression varied between histologic subtypes and was most prominent in nodular/desmoplastic tumors. In gliomas, it was frequently expressed in infiltrating astrocytomas and oligodendrogliomas but rarely in pilocytic astrocytomas. Using a loss-of-function approach, we show that YAP1 promoted growth of glioblastoma cell lines in vitro. High levels of YAP1 messenger RNA expression were associated with aggressive molecular subsets of glioblastoma and with a nonsignificant trend toward reduced mean survival in human astrocytoma patients. These findings suggest that YAP1 may play an important role in normal human brain development and that it could represent a new target in human brain tumors.

  12. Multicentric spinal cord and brain glioblastoma without previous craniotomy

    PubMed Central

    de Eulate-Beramendi, Sayoa A.; Piña-Batista, Kelvin M.; Rodrigo, Victor; Torres-Rivas, Hector E.; Rial-Basalo, Juan C.

    2016-01-01

    Background: Glioblastoma multiforme (GBS) is a highly malignant glioma that rarely presents as an infratentorial tumor. Multicentric gliomas lesions are widely separated in site and/or time and its incidence has been reported between 0.15 and 10%. Multicentric gliomas involving supratentorial and infratentorial region are even more rare. In most cases, infratentorial disease is seen after surgical manipulation or radiation therapy and is usually located in the cerebellum or cervical region. Case Report: We present a rare case of symptomatic multicentric glioma in the brain, fourth ventricle, cervical as well as lumbar glioblastoma in an adult without previous therapeutic intervention. We also review the literature of this rare presentation. Conclusions: This report suggests that GBM is a diffuse disease; the more extended the disease, the worse prognosis it has. The management still remains controversial and further studies are required to understand the prognosis factors of dissemination. PMID:27512613

  13. Nanotechnology applications for glioblastoma.

    PubMed

    Nduom, Edjah K; Bouras, Alexandros; Kaluzova, Milota; Hadjipanayis, Costas G

    2012-07-01

    Glioblastoma remains one of the most difficult cancers to treat and represents the most common primary malignancy of the brain. Although conventional treatments have found modest success in reducing the initial tumor burden, infiltrating cancer cells beyond the main mass are responsible for tumor recurrence and ultimate patient demise. Targeting residual infiltrating cancer cells requires the development of new treatment strategies. The emerging field of cancer nanotechnology holds promise in the use of multifunctional nanoparticles for imaging and targeted therapy of glioblastoma. This article examines the current state of nanotechnology in the treatment of glioblastoma and directions of further study.

  14. Glioblastoma

    MedlinePlus

    ... most common form of glioblastoma; it is very aggressive. Secondary: These tumors have a longer, somewhat slower growth history, but still are very aggressive. They may begin as lower-grade tumors which ...

  15. MicroRNAs in Cancer: Glioblastoma and Glioblastoma Cancer Stem Cells

    PubMed Central

    Brower, Jeffrey; Clark, Paul A.; Lyon, Will

    2015-01-01

    MicroRNAs represent an abundant class of endogenously expressed 18–25 nucleotide non-coding RNA molecules that function to silence gene expression through a process of post-transcriptional modification. They exhibit varied and widespread functions during normal development and tissue homeostasis, and accordingly their dysregulation plays major roles in many cancer types. Gliomas are cancers arising from the central nervous system. The most malignant and common glioma is glioblastoma multiforme (GBM), and even with aggressive treatment (surgical resection, chemotherapy, and radiation), average patient survival remains less than two years. In this review we will summarize the current findings regarding microRNAs in GBM and the biological and clinical implications of this data. PMID:24937770

  16. Opioid receptor activation triggering downregulation of cAMP improves effectiveness of anti-cancer drugs in treatment of glioblastoma

    PubMed Central

    Friesen, Claudia; Hormann, Inis; Roscher, Mareike; Fichtner, Iduna; Alt, Andreas; Hilger, Ralf; Debatin, Klaus-Michael; Miltner, Erich

    2014-01-01

    Glioblastoma are the most frequent and malignant human brain tumors, having a very poor prognosis. The enhanced radio- and chemoresistance of glioblastoma and the glioblastoma stem cells might be the main reason why conventional therapies fail. The second messenger cyclic AMP (cAMP) controls cell proliferation, differentiation, and apoptosis. Downregulation of cAMP sensitizes tumor cells for anti-cancer treatment. Opioid receptor agonists triggering opioid receptors can activate inhibitory Gi proteins, which, in turn, block adenylyl cyclase activity reducing cAMP. In this study, we show that downregulation of cAMP by opioid receptor activation improves the effectiveness of anti-cancer drugs in treatment of glioblastoma. The µ-opioid receptor agonist D,L-methadone sensitizes glioblastoma as well as the untreatable glioblastoma stem cells for doxorubicin-induced apoptosis and activation of apoptosis pathways by reversing deficient caspase activation and deficient downregulation of XIAP and Bcl-xL, playing critical roles in glioblastomas’ resistance. Blocking opioid receptors using the opioid receptor antagonist naloxone or increasing intracellular cAMP by 3-isobutyl-1-methylxanthine (IBMX) strongly reduced opioid receptor agonist-induced sensitization for doxorubicin. In addition, the opioid receptor agonist D,L-methadone increased doxorubicin uptake and decreased doxorubicin efflux, whereas doxorubicin increased opioid receptor expression in glioblastomas. Furthermore, opioid receptor activation using D,L-methadone inhibited tumor growth significantly in vivo. Our findings suggest that opioid receptor activation triggering downregulation of cAMP is a promising strategy to inhibit tumor growth and to improve the effectiveness of anti-cancer drugs in treatment of glioblastoma and in killing glioblastoma stem cells. PMID:24626197

  17. Analysis of fractional anisotropy facilitates differentiation of glioblastoma and brain metastases in a clinical setting.

    PubMed

    Bette, Stefanie; Huber, Thomas; Wiestler, Benedikt; Boeckh-Behrens, Tobias; Gempt, Jens; Ringel, Florian; Meyer, Bernhard; Zimmer, Claus; Kirschke, Jan S

    2016-12-01

    Differentiating glioblastoma from brain metastases is important for therapy planning. Diffusion tensor imaging (DTI) was described as a promising tool, however with conflicting results. of this study was to analyze the clinical utility of DTI for the differentiation of brain metastases and glioblastoma. 294 patients (165 glioblastoma, 129 brain metastases) with preoperative DTI were included in this retrospective study. Fractional anisotropy (FA) was measured via regions of interest (ROIs) in the contrast-enhancing tumor, the necrosis and the FLAIR-hyperintense non-enhancing peritumoral region (NEPTR). Two neuroradiologists classified patient cases as glioblastoma or brain metastases without and with knowledge of FA values. Glioblastoma showed significantly higher FAcontrast (median glioblastoma=0.33, metastases=0.23; P<0.001) whereas no significant difference was observed for FANEPTR (0.21 vs. 0.22; P=0.28) and for FAnecrosis (0.17 vs. 0.18, P=0.37). FA improved diagnostic accuracy of the neuroradiologists significantly from an AUC of 0.84/0.85 (Reader1/Reader2) to 0.89/0.92. Glioblastoma show significantly higher FA values in the contrast enhancing tumor part than brain metastases. Implementation of a ROI-based measurement of FA values and FA color maps in clinical routine helps to differentiate between glioblastoma and brain metastases. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  18. Intratumor heterogeneity in human glioblastoma reflects cancer evolutionary dynamics

    PubMed Central

    Sottoriva, Andrea; Spiteri, Inmaculada; Piccirillo, Sara G. M.; Touloumis, Anestis; Collins, V. Peter; Marioni, John C.; Curtis, Christina; Watts, Colin; Tavaré, Simon

    2013-01-01

    Glioblastoma (GB) is the most common and aggressive primary brain malignancy, with poor prognosis and a lack of effective therapeutic options. Accumulating evidence suggests that intratumor heterogeneity likely is the key to understanding treatment failure. However, the extent of intratumor heterogeneity as a result of tumor evolution is still poorly understood. To address this, we developed a unique surgical multisampling scheme to collect spatially distinct tumor fragments from 11 GB patients. We present an integrated genomic analysis that uncovers extensive intratumor heterogeneity, with most patients displaying different GB subtypes within the same tumor. Moreover, we reconstructed the phylogeny of the fragments for each patient, identifying copy number alterations in EGFR and CDKN2A/B/p14ARF as early events, and aberrations in PDGFRA and PTEN as later events during cancer progression. We also characterized the clonal organization of each tumor fragment at the single-molecule level, detecting multiple coexisting cell lineages. Our results reveal the genome-wide architecture of intratumor variability in GB across multiple spatial scales and patient-specific patterns of cancer evolution, with consequences for treatment design. PMID:23412337

  19. Calpain 2 Is Required for the Invasion of Glioblastoma Cells in the Zebrafish Brain Microenvironment

    PubMed Central

    Lal, Sangeet; La Du, Jane; Tanguay, Robert L.; Greenwood, Jeffrey A.

    2012-01-01

    Glioblastoma is an aggressive primary brain tumor with a 5-year survival rate of less than 5%. The ability of glioblastoma cells to invade surrounding brain tissue presents the primary challenge for the success of focal therapeutic approaches. We previously reported that the calcium-activated protease calpain 2 is critical for glioblastoma cell invasion in vitro. Here, we show that expression of calpain 2 is required for the dispersal of glioblastoma cells in a living brain microenvironment. Knockdown of calpain 2 resulted in a 2.9-fold decrease in the invasion of human glioblastoma cells in zebrafish brain. Control cells diffusely migrated up to 450 μm from the site of injection, whereas knockdown cells remained confined in clusters. The invasion study was repeated in organotypic mouse brain tissues, and calpain 2 knockdown cells demonstrated a 2.3-fold lower area of dispersal compared with control cells. In zebrafish brain, glioblastoma cells appeared to migrate in part along the blood vessels of the host. Furthermore, angiogenesis was detected in 27% of zebrafish injected with control cells, whereas only 12.5% of fish receiving knockdown cells showed the formation of new vessels, suggesting a role for calpain 2 in tumor cell angiogenesis. Consistent with the progression of glioblastoma in humans, transplanted tumor cells were not observed to metastasize outside the brain of zebrafish. This study demonstrates that calpain 2 expression is required for the dispersal of glioblastoma cells within the dynamic microenvironment of the brain, identifying zebrafish as a valuable orthotopic system for studying glioblastoma cell invasion. PMID:22183788

  20. BK K+ channel blockade inhibits radiation-induced migration/brain infiltration of glioblastoma cells

    PubMed Central

    Klumpp, Lukas; Haehl, Erik; Schilbach, Karin; Lukowski, Robert; Kühnle, Matthias; Bernhardt, Günther; Buschauer, Armin; Zips, Daniel; Ruth, Peter; Huber, Stephan M.

    2016-01-01

    Infiltration of the brain by glioblastoma cells reportedly requires Ca2+ signals and BK K+ channels that program and drive glioblastoma cell migration, respectively. Ionizing radiation (IR) has been shown to induce expression of the chemokine SDF-1, to alter the Ca2+ signaling, and to stimulate cell migration of glioblastoma cells. Here, we quantified fractionated IR-induced migration/brain infiltration of human glioblastoma cells in vitro and in an orthotopic mouse model and analyzed the role of SDF-1/CXCR4 signaling and BK channels. To this end, the radiation-induced migratory phenotypes of human T98G and far-red fluorescent U-87MG-Katushka glioblastoma cells were characterized by mRNA and protein expression, fura-2 Ca2+ imaging, BK patch-clamp recording and transfilter migration assay. In addition, U-87MG-Katushka cells were grown to solid glioblastomas in the right hemispheres of immunocompromised mice, fractionated irradiated (6 MV photons) with 5 × 0 or 5 × 2 Gy, and SDF-1, CXCR4, and BK protein expression by the tumor as well as glioblastoma brain infiltration was analyzed in dependence on BK channel targeting by systemic paxilline application concomitant to IR. As a result, IR stimulated SDF-1 signaling and induced migration of glioblastoma cells in vitro and in vivo. Importantly, paxilline blocked IR-induced migration in vivo. Collectively, our data demonstrate that fractionated IR of glioblastoma stimulates and BK K+ channel targeting mitigates migration and brain infiltration of glioblastoma cells in vivo. This suggests that BK channel targeting might represent a novel approach to overcome radiation-induced spreading of malignant brain tumors during radiotherapy. PMID:26893360

  1. More Complete Removal of Malignant Brain Tumors by Fluorescence-Guided Surgery

    ClinicalTrials.gov

    2016-05-13

    Benign Neoplasms, Brain; Brain Cancer; Brain Neoplasms, Benign; Brain Neoplasms, Malignant; Brain Tumor, Primary; Brain Tumor, Recurrent; Brain Tumors; Intracranial Neoplasms; Neoplasms, Brain; Neoplasms, Intracranial; Primary Brain Neoplasms; Primary Malignant Brain Neoplasms; Primary Malignant Brain Tumors; Gliomas; Glioblastoma

  2. Characterizing the peritumoral brain zone in glioblastoma: a multidisciplinary analysis.

    PubMed

    Lemée, Jean-Michel; Clavreul, Anne; Aubry, Marc; Com, Emmanuelle; de Tayrac, Marie; Eliat, Pierre-Antoine; Henry, Cécile; Rousseau, Audrey; Mosser, Jean; Menei, Philippe

    2015-03-01

    Glioblastoma (GB) is the most frequent and aggressive type of primary brain tumor. Recurrences are mostly located at the margin of the resection cavity in the peritumoral brain zone (PBZ). Although it is widely believed that infiltrative tumor cells in this zone are responsible for GB recurrence, few studies have examined this zone. In this study, we analyzed PBZ left after surgery with a variety of techniques including radiology, histopathology, flow cytometry, genomic, transcriptomic, proteomic, and primary cell cultures. The resulting PBZ profiles were compared with those of the GB tumor zone and normal brain samples to identify characteristics specific to the PBZ. We found that tumor cell infiltration detected by standard histological analysis was present in almost one third of PBZ taken from an area that was considered normal both on standard MRI and by the neurosurgeon under an operating microscope. The panel of techniques used in this study show that the PBZ, similar to the tumor zone itself, is characterized by substantial inter-patient heterogeneity, which makes it difficult to identify representative markers. Nevertheless, we identified specific alterations in the PBZ such as the presence of selected tumor clones and stromal cells with tumorigenic and angiogenic properties. The study of GB-PBZ is a growing field of interest and this region needs to be characterized further. This will facilitate the development of new, targeted therapies for patients with GB and the development of approaches to refine the per-operative evaluation of the PBZ to optimize the surgical resection of the tumor.

  3. Inhibition of Nucleotide Synthesis Targets Brain Tumor Stem Cells in a Subset of Glioblastoma.

    PubMed

    Laks, Dan R; Ta, Lisa; Crisman, Thomas J; Gao, Fuying; Coppola, Giovanni; Radu, Caius G; Nathanson, David A; Kornblum, Harley I

    2016-06-01

    Inhibition of both the de novo (DNP) and salvage (NSP) pathways of nucleoside synthesis has been demonstrated to impair leukemia cells. We endeavored to determine whether this approach would be efficacious in glioblastoma. To diminish nucleoside biosynthesis, we utilized compound DI-39, which selectively targets NSP, in combination with thymidine (dT), which selectively targets DNP. We employed in vitro and ex vivo models to determine the effects of pretreatment with dT + DI-39 on brain tumor stem cells (BTSC). Here, we demonstrate that this combinatorial therapy elicits a differential response across a spectrum of human patient-derived glioblastoma cultures. As determined by apoptotic markers, most cultures were relatively resistant to treatment, although a subset was highly sensitive. Sensitivity was unrelated to S-phase delay and to DNA damage induced by treatment. Bioinformatics analysis indicated that response across cultures was associated with the transcription factor PAX3 (associated with resistance) and with canonical pathways, including the nucleotide excision repair pathway, PTEN (associated with resistance), PI3K/AKT (associated with sensitivity), and ErbB2-ErbB3. Our in vitro assays demonstrated that, in sensitive cultures, clonal sphere formation was reduced upon removal from pretreatment. In contrast, in a resistant culture, clonal sphere formation was slightly increased upon removal from pretreatment. Moreover, in an intracranial xenograft model, pretreatment of a sensitive culture caused significantly smaller and fewer tumors. In a resistant culture, tumors were equivalent irrespective of pretreatment. These results indicate that, in the subset of sensitive glioblastoma, BTSCs are targeted by inhibition of pyrimidine synthesis. Mol Cancer Ther; 15(6); 1271-8. ©2016 AACR. ©2016 American Association for Cancer Research.

  4. A nanostructure of functional targeting epirubicin liposomes dually modified with aminophenyl glucose and cyclic pentapeptide used for brain glioblastoma treatment.

    PubMed

    Zhang, Cheng-Xiang; Zhao, Wei-Yu; Liu, Lei; Ju, Rui-Jun; Mu, Li-Min; Zhao, Yao; Zeng, Fan; Xie, Hong-Jun; Yan, Yan; Lu, Wan-Liang

    2015-10-20

    The objectives of the present study were to develop functional targeting epirubicin liposomes for transferring drugs across the blood-brain barrier (BBB), treating glioblastoma, and disabling neovascularization. The studies were performed on glioblastoma cells in vitro and on glioblastoma-bearing mice. The results showed that the constructed liposomes had a high encapsulation efficiency for drugs (>95%), suitable particle size (109 nm), and less leakage in the blood component-containing system; were significantly able to be transported across the BBB; and exhibited efficacies in killing glioblastoma cells and in destroying glioblastoma neovasculature in vitro and in glioblastoma-bearing mice. The action mechanisms of functional targeting epirubicin liposomes correlated with the following features: the long circulation in the blood system, the ability to be transported across the BBB via glucose transporter-1, and the targeting effects on glioblastoma cells and on the endothelial cells of the glioblastoma neovasculature via the integrin β3 receptor. In conclusion, functional targeting epirubicin liposomes could be used as a potential therapy for treating brain glioblastoma and disabling neovascularization in brain glioblastomas.

  5. A nanostructure of functional targeting epirubicin liposomes dually modified with aminophenyl glucose and cyclic pentapeptide used for brain glioblastoma treatment

    PubMed Central

    Zhang, Cheng-Xiang; Zhao, Wei-Yu; Liu, Lei; Ju, Rui-Jun; Mu, Li-Min; Zhao, Yao; Zeng, Fan; Xie, Hong-Jun; Yan, Yan; Lu, Wan-Liang

    2015-01-01

    The objectives of the present study were to develop functional targeting epirubicin liposomes for transferring drugs across the blood-brain barrier (BBB), treating glioblastoma, and disabling neovascularization. The studies were performed on glioblastoma cells in vitro and on glioblastoma-bearing mice. The results showed that the constructed liposomes had a high encapsulation efficiency for drugs (>95%), suitable particle size (109 nm), and less leakage in the blood component-containing system; were significantly able to be transported across the BBB; and exhibited efficacies in killing glioblastoma cells and in destroying glioblastoma neovasculature in vitro and in glioblastoma-bearing mice. The action mechanisms of functional targeting epirubicin liposomes correlated with the following features: the long circulation in the blood system, the ability to be transported across the BBB via glucose transporter-1, and the targeting effects on glioblastoma cells and on the endothelial cells of the glioblastoma neovasculature via the integrin β3 receptor. In conclusion, functional targeting epirubicin liposomes could be used as a potential therapy for treating brain glioblastoma and disabling neovascularization in brain glioblastomas. PMID:26418720

  6. Combining Immunotherapy with Standard Glioblastoma Therapy

    Cancer.gov

    This clinical trial is testing standard therapy (surgery, radiation and temozolomide) plus immunotherapy with pembrolizumab with or without a cancer treatment vaccine for patients with newly diagnosed glioblastoma, a common and deadly type of brain tumor.

  7. Cancer stem cells from a rare form of glioblastoma multiforme involving the neurogenic ventricular wall

    PubMed Central

    2012-01-01

    Background The cancer stem cell (CSC) hypothesis posits that deregulated neural stem cells (NSCs) form the basis of brain tumors such as glioblastoma multiforme (GBM). GBM, however, usually forms in the cerebral white matter while normal NSCs reside in subventricular and hippocampal regions. We attempted to characterize CSCs from a rare form of glioblastoma multiforme involving the neurogenic ventricular wall. Methods We described isolating CSCs from a GBM involving the lateral ventricles and characterized these cells with in vitro molecular biomarker profiling, cellular behavior, ex vivo and in vivo techniques. Results The patient’s MRI revealed a heterogeneous mass with associated edema, involving the left subventricular zone. Histological examination of the tumor established it as being a high-grade glial neoplasm, characterized by polygonal and fusiform cells with marked nuclear atypia, amphophilic cytoplasm, prominent nucleoli, frequent mitotic figures, irregular zones of necrosis and vascular hyperplasia. Recurrence of the tumor occurred shortly after the surgical resection. CD133-positive cells, isolated from the tumor, expressed stem cell markers including nestin, CD133, Ki67, Sox2, EFNB1, EFNB2, EFNB3, Cav-1, Musashi, Nucleostemin, Notch 2, Notch 4, and Pax6. Biomarkers expressed in differentiated cells included Cathepsin L, Cathepsin B, Mucin18, Mucin24, c-Myc, NSE, and TIMP1. Expression of unique cancer-related transcripts in these CD133-positive cells, such as caveolin-1 and −2, do not appear to have been previously reported in the literature. Ex vivo organotypic brain slice co-culture showed that the CD133+ cells behaved like tumor cells. The CD133-positive cells also induced tumor formation when they were stereotactically transplanted into the brains of the immune-deficient NOD/SCID mice. Conclusions This brain tumor involving the neurogenic lateral ventricular wall was comprised of tumor-forming, CD133-positive cancer stem cells, which are likely

  8. Molecular crosstalk between tumour and brain parenchyma instructs histopathological features in glioblastoma

    PubMed Central

    Bougnaud, Sébastien; Golebiewska, Anna; Oudin, Anaïs; Keunen, Olivier; Harter, Patrick N.; Mäder, Lisa; Azuaje, Francisco; Fritah, Sabrina; Stieber, Daniel; Kaoma, Tony; Vallar, Laurent; Brons, Nicolaas H.C.; Daubon, Thomas; Miletic, Hrvoje; Sundstrøm, Terje; Herold-Mende, Christel; Mittelbronn, Michel; Bjerkvig, Rolf; Niclou, Simone P.

    2016-01-01

    The histopathological and molecular heterogeneity of glioblastomas represents a major obstacle for effective therapies. Glioblastomas do not develop autonomously, but evolve in a unique environment that adapts to the growing tumour mass and contributes to the malignancy of these neoplasms. Here, we show that patient-derived glioblastoma xenografts generated in the mouse brain from organotypic spheroids reproducibly give rise to three different histological phenotypes: (i) a highly invasive phenotype with an apparent normal brain vasculature, (ii) a highly angiogenic phenotype displaying microvascular proliferation and necrosis and (iii) an intermediate phenotype combining features of invasion and vessel abnormalities. These phenotypic differences were visible during early phases of tumour development suggesting an early instructive role of tumour cells on the brain parenchyma. Conversely, we found that tumour-instructed stromal cells differentially influenced tumour cell proliferation and migration in vitro, indicating a reciprocal crosstalk between neoplastic and non-neoplastic cells. We did not detect any transdifferentiation of tumour cells into endothelial cells. Cell type-specific transcriptomic analysis of tumour and endothelial cells revealed a strong phenotype-specific molecular conversion between the two cell types, suggesting co-evolution of tumour and endothelial cells. Integrative bioinformatic analysis confirmed the reciprocal crosstalk between tumour and microenvironment and suggested a key role for TGFβ1 and extracellular matrix proteins as major interaction modules that shape glioblastoma progression. These data provide novel insight into tumour-host interactions and identify novel stroma-specific targets that may play a role in combinatorial treatment strategies against glioblastoma. PMID:27049916

  9. Intratumoral decorin gene delivery by AAV vector inhibits brain glioblastomas and prolongs survival of animals by inducing cell differentiation.

    PubMed

    Ma, Hsin-I; Hueng, Dueng-Yuan; Shui, Hao-Ai; Han, Jun-Ming; Wang, Chi-Hsien; Lai, Ying-Hsiu; Cheng, Shi-Yuan; Xiao, Xiao; Chen, Ming-Teh; Yang, Yi-Ping

    2014-03-12

    Glioblastoma multiforme (GBM) is the most malignant cancer in the central nervous system with poor clinical prognosis. In this study, we investigated the therapeutic effect of an anti-cancer protein, decorin, by delivering it into a xenograft U87MG glioma tumor in the brain of nude mice through an adeno-associated viral (AAV2) gene delivery system. Decorin expression from the AAV vector in vitro inhibited cultured U87MG cell growth by induction of cell differentiation. Intracranial injection of AAV-decorin vector to the glioma-bearing nude mice in vivo significantly suppressed brain tumor growth and prolonged survival when compared to control non-treated mice bearing the same U87MG tumors. Proteomics analysis on protein expression profiles in the U87MG glioma cells after AAV-mediated decorin gene transfer revealed up- and down-regulation of important proteins. Differentially expressed proteins between control and AAV-decorin-transduced cells were identified through MALDI-TOF MS and database mining. We found that a number of important proteins that are involved in apoptosis, transcription, chemotherapy resistance, mitosis, and fatty acid metabolism have been altered as a result of decorin overexpression. These findings offer valuable insight into the mechanisms of the anti-glioblastoma effects of decorin. In addition, AAV-mediated decorin gene delivery warrants further investigation as a potential therapeutic approach for brain tumors.

  10. Glycoprotein nonmetastatic melanoma protein B (GPNMB) promotes the progression of brain glioblastoma via Na(+)/K(+)-ATPase.

    PubMed

    Ono, Yoko; Chiba, Shinsuke; Yano, Hirohito; Nakayama, Noriyuki; Saio, Masanao; Tsuruma, Kazuhiro; Shimazawa, Masamitsu; Iwama, Toru; Hara, Hideaki

    2016-12-02

    Glycoprotein nonmetastatic melanoma protein B (GPNMB), which is involved in invasion and metastasis, was found to be overexpressed in various cancers. High levels of GPNMB and Na(+)/K(+)-ATPase α subunits are associated with a poor prognosis in glioblastoma patients. We showed that GPNMB interacts with Na(+)/K(+)-ATPase α subunits to activate PI3K/Akt and MEK/ERK pathways. However, it remains unclear whether the interaction of GPNMB and Na(+)/K(+)-ATPase α subunits is involves in progression of glioma. The tumor size induced by the injection of glioma GL261 cells was larger in transgenic mice overexpressing GPNMB when compared with wild-type mice. Additionally, the interaction of GPNMB and Na(+)/K(+)-ATPase α subunits was identified in the murine glioma model and in the tumors of glioblastoma patients. Ouabain, a Na(+)/K(+)-ATPase inhibitor, suppressed the glioma growth induced by the injection of glioma cells in the transgenic mice overexpressing GPNMB and blocked the GPNMB-induced migration of glioma cells. These findings indicate that GPNMB promotes glioma growth via Na(+)/K(+)-ATPase α subunits. Thus, the interaction between GPNMB and Na(+), K(+)-ATPase α subunits represents a novel therapeutic target for the treatment of brain glioblastomas. Copyright © 2016 Elsevier Inc. All rights reserved.

  11. Predicting the Electric Field Distribution in the Brain for the Treatment of Glioblastoma

    PubMed Central

    Miranda, Pedro C.; Mekonnen, Abeye; Salvador, Ricardo; Basser, Peter J.

    2014-01-01

    The use of alternating electric fields has been recently proposed for the treatment of recurrent glioblastoma. In order to predict the electric field distribution in the brain during the application of such tumor treating fields (TTF), we constructed a realistic head model from MRI data and placed transducer arrays on the scalp to mimic an FDA-approved medical device. Values for the tissue dielectric properties were taken from the literature; values for the device parameters were obtained from the manufacturer. The finite element method was used to calculate the electric field distribution in the brain. We also included a “virtual lesion” in the model to simulate the presence of an idealized tumor. The calculated electric field in the brain varied mostly between 0.5 and 2.0 V/cm and exceeded 1.0 V/cm in 60% of the total brain volume. Regions of local field enhancement occurred near interfaces between tissues with different conductivities wherever the electric field was perpendicular to those interfaces. These increases were strongest near the ventricles but were also present outside the tumor’s necrotic core and in some parts of the gray matter-white matter interface. The electric field values predicted in this model brain are in reasonably good agreement with those that have been shown to reduce cancer cell proliferation in vitro. The electric field distribution is highly non-uniform and depends on tissue geometry and dielectric properties. This could explain some of the variability in treatment outcomes. The proposed modeling framework could be used to better understand the physical basis of TTF efficacy through retrospective analysis and to improve TTF treatment planning. PMID:25003941

  12. Predicting the electric field distribution in the brain for the treatment of glioblastoma.

    PubMed

    Miranda, Pedro C; Mekonnen, Abeye; Salvador, Ricardo; Basser, Peter J

    2014-08-07

    The use of alternating electric fields has been recently proposed for the treatment of recurrent glioblastoma. In order to predict the electric field distribution in the brain during the application of such tumor treating fields (TTF), we constructed a realistic head model from MRI data and placed transducer arrays on the scalp to mimic an FDA-approved medical device. Values for the tissue dielectric properties were taken from the literature; values for the device parameters were obtained from the manufacturer. The finite element method was used to calculate the electric field distribution in the brain. We also included a 'virtual lesion' in the model to simulate the presence of an idealized tumor. The calculated electric field in the brain varied mostly between 0.5 and 2.0 V cm( - 1) and exceeded 1.0 V cm( - 1) in 60% of the total brain volume. Regions of local field enhancement occurred near interfaces between tissues with different conductivities wherever the electric field was perpendicular to those interfaces. These increases were strongest near the ventricles but were also present outside the tumor's necrotic core and in some parts of the gray matter-white matter interface. The electric field values predicted in this model brain are in reasonably good agreement with those that have been shown to reduce cancer cell proliferation in vitro. The electric field distribution is highly non-uniform and depends on tissue geometry and dielectric properties. This could explain some of the variability in treatment outcomes. The proposed modeling framework could be used to better understand the physical basis of TTF efficacy through retrospective analysis and to improve TTF treatment planning.

  13. Predicting the electric field distribution in the brain for the treatment of glioblastoma

    NASA Astrophysics Data System (ADS)

    Miranda, Pedro C.; Mekonnen, Abeye; Salvador, Ricardo; Basser, Peter J.

    2014-08-01

    The use of alternating electric fields has been recently proposed for the treatment of recurrent glioblastoma. In order to predict the electric field distribution in the brain during the application of such tumor treating fields (TTF), we constructed a realistic head model from MRI data and placed transducer arrays on the scalp to mimic an FDA-approved medical device. Values for the tissue dielectric properties were taken from the literature; values for the device parameters were obtained from the manufacturer. The finite element method was used to calculate the electric field distribution in the brain. We also included a ‘virtual lesion’ in the model to simulate the presence of an idealized tumor. The calculated electric field in the brain varied mostly between 0.5 and 2.0 V cm - 1 and exceeded 1.0 V cm - 1 in 60% of the total brain volume. Regions of local field enhancement occurred near interfaces between tissues with different conductivities wherever the electric field was perpendicular to those interfaces. These increases were strongest near the ventricles but were also present outside the tumor’s necrotic core and in some parts of the gray matter-white matter interface. The electric field values predicted in this model brain are in reasonably good agreement with those that have been shown to reduce cancer cell proliferation in vitro. The electric field distribution is highly non-uniform and depends on tissue geometry and dielectric properties. This could explain some of the variability in treatment outcomes. The proposed modeling framework could be used to better understand the physical basis of TTF efficacy through retrospective analysis and to improve TTF treatment planning.

  14. MOLECULAR ALTERATIONS IN GLIOBLASTOMA: POTENTIAL TARGETS FOR IMMUNOTHERAPY

    PubMed Central

    Haque, Azizul; Banik, Naren L.; Ray, Swapan K.

    2015-01-01

    Glioblastoma is the most common and deadly brain tumor, possibly arising from genetic and epigenetic alterations in normal astroglial cells. Multiple cytogenetic, chromosomal, and genetic alterations have been identified in glioblastoma, with distinct expression of antigens (Ags) and biomarkers that may alter therapeutic potential of this aggressive cancer. Current therapy consists of surgical resection, followed by radiation therapy and chemotherapy. In spite of these treatments, the prognosis for glioblastoma patients is poor. Although recent studies have focused on the development of novel immunotherapeutics against glioblastoma, little is known about glioblastoma specific immune responses. A better understanding of the molecular interactions among glioblastoma tumors, host immune cells, and the tumor microenvironment may give rise to novel integrated approaches for the simultaneous control of tumor escape pathways and the activation of antitumor immune responses. This review provides a detailed overview concerning genetic alterations in glioblastoma, their effects on Ag and biomarker expression and the future design of chemoimmunotherapeutics against glioblastoma. PMID:21199773

  15. Survival comparison between glioblastoma multiforme and other incurable cancers.

    PubMed

    Tran, B; Rosenthal, M A

    2010-04-01

    Glioblastoma multiforme (GBM) is an incurable disease that has a reputation as having one of the worst prognoses of all cancers. Recent advances in treatment have led to significant improvements in both progression-free and overall survival. Despite this, the wider medical community continues to perceive GBM as having an incomparably poor prognosis. This perception may stem from a lack of awareness regarding the significant survival advantage through the addition of concurrent and post-radiotherapy temozolomide, as well as unfair comparisons to cancers with curable early stages. In this analysis, we compared the efficacy data reported in pivotal studies for the incurable stage of common cancers to modern efficacy data for GBM. In particular, we compared median overall survival, median progression-free survival and 12-month and 5-year survival rates. Our results demonstrate that with modern treatment, GBM survival is now comparable to, if not better than, many other incurable cancers. (c) 2009. Published by Elsevier Ltd. All rights reserved.

  16. Therapy targets in glioblastoma and cancer stem cells: lessons from haematopoietic neoplasms.

    PubMed

    Cruceru, Maria Linda; Neagu, Monica; Demoulin, Jean-Baptiste; Constantinescu, Stefan N

    2013-10-01

    Despite intense efforts to identify cancer-initiating cells in malignant brain tumours, markers linked to the function of these cells have only very recently begun to be uncovered. The notion of cancer stem cell gained prominence, several molecules and signalling pathways becoming relevant for diagnosis and treatment. Whether a substantial fraction or only a tiny minority of cells in a tumor can initiate and perpetuate cancer, is still debated. The paradigm of cancer-initiating stem cells has initially been developed with respect to blood cancers where chronic conditions such as myeloproliferative neoplasms are due to mutations acquired in a haematopoietic stem cell (HSC), which maintains the normal hierarchy to neoplastic haematopoiesis. In contrast, acute leukaemia transformation of such blood neoplasms appears to derive not only from HSCs but also from committed progenitors that cannot differentiate. This review will focus on putative novel therapy targets represented by markers described to define cancer stem/initiating cells in malignant gliomas, which have been called 'leukaemia of the brain', given their rapid migration and evolution. Parallels are drawn with other cancers, especially haematopoietic, given the similar rampant proliferation and treatment resistance of glioblastoma multiforme and secondary acute leukaemias. Genes associated with the malignant conditions and especially expressed in glioma cancer stem cells are intensively searched. Although many such molecules might only coincidentally be expressed in cancer-initiating cells, some may function in the oncogenic process, and those would be the prime candidates for diagnostic and targeted therapy. For the latter, combination therapies are likely to be envisaged, given the robust and plastic signalling networks supporting malignant proliferation. © 2013 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  17. Neurosurgical Techniques for Disruption of the Blood–Brain Barrier for Glioblastoma Treatment

    PubMed Central

    Rodriguez, Analiz; Tatter, Stephen B.; Debinski, Waldemar

    2015-01-01

    The blood–brain barrier remains a main hurdle to drug delivery to the brain. The prognosis of glioblastoma remains grim despite current multimodal medical management. We review neurosurgical technologies that disrupt the blood–brain barrier (BBB). We will review superselective intra-arterial mannitol infusion, focused ultrasound, laser interstitial thermotherapy, and non-thermal irreversible electroporation (NTIRE). These technologies can lead to transient BBB and blood–brain tumor barrier disruption and allow for the potential of more effective local drug delivery. Animal studies and preliminary clinical trials show promise for achieving this goal. PMID:26247958

  18. Stopping cancer in its tracks: using small molecular inhibitors to target glioblastoma migrating cells.

    PubMed

    Mattox, Austin K; Li, Jing; Adamson, David C

    2012-12-01

    Glioblastoma multiforme (GBM) represents one of the most common aggressive types of primary brain tumors. Despite advances in surgical resection, novel neuroimaging procedures, and the most recent adjuvant radiotherapy and chemotherapy, the median survival after diagnosis is about 12-14 months. Targeting migrating GBM cells is a key research strategy in the fight against this devastating cancer. Though the vast majority of the primary tumor focus can be surgically resected, these migrating cells are responsible for its universal recurrence. Numerous strategies and technologies are being explored to target migrating glioma cells, with small molecular inhibitors as one of the most commonly studied. Small molecule inhibitors, such as protein kinase inhibitors, phosphorylation site inhibitors, protease inhibitors, and antisense oligonucleotides show promise in slowing the progression of this disease. A better understanding of these small molecule inhibitors and how they target various extra- and intracellular signaling pathways may eventually lead to a cure for GBM.

  19. Neural Stem Cells and Glioblastoma

    PubMed Central

    Rispoli, Rossella; Conti, Carlo; Celli, Paolo; Caroli, Emanuela; Carletti, Sandro

    2014-01-01

    Summary Glioblastoma multiforme represents one of the most common brain cancers with a rather heterogeneous cellular composition, as indicated by the term “multiforme". Recent reports have described the isolation and identification of cancer neural stem cells from human adult glioblastoma multiforme, which possess the capacity to establish, sustain, and expand these tumours, even under the challenging settings posed by serial transplantation experiments. Our study focused on the distribution of neural cancer stem cells inside the tumour. The study is divided into three phases: removal of tumoral specimens in different areas of the tumour (centre, periphery, marginal zone) in an operative room equipped with a 1.5 T scanner; isolation and characterization of neural cancer stem cells from human adult glioblastoma multiforme; identification of neural cancer stem cell distribution inside the tumour. PMID:24750704

  20. The novel CXCR4 antagonist, PRX177561, reduces tumor cell proliferation and accelerates cancer stem cell differentiation in glioblastoma preclinical models.

    PubMed

    Gravina, Giovanni Luca; Mancini, Andrea; Colapietro, Alessandro; Vitale, Flora; Vetuschi, Antonella; Pompili, Simona; Rossi, Giulia; Marampon, Francesco; Richardson, Peter J; Patient, Lee; Patient, Lee; Burbidge, Stephen; Festuccia, Claudio

    2017-06-01

    Glioblastoma is the most frequent and the most lethal primary brain tumor among adults. Standard of care is the association of radiotherapy with concomitant or adjuvant temozolomide. However, to date, recurrence is inevitable. The CXCL12/CXCR4 pathway is upregulated in the glioblastoma tumor microenvironment regulating tumor cell proliferation, local invasion, angiogenesis, and the efficacy of radio-chemotherapy. In this study, we evaluated the effects of the novel CXCR4 antagonist, PRX177561, in preclinical models of glioblastoma. CXCR4 expression and PRX177561 effects were assessed on a panel of 12 human glioblastoma cells lines and 5 patient-derived glioblastoma stem cell cultures. Next, the effect of PRX177561 was tested in vivo, using subcutaneous injection of U87MG, U251, and T98G cells as well as orthotopic intrabrain inoculation of luciferase-transfected U87MG cells. Here we found that PRX177561 impairs the proliferation of human glioblastoma cell lines, increases apoptosis, and reduces CXCR4 expression and cell migration in response to stromal cell-derived factor 1alpha in vitro. PRX177561 reduced the expression of stem cell markers and increased that of E-cadherin and glial fibrillary acidic protein in U87MG cells consistent with a reduction in cancer stem cells. In vivo, PRX177561 reduced the weight and increased the time to progression of glioblastoma subcutaneous tumors while increasing disease-free survival and overall survival of mice bearing orthotopic tumors. Our findings suggest that targeting stromal cell-derived factor 1 alpha/CXCR4 axis by PRX177561 might represent a novel therapeutic approach against glioblastoma and support further investigation of this compound in more complex preclinical settings in order to determine its therapeutic potential.

  1. Genome-wide analysis of OCT4 binding sites in glioblastoma cancer cells.

    PubMed

    Fang, Xue-feng; Zhang, Wei-yi; Zhao, Na; Yu, Wei; Ding, Dong; Hong, Xu; Li, Li-sha; Zhang, Hua-rong; Zheng, Shu; Lin, Biao-yang

    2011-10-01

    OCT4, a member of the POU family of gene products, is an octamer motif-binding transcription factor. As it is known to play a crucial role in cancer processes including proliferation, invasion, and chemoradioresistance, it is important to identify the direct targets of OCT4 in living cancer cells. Here, chromatin immunoprecipitation-sequencing (ChIP-seq) was used to identify OCT4 binding sites in glioblastoma cancer cells. The results showed that 5438 OCT4 binding sites were localized in the glioblastoma cancer genome and that these sites contained a consensus sequence TTTkswTw (k=T or G, s=C or G, w=A or T), which occurred 3931 times in 2312 OCT4 binding regions. Furthermore, binding motifs of some other transcription factors were identified in OCT4 binding regions. Our results provide a valuable dataset for understanding gene regulation mechanisms underlying the function of OCT4 in glioblastoma cancer.

  2. Brain cancer spreads.

    PubMed

    Perryman, Lara; Erler, Janine T

    2014-07-30

    The discovery that ~20% of patients with brain cancer have circulating tumor cells breaks the dogma that these cells are confined to the brain and has important clinical implications (Müller et al., this issue).

  3. Label-Free Delineation of Brain Tumors by Coherent Anti-Stokes Raman Scattering Microscopy in an Orthotopic Mouse Model and Human Glioblastoma

    PubMed Central

    Tamosaityte, Sandra; Leipnitz, Elke; Geiger, Kathrin D.; Schackert, Gabriele; Koch, Edmund; Steiner, Gerald; Kirsch, Matthias

    2014-01-01

    Background Coherent anti-Stokes Raman scattering (CARS) microscopy provides fine resolution imaging and displays morphochemical properties of unstained tissue. Here, we evaluated this technique to delineate and identify brain tumors. Methods Different human tumors (glioblastoma, brain metastases of melanoma and breast cancer) were induced in an orthotopic mouse model. Cryosections were investigated by CARS imaging tuned to probe C-H molecular vibrations, thereby addressing the lipid content of the sample. Raman microspectroscopy was used as reference. Histopathology provided information about the tumor's localization, cell proliferation and vascularization. Results The morphochemical contrast of CARS images enabled identifying brain tumors irrespective of the tumor type and properties: All tumors were characterized by a lower CARS signal intensity than the normal parenchyma. On this basis, tumor borders and infiltrations could be identified with cellular resolution. Quantitative analysis revealed that the tumor-related reduction of CARS signal intensity was more pronounced in glioblastoma than in metastases. Raman spectroscopy enabled relating the CARS intensity variation to the decline of total lipid content in the tumors. The analysis of the immunohistochemical stainings revealed no correlation between tumor-induced cytological changes and the extent of CARS signal intensity reductions. The results were confirmed on samples of human glioblastoma. Conclusions CARS imaging enables label-free, rapid and objective identification of primary and secondary brain tumors. Therefore, it is a potential tool for diagnostic neuropathology as well as for intraoperative tumor delineation. PMID:25198698

  4. Therapy targets in glioblastoma and cancer stem cells: lessons from haematopoietic neoplasms

    PubMed Central

    Cruceru, Maria Linda; Neagu, Monica; Demoulin, Jean-Baptiste; Constantinescu, Stefan N

    2013-01-01

    Despite intense efforts to identify cancer-initiating cells in malignant brain tumours, markers linked to the function of these cells have only very recently begun to be uncovered. The notion of cancer stem cell gained prominence, several molecules and signalling pathways becoming relevant for diagnosis and treatment. Whether a substantial fraction or only a tiny minority of cells in a tumor can initiate and perpetuate cancer, is still debated. The paradigm of cancer-initiating stem cells has initially been developed with respect to blood cancers where chronic conditions such as myeloproliferative neoplasms are due to mutations acquired in a haematopoietic stem cell (HSC), which maintains the normal hierarchy to neoplastic haematopoiesis. In contrast, acute leukaemia transformation of such blood neoplasms appears to derive not only from HSCs but also from committed progenitors that cannot differentiate. This review will focus on putative novel therapy targets represented by markers described to define cancer stem/initiating cells in malignant gliomas, which have been called ‘leukaemia of the brain’, given their rapid migration and evolution. Parallels are drawn with other cancers, especially haematopoietic, given the similar rampant proliferation and treatment resistance of glioblastoma multiforme and secondary acute leukaemias. Genes associated with the malignant conditions and especially expressed in glioma cancer stem cells are intensively searched. Although many such molecules might only coincidentally be expressed in cancer-initiating cells, some may function in the oncogenic process, and those would be the prime candidates for diagnostic and targeted therapy. For the latter, combination therapies are likely to be envisaged, given the robust and plastic signalling networks supporting malignant proliferation. PMID:23998913

  5. Lineage-specific splicing of a brain-enriched alternative exon promotes glioblastoma progression

    PubMed Central

    Ferrarese, Roberto; Harsh, Griffith R.; Yadav, Ajay K.; Bug, Eva; Maticzka, Daniel; Reichardt, Wilfried; Dombrowski, Stephen M.; Miller, Tyler E.; Masilamani, Anie P.; Dai, Fangping; Kim, Hyunsoo; Hadler, Michael; Scholtens, Denise M.; Yu, Irene L.Y.; Beck, Jürgen; Srinivasasainagendra, Vinodh; Costa, Fabrizio; Baxan, Nicoleta; Pfeifer, Dietmar; von Elverfeldt, Dominik; Backofen, Rolf; Weyerbrock, Astrid; Duarte, Christine W.; He, Xiaolin; Prinz, Marco; Chandler, James P.; Vogel, Hannes; Chakravarti, Arnab; Rich, Jeremy N.; Carro, Maria S.; Bredel, Markus

    2014-01-01

    Tissue-specific alternative splicing is critical for the emergence of tissue identity during development, yet the role of this process in malignant transformation is undefined. Tissue-specific splicing involves evolutionarily conserved, alternative exons that represent only a minority of the total alternative exons identified. Many of these conserved exons have functional features that influence signaling pathways to profound biological effect. Here, we determined that lineage-specific splicing of a brain-enriched cassette exon in the membrane-binding tumor suppressor annexin A7 (ANXA7) diminishes endosomal targeting of the EGFR oncoprotein, consequently enhancing EGFR signaling during brain tumor progression. ANXA7 exon splicing was mediated by the ribonucleoprotein PTBP1, which is normally repressed during neuronal development. PTBP1 was highly expressed in glioblastomas due to loss of a brain-enriched microRNA (miR-124) and to PTBP1 amplification. The alternative ANXA7 splicing trait was present in precursor cells, suggesting that glioblastoma cells inherit the trait from a potential tumor-initiating ancestor and that these cells exploit this trait through accumulation of mutations that enhance EGFR signaling. Our data illustrate that lineage-specific splicing of a tissue-regulated alternative exon in a constituent of an oncogenic pathway eliminates tumor suppressor functions and promotes glioblastoma progression. This paradigm may offer a general model as to how tissue-specific regulatory mechanisms can reprogram normal developmental processes into oncogenic ones. PMID:24865424

  6. miR-340 predicts glioblastoma survival and modulates key cancer hallmarks through down-regulation of NRAS

    PubMed Central

    Fiore, Danilo; Donnarumma, Elvira; Roscigno, Giuseppina; Iaboni, Margherita; Russo, Valentina; Affinito, Alessandra; Adamo, Assunta; De Martino, Fabio; Quintavalle, Cristina; Romano, Giulia; Greco, Adelaide; Soini, Ylermi; Brunetti, Arturo; Croce, Carlo M.; Condorelli, Gerolama

    2016-01-01

    Glioblastoma is the most common primary brain tumor in adults; with a survival rate of 12 months from diagnosis. However, a small subgroup of patients, termed long-term survivors (LTS), has a survival rate longer then 12–14 months. There is thus increasing interest in the identification of molecular signatures predicting glioblastoma prognosis and in how to improve the therapeutic approach. Here, we report miR-340 as prognostic tumor-suppressor microRNA for glioblastoma. We analyzed microRNA expression in > 500 glioblastoma patients and found that although miR-340 is strongly down-regulated in glioblastoma overall, it is up-regulated in LTS patients compared to short-term survivors (STS). Indeed, miR-340 expression predicted better prognosis in glioblastoma patients. Coherently, overexpression of miR-340 in glioblastoma cells was found to produce a tumor-suppressive activity. We identified NRAS mRNA as a critical, direct target of miR-340: in fact, miR-340 negatively influenced multiple aspects of glioblastoma tumorigenesis by down-regulating NRAS and downstream AKT and ERK pathways. Thus, we demonstrate that expression of miR-340 in glioblastoma is responsible for a strong tumor-suppressive effect in LTS patients by down-regulating NRAS. miR-340 may thus represent a novel marker for glioblastoma diagnosis and prognosis, and may be developed into a tool to improve treatment of glioblastoma. PMID:26799668

  7. Casein Kinase 2: a novel player in glioblastoma therapy and cancer stem cells

    PubMed Central

    Agarwal, Maya; Nitta, Ryan T.; Li, Gordon

    2014-01-01

    Casein kinase 2 (CK2) is an oncogenic protein kinase which contributes to tumor development, proliferation, and suppression of apoptosis in multiple cancer types. The mechanism by which CK2 expression and activity leads to tumorigenesis in glioblastoma (GBM), a stage IV primary brain tumor, is being studied. Recent studies demonstrate that CK2 plays an important role in GBM formation and growth through the inhibition of tumor suppressors and activation of oncogenes. In addition, intriguing new reports indicate that CK2 may regulate GBM formation in a novel manner; CK2 may play a critical role in cancer stem cell (CSC) maintenance. Since glial CSCs have the ability to self-renew and initiate tumor growth, new treatments which target these CSCs are needed to treat this fatal disease. Inhibition of CK2 is potentially a novel method to inhibit GBM growth and reoccurrence by targeting the glial CSCs. A new, orally available, selective CK2 inhibitor, CX-4945 has had promising results when tested in cancer cell lines, in vivo xenograft models, and human clinical trials. The development of CK2 targeted inhibitors, starting with CX-4945, may lead to a new class of more effective cancer therapies. PMID:25264454

  8. Evaluation of blood-brain barrier-stealth nanocomposites for in situ glioblastoma theranostics applications

    NASA Astrophysics Data System (ADS)

    Su, Chia-Hao; Tsai, Ching-Yi; Tomanek, Boguslaw; Chen, Wei-Yu; Cheng, Fong-Yu

    2016-04-01

    The blood-brain barrier (BBB) is a physiological structure of the blood vessels in the brain. The BBB efficiently traps most therapeutic drugs in the blood vessels and stops them from entering the brain tissue, resulting in a decreased therapeutic efficiency. In this study, we developed BBB-stealth nanocomposites composed of iron oxide (Fe3O4) nanoparticles (NPs) as a safe nanocarrier for glioblastoma therapy. We showed the antitumor activity of Dox/alg-Fe3O4 NPs using in vitro and in vivo tests. We demonstrated that G23-alg-Fe3O4 NPs crossed the BBB and entered the brain. In situ glioblastoma tumor-bearing mice were used to successfully evaluate the antitumor activity of G23-Dox/alg-Fe3O4 NPs. Magnetic resonance imaging (MRI) and bioluminescence imaging (BLI) confirmed the BBB crossing. The BBB-stealth nanocomposites show great potential for a proof-of-concept clinical trial as a theranostics platform for human brain tumor therapy.The blood-brain barrier (BBB) is a physiological structure of the blood vessels in the brain. The BBB efficiently traps most therapeutic drugs in the blood vessels and stops them from entering the brain tissue, resulting in a decreased therapeutic efficiency. In this study, we developed BBB-stealth nanocomposites composed of iron oxide (Fe3O4) nanoparticles (NPs) as a safe nanocarrier for glioblastoma therapy. We showed the antitumor activity of Dox/alg-Fe3O4 NPs using in vitro and in vivo tests. We demonstrated that G23-alg-Fe3O4 NPs crossed the BBB and entered the brain. In situ glioblastoma tumor-bearing mice were used to successfully evaluate the antitumor activity of G23-Dox/alg-Fe3O4 NPs. Magnetic resonance imaging (MRI) and bioluminescence imaging (BLI) confirmed the BBB crossing. The BBB-stealth nanocomposites show great potential for a proof-of-concept clinical trial as a theranostics platform for human brain tumor therapy. Electronic supplementary information (ESI) available: Experimental details. See DOI: 10.1039/c6nr00280c

  9. Nanotechnology Applications for Glioblastoma

    PubMed Central

    Nduom, Edjah; Bouras, Alexandros; Kaluzova, Milota; Hadjipanayis, Costas G.

    2012-01-01

    Synopsis Glioblastoma remains one of the most difficult cancers to treat and represents the most common primary malignancy of the brain. While conventional treatments have found modest success in reducing the initial tumor burden, infiltrating cancer cells beyond the main mass are responsible for tumor recurrence and ultimate patient demise. Targeting the residual infiltrating cancer cells requires the development of new treatment strategies. The emerging field of cancer nanotechnology holds much promise in the use of multifunctional nanoparticles for the imaging and targeted therapy of GBM.. Nanoparticles have emerged as potential “theranostic” agents that can permit the diagnosis and therapeutic treatment of GBM tumors. A recent human clinical trial with magnetic nanoparticles has provided feasibility and efficacy data for potential treatment of GBM patients with thermotherapy. Here we examine the current state of nanotechnology in the treatment of glioblastoma and interesting directions of further study. PMID:22748656

  10. Glioblastoma multiforme in patients with history of extracranial cancer: Case series.

    PubMed

    Kalita, O; Trojanec, R; Megova, M; Hajduch, M; Vaverka, M; Hrabalek, L; Zlevorova, M; Drabek, J; Tuckova, L; Vrbkova, J

    2016-05-01

    Significant progress in treatment strategies improves the expectations of patients with extracranial cancers. Metastases are the primary consideration in patients with cancer history. In the case of neurologic disorders, the patient should undergo brain MRI. A rationale is presented for surgery, whole-brain or stereotactic radiotherapy, or chemotherapy. Recently, we have encountered misdiagnosed primary malignant brain tumours in patients with oncologic history who had been admitted for surgery for brain metastases. The aim of our study is to evaluate the incidence of concurrent cancers, to assess the relationship between previous cancer staging and primary brain tumour evaluation as well as to determine treatment efficiency. From January 2007 to December 2011, we prospectively followed up patients with concurrent history of both extracranial cancer and subsequent glioblastoma multiforme. Information was collected on the clinical condition, imaging, history of extracranial cancer, previous and present surgical and oncologic procedures, and GBM histologic, cytogenetic, and molecular genetic investigations. Five patients were recruited: three females and two males. The average patient age at the time of GBM diagnosis was 65.6 years. Three patients had a history of breast carcinoma, one of renal carcinoma and one of colorectal carcinoma. Following the diagnosis of carcinoma, three patients received chemotherapy and radiotherapy, one patient had radiotherapy alone, and one had no adjuvant therapy. In all the cases, surgery revealed primary GBM, with a standard occurrence of genetic abnormalities (Table 1). The average time from the diagnosis of extracranial cancer to that of GBM was 4 years. Four patients underwent chemoradiotherapy and one had palliative radiotherapy. Two patients completed oncotherapy and their OS was 27 months and 19 months, respectively. One patient had post-surgical progression of hemiparesis. One patient had pulmonary embolism during oncotherapy

  11. MGMT hypermethylation and MDR system in glioblastoma cancer stem cells.

    PubMed

    Caldera, Valentina; Mellai, Marta; Annovazzi, Laura; Monzeglio, Oriana; Piazzi, Angela; Schiffer, Davide

    2012-01-01

    Cancer stem cells (CSCs) in gliomas are associated with resistance to radio- and chemotherapy, based on O(6)-methylguanine-DNA methyltransferase (MGMT) hypermethylation and the Multidrug resistance (MDR) system activation. Samples from 21 glioblastomas (GBMs) were put in culture with growth factors or serum in order to obtain neurospheres or adherent cells. Both were genetically and immunohistochemically characterized for ATP-binding cassette, sub-family B (MDR/TAP), member 1 (ABCB1), ATP-binding cassette, sub-family C (CFTR/MRP), member 1 (ABCC1) and MGMT expression together with primary tumors. ABCB1 expression was positive in endothelial cells of primary tumors. ABCC1 expression was variably positive in tumor cells and positive in neurospheres, and less expressed in adherent cells. MGMT was methylated and unmethylated in primary tumors and in neurospheres, respectively, and unmethylated in adherent cells. Methylation is an epigenetic event affecting progenitors before the separation of the two glia lineages and maximally the future initiating cells. ABCB1 expression is limited to endothelial cells, whereas ABCC1 expression could mark a minority of tumor cells approaching a stem-like status.

  12. Glioblastoma cells inhibit astrocytic p53-expression favoring cancer malignancy

    PubMed Central

    Biasoli, D; Sobrinho, M F; da Fonseca, A C C; de Matos, D G; Romão, L; de Moraes Maciel, R; Rehen, S K; Moura-Neto, V; Borges, H L; Lima, F R S

    2014-01-01

    The tumor microenvironment has a dynamic and usually cancer-promoting function during all tumorigenic steps. Glioblastoma (GBM) is a fatal tumor of the central nervous system, in which a substantial number of non-tumoral infiltrated cells can be found. Astrocytes neighboring these tumor cells have a particular reactive phenotype and can enhance GBM malignancy by inducing aberrant cell proliferation and invasion. The tumor suppressor p53 has a potential non-cell autonomous function by modulating the expression of secreted proteins that influence neighbor cells. In this work, we investigated the role of p53 on the crosstalk between GBM cells and astrocytes. We show that extracellular matrix (ECM) from p53+/− astrocytes is richer in laminin and fibronectin, compared with ECM from p53+/+ astrocytes. In addition, ECM from p53+/− astrocytes increases the survival and the expression of mesenchymal markers in GBM cells, which suggests haploinsufficient phenotype of the p53+/– microenvironment. Importantly, conditioned medium from GBM cells blocks the expression of p53 in p53+/+ astrocytes, even when DNA was damaged. These results suggest that GBM cells create a dysfunctional microenvironment based on the impairment of p53 expression that in turns exacerbates tumor endurance. PMID:25329722

  13. Analysis of tumor metabolism reveals mitochondrial glucose oxidation in genetically diverse, human glioblastomas in the mouse brain in vivo

    PubMed Central

    Marin-Valencia, Isaac; Yang, Chendong; Mashimo, Tomoyuki; Cho, Steve; Baek, Hyeonman; Yang, Xiao-Li; Rajagopalan, Kartik N.; Maddie, Melissa; Vemireddy, Vamsidhara; Zhao, Zhenze; Cai, Ling; Good, Levi; Tu, Benjamin P.; Hatanpaa, Kimmo J.; Mickey, Bruce E.; Matés, José M.; Pascual, Juan M.; Maher, Elizabeth A.; Malloy, Craig R.; DeBerardinis, Ralph J.; Bachoo, Robert M.

    2012-01-01

    SUMMARY Dysregulated metabolism is a hallmark of cancer cell lines, but little is known about the fate of glucose and other nutrients in tumors growing in their native microenvironment. To study tumor metabolism in vivo, we used an orthotopic mouse model of primary human glioblastoma (GBM). We infused 13C-labeled nutrients into mice bearing three independent GBM lines, each with a distinct set of mutations. All three lines displayed glycolysis, as expected for aggressive tumors. They also displayed unexpected metabolic complexity, oxidizing glucose via pyruvate dehydrogenase and the citric acid cycle, and using glucose to supply anaplerosis and other biosynthetic activities. Comparing the tumors to surrounding brain revealed obvious metabolic differences, notably the accumulation of a large glutamine pool within the tumors. Many of these same activities were conserved in cells cultured ex vivo from the tumors. Thus GBM cells utilize mitochondrial glucose oxidation during aggressive tumor growth in vivo. PMID:22682223

  14. Glioblastoma multiforme of the brain stem in a patient with acquired immunodeficiency syndrome.

    PubMed

    Wolff, R; Zimmermann, M; Marquardt, Gerhard; Lanfermann, H; Nafe, R; Seifert, V

    2002-09-01

    Glioblastoma of the brain stem is rare and there is no description of such a lesion in patients suffering from acquired immunodeficiency syndrome. The majority of intracerebral mass lesions are due either to toxoplasmosis or primary central nervous system lymphomas so that it is usually not included in the differential diagnosis of enhancing lesions of the central nervous system in these patients. A 31-year-old human immunodeficiency virus (HIV) infected man presented with a four months history of slowly progressive deterioration of brainstem associated symptoms despite antitoxoplasmic therapy. Magnetic resonance imaging revealed a large ring enhancing lesion in the brainstem. Clinical and neuroradiological data could not establish a proper diagnosis and a stereotactic serial biopsy was undertaken. Histological examination of the specimen showed a glioblastoma multiforme (GBM) as the first reported case of GBM located in the brainstem in an acquired immunodeficiency syndrome (AIDS) patient. Patient management and effectiveness of stereotactic serial biopsy are discussed.

  15. SC-27CD13 REPRESENTS A NOVEL BRAIN TUMOR STEM CELL MARKER FOR GLIOBLASTOMA

    PubMed Central

    Reeve, Nathaniel; Markert, Tara; Oliva, Claudia; Griguer, Corinne

    2014-01-01

    Glioblastoma multiforme (GBM) is a very deadly and highly vascularized tumor, but targeting glioma angiogenesis by vascular endothelial growth factor inhibition has been minimally successful. Thus, understanding the molecular mechanisms that control glioma angiogenesis and progression could lead to significant new therapies. We previously described that mitochondrial DNA (mtDNA) depletion induces increased tumor angiogenesis, decreased mouse survival, increased resistance to chemotherapy, and an increase in CD133 (a well-known stem cell marker). Because glioma enriched with brain tumor stem cells (BTSCs) share similar properties with mtDNA depleted glioma cells, we hypothesize that genes up-regulated in mitochondrial depleted cells could be signature markers of BTSCs. Thus, mtDNA could be essential for the maintenance and expansion of BTSC populations. We ran an RT Profiler PCR array for angiogenesis on both U251 ρ° cells depleted of mtDNA and on the parental, isogenic U251 glioma cells. CD13 mRNA expression was increased 200 fold in ρ° cells over U251 cells. Using fluorescence-activated cell sorting and immunocytochemisty we found that CD13 is significantly increased in ρ° cells over U251 cells, and is not regulated by hypoxia (1% O2). Purification of the CD13+ population by magnetic-activated cell sorting revealed that these cells form neurospheres when cultured in Neurobasal (NB) medium. In addition, 60% of CD13+ cells were also CD133+ in NB medium, while only 10% of CD13+ cells were also CD133+ in DMEM/F-12 medium. These findings suggest CD13 may be a marker of cancer stem cells in GBM. Further elucidation of the molecular mechanisms controlling the expression of CD13 may reveal novel therapuetic targets capable of improving the treatment of GBM.

  16. Immunobiological Characterization of Cancer Stem Cells Isolated from Glioblastoma Patients

    PubMed Central

    Di Tomaso, Tiziano; Mazzoleni, Stefania; Wang, Ena; Sovena, Gloria; Clavenna, Daniela; Franzin, Alberto; Mortini, Pietro; Ferrone, Soldano; Doglioni, Claudio; Marincola, Francesco M.; Galli, Rossella; Parmiani, Giorgio; Maccalli, Cristina

    2010-01-01

    Purpose Cancer stem cells (CSC) have been isolated from human tumors, including glioblastoma multiforme (GBM). The aims of this study were the immunobiological characterization of GBM CSCs and the assessment of whether these cells represent suitable targets for immunotherapy. Experimental Design GBM CSC lines and their fetal bovine serum (FBS)–cultured non-CSC pair lines were generated and examined by flow cytometry for expression of known tumor antigens, MHC-I and MHC-II molecules, antigen-processing machinery components, and NKG2D ligands. In addition, immunogenicity and immunosuppression of such cell lines for autologous or allogeneic T lymphocytes were tested by cytokine secretion (ELISPOT) or proliferation (carboxyfluorescein diacetate succinimidyl ester) assays, respectively. Results Both GBM CSC and FBS lines were weakly positive and negative for MHC-I, MHC-II, and NKG2D ligand molecules, respectively. Antigen-processing machinery molecules were also defective in both cell types. Upregulation of most molecules was induced by IFNs or 5-Aza deoxycytidine, although more efficiently in FBS than in CSCs. Patient T-cell responses, mediated by both TH1 and the TH2 subsets, against autologous CSC could be induced in vitro. In addition, CSC but not their paired FBS tumor lines inhibited T-cell proliferation of healthy donors. Notably, a differential gene signature that was confirmed at the protein levels for some immunologic-related molecules was also found between CSC and FBS lines. Conclusions These results indicate lower immunogenicity and higher suppressive activity of GBM CSC compared with FBS lines. The immunogenicity, however, could be rescued by immune modulation leading to anti-GBM T cell–mediated immune response. PMID:20103663

  17. Chemoirradiation for glioblastoma multiforme: the national cancer institute experience.

    PubMed

    Ho, Jennifer; Ondos, John; Ning, Holly; Smith, Sharon; Kreisl, Teri; Iwamoto, Fabio; Sul, Joohee; Kim, Lyndon; McNeil, Kate; Krauze, Andra; Shankavaram, Uma; Fine, Howard A; Camphausen, Kevin

    2013-01-01

    Standard treatment for glioblastoma (GBM) is surgery followed by radiation (RT) and temozolomide (TMZ). While there is variability in survival based on several established prognostic factors, the prognostic utility of other factors such as tumor size and location are not well established. The charts of ninety two patients with GBM treated with RT at the National Cancer Institute (NCI) between 1998 and 2012 were retrospectively reviewed. Most patients received RT with concurrent and adjuvant TMZ. Topographic locations were classified using preoperative imaging. Gross tumor volumes were contoured using treatment planning systems utilizing both pre-operative and post-operative MR imaging. At a median follow-up of 18.7 months, the median overall survival (OS) and progression-free survival (PFS) for all patients was 17.9 and 7.6 months. Patients with the smallest tumors had a median OS of 52.3 months compared to 16.3 months among patients with the largest tumors, P = 0.006. The patients who received bevacizumab after recurrence had a median OS of 23.3 months, compared to 16.3 months in patients who did not receive it, P = 0.0284. The median PFS and OS in patients with periventricular tumors was 5.7 and 17.5 months, versus 8.9 and 23.3 months in patients with non-periventricular tumors, P = 0.005. Survival in our cohort was comparable to the outcome of the defining EORTC-NCIC trial establishing the use of RT+TMZ. This study also identifies several potential prognostic factors that may be useful in stratifying patients.

  18. Chemoirradiation for Glioblastoma Multiforme: The National Cancer Institute Experience

    PubMed Central

    Ho, Jennifer; Ondos, John; Ning, Holly; Smith, Sharon; Kreisl, Teri; Iwamoto, Fabio; Sul, Joohee; Kim, Lyndon; McNeil, Kate; Krauze, Andra; Shankavaram, Uma; Fine, Howard A.; Camphausen, Kevin

    2013-01-01

    Purpose Standard treatment for glioblastoma (GBM) is surgery followed by radiation (RT) and temozolomide (TMZ). While there is variability in survival based on several established prognostic factors, the prognostic utility of other factors such as tumor size and location are not well established. Experimental Design The charts of ninety two patients with GBM treated with RT at the National Cancer Institute (NCI) between 1998 and 2012 were retrospectively reviewed. Most patients received RT with concurrent and adjuvant TMZ. Topographic locations were classified using preoperative imaging. Gross tumor volumes were contoured using treatment planning systems utilizing both pre-operative and post-operative MR imaging. Results At a median follow-up of 18.7 months, the median overall survival (OS) and progression-free survival (PFS) for all patients was 17.9 and 7.6 months. Patients with the smallest tumors had a median OS of 52.3 months compared to 16.3 months among patients with the largest tumors, P = 0.006. The patients who received bevacizumab after recurrence had a median OS of 23.3 months, compared to 16.3 months in patients who did not receive it, P = 0.0284. The median PFS and OS in patients with periventricular tumors was 5.7 and 17.5 months, versus 8.9 and 23.3 months in patients with non-periventricular tumors, P = 0.005. Conclusions Survival in our cohort was comparable to the outcome of the defining EORTC-NCIC trial establishing the use of RT+TMZ. This study also identifies several potential prognostic factors that may be useful in stratifying patients. PMID:23940635

  19. Traumatic brain injury and subsequent glioblastoma development: Review of the literature and case reports

    PubMed Central

    Tyagi, Vineet; Theobald, Jason; Barger, James; Bustoros, Mark; Bayin, N. Sumru; Modrek, Aram S.; Kader, Michael; Anderer, Erich G.; Donahue, Bernadine; Fatterpekar, Girish; Placantonakis, Dimitris G

    2016-01-01

    Background: Previous reports have proposed an association between traumatic brain injury (TBI) and subsequent glioblastoma (GBM) formation. Methods: We used literature searches and radiographic evidence from two patients to assess the possibility of a link between TBI and GBM. Results: Epidemiological studies are equivocal on a possible link between brain trauma and increased risk of malignant glioma formation. We present two case reports of patients with GBM arising at the site of prior brain injury. Conclusion: The hypothesis that TBI may predispose to gliomagenesis is disputed by several large-scale epidemiological studies, but supported by some. Radiographic evidence from two cases presented here suggest that GBM formed at the site of brain injury. We propose a putative pathogenesis model that connects post-traumatic inflammation, stem and progenitor cell transformation, and gliomagenesis. PMID:27625888

  20. Two mature products of MIR-491 coordinate to suppress key cancer hallmarks in glioblastoma.

    PubMed

    Li, X; Liu, Y; Granberg, K J; Wang, Q; Moore, L M; Ji, P; Gumin, J; Sulman, E P; Calin, G A; Haapasalo, H; Nykter, M; Shmulevich, I; Fuller, G N; Lang, F F; Zhang, W

    2015-03-26

    MIR-491 is commonly co-deleted with its adjacent CDKN2A on chromosome 9p21.3 in glioblastoma multiforme (GBM). However, it is not known whether deletion of MIR-491 is only a passenger event or has an important role. Small-RNA sequencing of samples from GBM patients demonstrated that both mature products of MIR-491 (miR-491-5p and -3p) are downregulated in tumors compared with the normal brain. The integration of GBM data from The Cancer Genome Atlas (TCGA), miRNA target prediction and reporter assays showed that miR-491-5p directly targets EGFR, CDK6 and Bcl-xL, whereas miR-491-3p targets IGFBP2 and CDK6. Functionally, miR-491-3p inhibited glioma cell invasion; overexpression of both miR-491-5p and -3p inhibited proliferation of glioma cell lines and impaired the propagation of glioma stem cells (GSCs), thereby prolonging survival of xenograft mice. Moreover, knockdown of miR-491-5p in primary Ink4a-Arf-null mouse glial progenitor cells exacerbated cell proliferation and invasion. Therefore, MIR-491 is a tumor suppressor gene that, by utilizing both mature forms, coordinately controls the key cancer hallmarks: proliferation, invasion and stem cell propagation.

  1. Nucleolin antagonist triggers autophagic cell death in human glioblastoma primary cells and decreased in vivo tumor growth in orthotopic brain tumor model

    PubMed Central

    d'Angelo, Michele; Cristiano, Loredana; Galzio, Renato; Destouches, Damien; Florio, Tiziana Marilena; Dhez, Anne Chloé; Astarita, Carlo; Cinque, Benedetta; Fidoamore, Alessia; Rosati, Floriana; Cifone, Maria Grazia; Ippoliti, Rodolfo; Giordano, Antonio; Courty, José; Cimini, Annamaria

    2015-01-01

    Nucleolin (NCL) is highly expressed in several types of cancer and represents an interesting therapeutic target. It is expressed at the plasma membrane of tumor cells, a property which is being used as a marker for several human cancer including glioblastoma. In this study we investigated targeting NCL as a new therapeutic strategy for the treatment of this pathology. To explore this possibility, we studied the effect of an antagonist of NCL, the multivalent pseudopeptide N6L using primary culture of human glioblastoma cells. In this system, N6L inhibits cell growth with different sensitivity depending to NCL localization. Cell cycle analysis indicated that N6L-induced growth reduction was due to a block of the G1/S transition with down-regulation of the expression of cyclin D1 and B2. By monitoring autophagy markers such as p62 and LC3II, we demonstrate that autophagy is enhanced after N6L treatment. In addition, N6L-treatment of mice bearing tumor decreased in vivo tumor growth in orthotopic brain tumor model and increase mice survival. The results obtained indicated an anti-proliferative and pro-autophagic effect of N6L and point towards its possible use as adjuvant agent to the standard therapeutic protocols presently utilized for glioblastoma. PMID:26540346

  2. Strategies to improve delivery of anticancer drugs across the blood–brain barrier to treat glioblastoma

    PubMed Central

    Oberoi, Rajneet K.; Parrish, Karen E.; Sio, Terence T.; Mittapalli, Rajendar K.; Elmquist, William F.; Sarkaria, Jann N.

    2016-01-01

    Glioblastoma (GBM) is a lethal and aggressive brain tumor that is resistant to conventional radiation and cytotoxic chemotherapies. Molecularly targeted agents hold great promise in treating these genetically heterogeneous tumors, yet have produced disappointing results. One reason for the clinical failure of these novel therapies can be the inability of the drugs to achieve effective concentrations in the invasive regions beyond the bulk tumor. In this review, we describe the influence of the blood–brain barrier on the distribution of anticancer drugs to both the tumor core and infiltrative regions of GBM. We further describe potential strategies to overcome these drug delivery limitations. Understanding the key factors that limit drug delivery into brain tumors will guide future development of approaches for enhanced delivery of effective drugs to GBM. PMID:26359209

  3. Benzyl isothiocyanate alters the gene expression with cell cycle regulation and cell death in human brain glioblastoma GBM 8401 cells.

    PubMed

    Tang, Nou-Ying; Chueh, Fu-Shin; Yu, Chien-Chih; Liao, Ching-Lung; Lin, Jen-Jyh; Hsia, Te-Chun; Wu, King-Chuen; Liu, Hsin-Chung; Lu, Kung-Wen; Chung, Jing-Gung

    2016-04-01

    Glioblastoma multiforme (GBM) is a highly malignant devastating brain tumor in adults. Benzyl isothiocyanate (BITC) is one of the isothiocyanates that have been shown to induce human cancer cell apoptosis and cell cycle arrest. Herein, the effect of BITC on cell viability and apoptotic cell death and the genetic levels of human brain glioblastoma GBM 8401 cells in vitro were investigated. We found that BITC induced cell morphological changes, decreased cell viability and the induction of cell apoptosis in GBM 8401 cells was time-dependent. cDNA microarray was used to examine the effects of BITC on GBM 8401 cells and we found that numerous genes associated with cell death and cell cycle regulation in GBM 8401 cells were altered after BITC treatment. The results show that expression of 317 genes was upregulated, and two genes were associated with DNA damage, the DNA-damage-inducible transcript 3 (DDIT3) was increased 3.66-fold and the growth arrest and DNA-damage-inducible α (GADD45A) was increased 2.34-fold. We also found that expression of 182 genes was downregulated and two genes were associated with receptor for cell responses to stimuli, the EGF containing fibulin-like extracellular matrix protein 1 (EFEMP1) was inhibited 2.01-fold and the TNF receptor-associated protein 1 (TRAP1) was inhibited 2.08-fold. BITC inhibited seven mitochondria ribosomal genes, the mitochondrial ribosomal protein; tumor protein D52 (MRPS28) was inhibited 2.06-fold, the mitochondria ribosomal protein S2 (MRPS2) decreased 2.07-fold, the mitochondria ribosomal protein L23 (MRPL23) decreased 2.08-fold, the mitochondria ribosomal protein S2 (MRPS2) decreased 2.07-fold, the mitochondria ribosomal protein S12 (MRPS12) decreased 2.08-fold, the mitochondria ribosomal protein L12 (MRPL12) decreased 2.25-fold and the mitochondria ribosomal protein S34 (MRPS34) was decreased 2.30-fold in GBM 8401 cells. These changes of gene expression can provide the effects of BITC on the genetic level and are

  4. Glioblastoma brain tumours: estimating the time from brain tumour initiation and resolution of a patient survival anomaly after similar treatment protocols.

    PubMed

    Murray, J D

    2012-01-01

    A practical mathematical model for glioblastomas (brain tumours), which incorporates the two key parameters of tumour growth, namely the cancer cell diffusion and the cell proliferation rate, has been shown to be clinically useful and predictive. Previous studies explain why multifocal recurrence is inevitable and show how various treatment scenarios have been incorporated in the model. In most tumours, it is not known when the cancer started. Based on patient in vivo parameters, obtained from two brain scans, it is shown how to estimate the time, after initial detection, when the tumour started. This is an input of potential importance in any future controlled clinical study of any connection between cell phone radiation and brain tumour incidence. It is also used to estimate more accurately survival times from detection. Finally, based on patient parameters, the solution of the model equation of the tumour growth helps to explain why certain patients live longer than others after similar treatment protocols specifically surgical resection (removal) and irradiation.

  5. Downregulation of solute carriers of glutamate in gliosomes and synaptosomes may explain local brain metastasis in anaplastic glioblastoma.

    PubMed

    Tong, Huaiyu; Yu, Xinguang; Lu, Xuechun; Wang, Peng

    2015-04-01

    Advanced grades of glioblastoma are highly aggressive, especially in terms of multisite spread within the brain or even to distant sites at the spinal cord. In advanced grades of glioblastoma, glutamate and glutamine are reported to be increased in concentration in the extracellular fluid. It has been reported that glutamate acts as an extracellular signaling molecule for facilitating local spread of advanced grades of glioblastoma. In the present study, we aimed to examine whether glutamate uptake mechanisms is impaired in advanced glioblastoma. The possible downregulated mechanisms of glutamate uptake would facilitate persistence of glutamate in the extracellular environment, rather than intracellular uptake. We obtained biobanked human specimens of glioblastoma and tested expression of proteins belonging to the solute carrier families of proteins that are known to function as membrane-located excitatory amino acid like glutamate transporters. The present study provides preliminary evidence of the downregulation of membrane expression of excitatory amino acid transporters solute carrier family 1 member 3 (SLC1A3) and its palmitoylated form in gliosomes, as well as SLC1A2 in the glio-synaptosomes. Compounds like riluzole used in the treatment of amyotrophic lateral sclerosis and the antibiotic ceftriaxone have the potential to facilitate glutamate uptake. These medications may be examined as adjunct chemotherapy in the massively aggressive tumor glioblastoma multiforme. © 2015 International Union of Biochemistry and Molecular Biology.

  6. Repurposing some older drugs that cross the blood–brain barrier and have potential anticancer activity to provide new treatment options for glioblastoma

    PubMed Central

    Head, Richard; Cosgrove, Leah; Martin, Jennifer H.

    2015-01-01

    Glioblastoma is a brain neoplasm with limited 5‐year survival rates. Developments of new treatment regimens that improve patient survival in patients with glioblastoma are needed. It is likely that a number of existing drugs used in other conditions have potential anticancer effects that offer significant survival benefit to glioblastoma patients. Identification of such drugs could provide a novel treatment paradigm. PMID:26374633

  7. Lectins Identify Glycan Biomarkers on Glioblastoma-Derived Cancer Stem Cells

    PubMed Central

    Tucker-Burden, Carol; Chappa, Prasanthi; Krishnamoorthy, Malini; Gerwe, Brian A.; Scharer, Christopher D.; Heimburg-Molinaro, Jamie; Harris, Wayne; Usta, Sümeyra Naz; Eilertson, Carmen D.; Hadjipanayis, Constantinos G.; Stice, Steven L.; Brat, Daniel J.

    2012-01-01

    Glioblastoma (GBM) is a highly aggressive primary brain tumor with a poor prognosis. Despite aggressive therapy with surgery, radiotherapy, and chemotherapy, nearly all patients succumb to disease within 2 years. Several studies have supported the presence of stem-like cells in brain tumor cultures that are CD133-positive, are capable of self-renewal, and give rise to all cell types found within the tumor, potentially perpetuating growth. CD133 is a widely accepted marker for glioma-derived cancer stem cells; however, its reliability has been questioned, creating a need for other identifiers of this biologically important subpopulation. We used a panel of 20 lectins to identify differences in glycan expression found in the glycocalyx of undifferentiated glioma-derived stem cells and differentiated cells that arise from them. Fluorescently labeled lectins that specifically recognize α-N-acetylgalactosamine (GalNAc) and α-N-acetylglucosamine (GlcNAc) differentially bound to the cell surface based on the state of cellular differentiation. GalNAc and GlcNAc were highly expressed on the surface of undifferentiated cells and showed markedly reduced expression over a 12-day duration of differentiation. Additionally, the GalNAc-recognizing lectin Dolichos biflorus agglutinin was capable of specifically selecting and sorting glioma-derived stem cell populations from an unsorted tumor stock and this subpopulation had proliferative properties similar to CD133+ cells in vitro and also had tumor-forming capability in vivo. Our preliminary results on a single cerebellar GBM suggest that GalNAc and GlcNAc are novel biomarkers for identifying glioma-derived stem cells and can be used to isolate cancer stem cells from unsorted cell populations, thereby creating new cell lines for research or clinical testing. PMID:22435486

  8. The network of immunosuppressive pathways in glioblastoma.

    PubMed

    Mangani, Davide; Weller, Michael; Roth, Patrick

    2017-04-15

    Glioblastoma remains a fatal tumor despite increased knowledge regarding the complex signalling pathways that drive this devastating disease. Recently, immunotherapeutic approaches have shown remarkable and durable responses in various cancers including metastatic melanoma and advanced non-small cell lung cancer. So far, it remains unclear whether these immunotherapeutics may also work against glioblastoma and other tumors residing in the central nervous system. It is well known that patients with glioblastoma suffer from profound local immunosuppression that represents the major hurdle to overcome in the context of immunotherapy. Several studies have demonstrated that this immunosuppressive phenotype is orchestrated by glioma-derived membrane-bound and soluble factors as well as the particular microenvironment within the brain. Here, we discuss the molecular and cellular pathways involved in glioblastoma-mediated inhibition of the immune system and highlight possible treatment approaches aiming at reinvigorating anti-tumor immune responses. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. Bilateral Triple-Negative Invasive Breast Cancer with a BRCA2 Mutation, and Glioblastoma: A Case Report and Literature Review

    PubMed Central

    Alsharedi, Mohamed; Khelfa, Yousef; Tirona, Maria

    2017-01-01

    Breast cancer is the second leading cause of death among women in North America. Glioblastoma is the most common primary malignant central nervous system tumor in adults. The majority of hereditary breast cancers are associated with deleterious mutations in the BRCA1 and BRCA2 genes. Although few case reports have described the incidence of glioblastoma in patients previously diagnosed with breast cancer, any association between BRCA2 mutations and glioblastoma has not been demonstrated to date. Herein, we report a woman who is a carrier of a familial BRCA2 mutation, and was previously diagnosed with triple-negative breast cancer (TNBC) and subsequently with a second primary TNBC and glioblastoma. Further investigation is required to define the possible relationship between these two aggressive malignances and the BRCA2 mutation, which might be critical for the proper management and treatment of this disease. PMID:28382102

  10. The Three-Layer Concentric Model of Glioblastoma: Cancer Stem Cells, Microenvironmental Regulation, and Therapeutic Implications

    PubMed Central

    Persano, Luca; Rampazzo, Elena; Della Puppa, Alessandro; Pistollato, Francesca; Basso, Giuseppe

    2011-01-01

    Tumors arising in the central nervous system are thought to originate from a sub-population of cells named cancer stem cells (CSCs) or tumor initiating cells (TICs) that possess an immature phenotype, combined with self-renewal and chemotherapy resistance capacity. Moreover, in the last years, these cells have been identified in particular brain tumor niches fundamental for supporting their characteristics. In this paper, we report studies from many authors demonstrating that hypoxia or the so called “hypoxic niche” plays a crucial role in controlling CSC molecular and phenotypic profile. We recently investigated the relationship existing between Glioblastoma (GBM) stem cells and their niche, defining the theory of three-concentric layers model for GBM mass. According to this model, GBM stem cells reside preferentially within the hypoxic core of the tumour mass, while more differentiated cells are mainly localized along the peripheral and vascularized part of the tumour. This GBM model provides explanation of the effects mediated by the tumour microenvironment on the phenotypic and molecular regulation of GBM stem cells, describing their spatial distribution in the tumor bulk. Moreover, we discuss the possible clinical implications of the creation of this model for future GBM patient management and novel therapeutic strategies development. PMID:22125441

  11. Chemoresistance of glioblastoma cancer stem cells--much more complex than expected.

    PubMed

    Beier, Dagmar; Schulz, Joerg B; Beier, Christoph P

    2011-10-11

    Glioblastomas (GBM) are a paradigm for the investigation of cancer stem cells (CSC) in solid malignancies. The susceptibility of GBM CSC to standard chemotherapeutic drugs is controversial as the existing literature presents conflicting experimental data. Here, we summarize the experimental evidence on the resistance of GBM CSC to alkylating chemotherapeutic agents, with a special focus on temozolomide (TMZ). The data suggests that CSC are neither resistant nor susceptible to chemotherapy per se. Detoxifying proteins such as O6-methylguanine-DNA-methyltransferase (MGMT) confer a strong intrinsic resistance to CSC in all studies. Extrinsic factors may also contribute to the resistance of CSC to TMZ. These may include TMZ concentrations in the brain parenchyma, TMZ dosing schemes, hypoxic microenvironments, niche factors, and the re-acquisition of stem cell properties by non-stem cells. Thus, the interaction of CSC and chemotherapy is more complex than may be expected and it is necessary to consider these factors in order to overcome chemoresistance in the patient.

  12. Lung Cancer Brain Metastases.

    PubMed

    Goldberg, Sarah B; Contessa, Joseph N; Omay, Sacit B; Chiang, Veronica

    2015-01-01

    Brain metastases are common among patients with lung cancer and have been associated with significant morbidity and limited survival. However, the treatment of brain metastases has evolved as the field has advanced in terms of central nervous system imaging, surgical technique, and radiotherapy technology. This has allowed patients to receive improved treatment with less toxicity and more durable benefit. In addition, there have been significant advances in systemic therapy for lung cancer in recent years, and several treatments including chemotherapy, targeted therapy, and immunotherapy exhibit activity in the central nervous system. Utilizing systemic therapy for treating brain metastases can avoid or delay local therapy and often allows patients to receive effective treatment for both intracranial and extracranial disease. Determining the appropriate treatment for patients with lung cancer brain metastases therefore requires a clear understanding of intracranial disease burden, tumor histology, molecular characteristics, and overall cancer prognosis. This review provides updates on the current state of surgery and radiotherapy for the treatment of brain metastases, as well as an overview of systemic therapy options that may be effective in select patients with intracranial metastases from lung cancer.

  13. Transmembrane protein CD9 is glioblastoma biomarker, relevant for maintenance of glioblastoma stem cells

    PubMed Central

    Podergajs, Neža; Motaln, Helena; Rajčević, Uroš; Verbovšek, Urška; Koršič, Marjan; Obad, Nina; Espedal, Heidi; Vittori, Miloš; Herold-Mende, Christel; Miletic, Hrvoje; Bjerkvig, Rolf; Turnšek, Tamara Lah

    2016-01-01

    The cancer stem cell model suggests that glioblastomas contain a subpopulation of stem-like tumor cells that reproduce themselves to sustain tumor growth. Targeting these cells thus represents a novel treatment strategy and therefore more specific markers that characterize glioblastoma stem cells need to be identified. In the present study, we performed transcriptomic analysis of glioblastoma tissues compared to normal brain tissues revealing sensible up-regulation of CD9 gene. CD9 encodes the transmembrane protein tetraspanin which is involved in tumor cell invasion, apoptosis and resistance to chemotherapy. Using the public REMBRANDT database for brain tumors, we confirmed the prognostic value of CD9, whereby a more than two fold up-regulation correlates with shorter patient survival. We validated CD9 gene and protein expression showing selective up-regulation in glioblastoma stem cells isolated from primary biopsies and in primary organotypic glioblastoma spheroids as well as in U87-MG and U373 glioblastoma cell lines. In contrast, no or low CD9 gene expression was observed in normal human astrocytes, normal brain tissue and neural stem cells. CD9 silencing in three CD133+ glioblastoma cell lines (NCH644, NCH421k and NCH660h) led to decreased cell proliferation, survival, invasion, and self-renewal ability, and altered expression of the stem-cell markers CD133, nestin and SOX2. Moreover, CD9-silenced glioblastoma stem cells showed altered activation patterns of the Akt, MapK and Stat3 signaling transducers. Orthotopic xenotransplantation of CD9-silenced glioblastoma stem cells into nude rats promoted prolonged survival. Therefore, CD9 should be further evaluated as a target for glioblastoma treatment. PMID:26573230

  14. Transmembrane protein CD9 is glioblastoma biomarker, relevant for maintenance of glioblastoma stem cells.

    PubMed

    Podergajs, Neža; Motaln, Helena; Rajčević, Uroš; Verbovšek, Urška; Koršič, Marjan; Obad, Nina; Espedal, Heidi; Vittori, Miloš; Herold-Mende, Christel; Miletic, Hrvoje; Bjerkvig, Rolf; Turnšek, Tamara Lah

    2016-01-05

    The cancer stem cell model suggests that glioblastomas contain a subpopulation of stem-like tumor cells that reproduce themselves to sustain tumor growth. Targeting these cells thus represents a novel treatment strategy and therefore more specific markers that characterize glioblastoma stem cells need to be identified. In the present study, we performed transcriptomic analysis of glioblastoma tissues compared to normal brain tissues revealing sensible up-regulation of CD9 gene. CD9 encodes the transmembrane protein tetraspanin which is involved in tumor cell invasion, apoptosis and resistance to chemotherapy. Using the public REMBRANDT database for brain tumors, we confirmed the prognostic value of CD9, whereby a more than two fold up-regulation correlates with shorter patient survival. We validated CD9 gene and protein expression showing selective up-regulation in glioblastoma stem cells isolated from primary biopsies and in primary organotypic glioblastoma spheroids as well as in U87-MG and U373 glioblastoma cell lines. In contrast, no or low CD9 gene expression was observed in normal human astrocytes, normal brain tissue and neural stem cells. CD9 silencing in three CD133+ glioblastoma cell lines (NCH644, NCH421k and NCH660h) led to decreased cell proliferation, survival, invasion, and self-renewal ability, and altered expression of the stem-cell markers CD133, nestin and SOX2. Moreover, CD9-silenced glioblastoma stem cells showed altered activation patterns of the Akt, MapK and Stat3 signaling transducers. Orthotopic xenotransplantation of CD9-silenced glioblastoma stem cells into nude rats promoted prolonged survival. Therefore, CD9 should be further evaluated as a target for glioblastoma treatment.

  15. New study tests the safety and efficacy of combination therapy in adults with astrocytoma and glioblastoma | Center for Cancer Research

    Cancer.gov

    A two-part clinical trial of a multikinase inhibitor plus chemotherapy in patients with two types of brain tumors is enrolling in Bethesda, MD. The study will be open to patients with anaplastic astrocytoma, an uncommon malignant brain tumor that develops from star-shaped brain cells called astrocytes and glioblastoma, the most common and aggressive form of astrocytoma. Learn more...

  16. Acetate is a Bioenergetic Substrate for Human Glioblastoma and Brain Metastases

    PubMed Central

    Mashimo, Tomoyuki; Pichumani, Kumar; Vemireddy, Vamsidhara; Hatanpaa, Kimmo J.; Singh, Dinesh Kumar; Sirasanagandla, Shyam; Nannepaga, Suraj; Piccirillo, Sara G.; Kovacs, Zoltan; Foong, Chan; Huang, Zhiguang; Barnett, Samuel; Mickey, Bruce E.; DeBerardinis, Ralph J.; Tu, Benjamin P.; Maher, Elizabeth A.; Bachoo, Robert M.

    2015-01-01

    Glioblastomas and brain metastases are highly proliferative brain tumors with short survival times. Previously, using 13C-NMR analysis of brain tumors resected from patients during infusion of 13C-glucose, we demonstrated that there is robust oxidation of glucose in the citric acid cycle, yet glucose contributes less than 50% of the carbons to the acetyl-CoA pool. Here we show that primary and metastatic mouse orthotopic brain tumors have the capacity to oxidize [1,2-13C]acetate and can do so simultaneously with [1,6-13C]glucose oxidation. The tumors do not oxidize [U-13C]glutamine. In vivo oxidation of [1,2-13C]acetate was validated in brain tumor patients and was correlated with expression of acetyl-CoA synthetase enzyme 2, ACSS2. Together the data demonstrate a strikingly common metabolic phenotype in diverse brain tumors that includes the ability to oxidize acetate in the citric acid cycle. This adaptation may be important for meeting the high biosynthetic and bioenergetic demands of malignant growth. PMID:25525878

  17. Epigenetic Regulation of ZBTB18 Promotes Glioblastoma Progression. | Office of Cancer Genomics

    Cancer.gov

    Glioblastoma (GBM) comprises distinct subtypes characterized by their molecular profile. Mesenchymal identity in GBM has been associated with a comparatively unfavorable prognosis, primarily due to inherent resistance of these tumors to current therapies. The identification of molecular determinants of mesenchymal transformation could potentially allow for the discovery of new therapeutic targets. Zinc Finger and BTB Domain Containing 18 (ZBTB18/ZNF238/RP58) is a zinc finger transcriptional repressor with a crucial role in brain development and neuronal differentiation.

  18. Gadolinium uptake by brain cancer cells: Quantitative analysis with X-PEEM spectromicroscopy for cancer therapy

    NASA Astrophysics Data System (ADS)

    De Stasio, Gelsomina; Gilbert, B.; Perfetti, P.; Margaritondo, G.; Mercanti, D.; Ciotti, M. T.; Casalbore, P.; Larocca, L. M.; Rinelli, A.; Pallini, R.

    2000-05-01

    We present the first X-PEEM spectromicroscopy semi-quantitative data, acquired on Gd in glioblastoma cell cultures from human brain cancer. The cells were treated with a Gd compound for the optimization of GdNCT (Gadolinium Neutron Capture Therapy). We analyzed the kinetics of Gd uptake as a function of exposure time, and verified that a quantitative analytical technique gives the same results as our MEPHISTO X-PEEM, demonstrating the feasibility of semi-quantitative spectromicroscopy.

  19. Marker-independent Method for Isolating Slow-Dividing Cancer Stem Cells in Human Glioblastoma12

    PubMed Central

    Richichi, Cristina; Brescia, Paola; Alberizzi, Valeria; Fornasari, Lorenzo; Pelicci, Giuliana

    2013-01-01

    Glioblastoma (GBM) is a devastating brain tumor with a poor survival outcome. It is generated and propagated by a small subpopulation of rare and hierarchically organized cells that share stem-like features with normal stem cells but, however, appear dysregulated in terms of self-renewal and proliferation and aberrantly differentiate into cells forming the bulk of the disorganized cancer tissues. The complexity and heterogeneity of human GBMs underlie the lack of standardized and effective treatments. This study is based on the assumption that available markers defining cancer stem cells (CSCs) in all GBMs are not conclusive and further work is required to identify the CSC. We implemented a method to isolate CSCs independently from cell surface markers: four patient-derived GBM neurospheres containing stem, progenitors, and differentiated cells were labeled with PKH-26 fluorescent dye that reliably selects for cells that divide at low rate. Through in vitro and in vivo assays, we investigated the growth and self-renewal properties of the two different compartments of high- and slow-dividing cells. Our data demonstrate that only slow-dividing cells retain the ability of a long-lasting self-renewal capacity after serial in vitro passaging, while high-dividing cells eventually exhaust. Moreover, orthotopic transplantation assay revealed that the incidence of tumors generated by the slow-dividing compartment is significantly higher in the four patient-derived GBM neurospheres analyzed. Importantly, slow-dividing cells feature a population made up of homogeneous stem cells that sustain tumor growth and therefore represent a viable target for GBM therapy development. PMID:23814495

  20. Usefulness of the apparent diffusion coefficient for the evaluation of the white matter to differentiate between glioblastoma and brain metastases.

    PubMed

    Miquelini, L A; Pérez Akly, M S; Funes, J A; Besada, C H

    2016-01-01

    To determine whether there are significant differences in the apparent diffusion coefficient (ADC) between the apparently normal peritumor white matter surrounding glioblastomas and that surrounding brain metastases. We retrospectively reviewed 42 patients with histologically confirmed glioblastomas and 42 patients with a single cerebral metastasis. We measured the signal intensity in the apparently normal peritumor white matter and in the abnormal peritumor white matter on the ADC maps. We used mean ADC values in the contralateral occipital white matter as a reference from which to design normalized ADC indices. We compared mean values between the two tumor types. We calculated the area under the receiver operator characteristic curve and estimated the sensitivity and specificity of the measurements taken. Supratentorial lesions and compromise of the corpus callosum were more common in patients with glioblastoma than in patients with brain metastases. The maximum diameter of the enhanced area after injection of a contrast agent was greater in the glioblastomas (p<0.001). The minimum ADC value measured in the apparently normal peritumor white matter was higher for the glioblastomas than for the metastases (p=0.002). Significant differences in the ADC index were found only for the minimum ADC value in apparently normal peritumor white matter. The sensitivity and specificity were less than 70% for all variables analyzed. There are differences in the ADC values of apparently normal peritumor white matter between glioblastomas and cerebral metastases, but the magnitude of these differences is slight and the application of these differences in clinical practice is still limited. Copyright © 2015 SERAM. Published by Elsevier España, S.L.U. All rights reserved.

  1. Stage-specific embryonic antigen: determining expression in canine glioblastoma, melanoma, and mammary cancer cells.

    PubMed

    Lin, Weiming; Modiano, Jaime F; Ito, Daisuke

    2017-03-30

    The expression of stage-specific embryonic antigens (SSEAs) was determined in several types of canine cancer cells. Flow cytometry showed SSEA-1 expression in glioblastoma, melanoma, and mammary cancer cells, although none expressed SSEA-3 or SSEA-4. Expression of SSEA-1 was not detected in lymphoma, osteosarcoma, or hemangiosarcoma cell lines. Relatively stable SSEA-1 expression was observed between 24 and 72 h of culture. After 8 days in culture, sorted SSEA-1(-) and SSEA-1(+) cells re-established SSEA-1 expression to levels comparable to those observed in unsorted cells. Our results document, for the first time, the expression of SSEA-1 in several canine cancer cell lines.

  2. Endoscopy-verified occult subependymal dissemination of glioblastoma and brain metastasis undetected by MRI: prognostic significance

    PubMed Central

    Iacoangeli, Maurizio; Di Rienzo, Alessandro; Colasanti, Roberto; Zizzi, Antonio; Gladi, Maurizio; Alvaro, Lorenzo; Nocchi, Niccolò; Di Somma, Lucia Giovanna Maria; Scarpelli, Marina; Scerrati, Massimo

    2012-01-01

    Although various prognostic indices exist for patients with malignant brain tumors, the prognostic significance of the subependymal spread of intracranial tumors is still a matter of debate. In this paper, we report the cases of two intraventricular lesions, a recurrent glioblastoma multiforme (GBM) and a brain metastasis, each successfully treated with a neuroendoscopic approach. Thanks to this minimally invasive approach, we achieved good therapeutic results: we obtained a histological diagnosis; we controlled intracranial hypertension by treating the associated hydrocephalus and, above all, compared with a microsurgical approach, we reduced the risks related to dissection and brain retraction. Moreover, in both cases, neuroendoscopy enabled us to identify an initial, precocious subependymal tumor spreading below the threshold of magnetic resonance imaging (MRI) detection. This finding, undetected in pre-operative MRI scans, was then evident during follow-up neuroimaging studies. In light of these data, a neuroendoscopic approach might play a leading role in better defining the prognosis and optimally tailored management protocols for GBM and brain metastasis. PMID:23271915

  3. Definition of miRNAs expression profile in glioblastoma samples: the relevance of non-neoplastic brain reference.

    PubMed

    Visani, Michela; de Biase, Dario; Marucci, Gianluca; Taccioli, Cristian; Baruzzi, Agostino; Pession, Annalisa

    2013-01-01

    Glioblastoma is the most aggressive brain tumor that may occur in adults. Regardless of the huge improvements in surgery and molecular therapy, the outcome of neoplasia remains poor. MicroRNAs are small molecules involved in several cellular processes, and their expression is altered in the vast majority of tumors. Several studies reported the expression of different miRNAs in glioblastoma, but one of the most critical point in understanding glioblastoma miRNAs profile is the comparison of these studies. In this paper, we focused our attention on the non-neoplastic references used for determining miRNAs expression. The aim of this study was to investigate if using three different non-neoplastic brain references (normal adjacent the tumor, commercial total RNA, and epileptic specimens) could provide discrepant results. The analysis of 19 miRNAs was performed using Real-Time PCR, starting from the set of samples described above and the expression values compared. Moreover, the three different normal RNAs were used to determine the miRNAs profile in 30 glioblastomas. The data showed that different non-neoplastic controls could lead to different results and emphasize the importance of comparing miRNAs profiles obtained using the same experimental condition.

  4. Progenitor/Stem Cell Markers in Brain Adjacent to Glioblastoma: GD3 Ganglioside and NG2 Proteoglycan Expression.

    PubMed

    Lama, Gina; Mangiola, Annunziato; Proietti, Gabriella; Colabianchi, Anna; Angelucci, Cristiana; D' Alessio, Alessio; De Bonis, Pasquale; Geloso, Maria Concetta; Lauriola, Libero; Binda, Elena; Biamonte, Filippo; Giuffrida, Maria Grazia; Vescovi, Angelo; Sica, Gigliola

    2016-02-01

    Characterization of tissue surrounding glioblastoma (GBM) is a focus for translational research because tumor recurrence invariably occurs in this area. We investigated the expression of the progenitor/stem cell markers GD3 ganglioside and NG2 proteoglycan in GBM, peritumor tissue (brain adjacent to tumor, BAT) and cancer stem-like cells (CSCs) isolated from GBM (GCSCs) and BAT (PCSCs). GD3 and NG2 immunohistochemistry was performed in paired GBM and BAT specimens from 40 patients. Double-immunofluorescence was carried out to characterize NG2-positive cells of vessel walls. GD3 and NG2 expression was investigated in GCSCs and PCSCs whose tumorigenicity was also evaluated in Scid/bg mice. GD3 and NG2 expression was higher in tumor tissue than in BAT. NG2 decreased as the distance from tumor margin increased, regardless of the tumor cell presence, whereas GD3 correlated with neoplastic infiltration. In BAT, NG2 was coexpressed with a-smooth muscle actin (a-SMA) in pericytes and with nestin in the endothelium. Higher levels of NG2 mRNA and protein were found in GCSCs while GD3 synthase was expressed at similar levels in the 2 CSC populations. PCSCs had lower tumorigenicity than GCSCs. These data suggest the possible involvement of GD3 and NG2 in pre/pro-tumorigenic events occurring in the complex microenvironment of the tissue surrounding GBM.

  5. Wnt5a Drives an Invasive Phenotype in Human Glioblastoma Stem-like Cells.

    PubMed

    Binda, Elena; Visioli, Alberto; Giani, Fabrizio; Trivieri, Nadia; Palumbo, Orazio; Restelli, Silvia; Dezi, Fabio; Mazza, Tommaso; Fusilli, Caterina; Legnani, Federico; Carella, Massimo; Di Meco, Francesco; Duggal, Rohit; Vescovi, Angelo L

    2017-02-15

    Brain invasion by glioblastoma determines prognosis, recurrence, and lethality in patients, but no master factor coordinating the invasive properties of glioblastoma has been identified. Here we report evidence favoring such a role for the noncanonical WNT family member Wnt5a. We found the most invasive gliomas to be characterized by Wnt5a overexpression, which correlated with poor prognosis and also discriminated infiltrating mesenchymal glioblastoma from poorly motile proneural and classical glioblastoma. Indeed, Wnt5a overexpression associated with tumor-promoting stem-like characteristics (TPC) in defining the character of highly infiltrating mesenchymal glioblastoma cells (Wnt5a(High)). Inhibiting Wnt5a in mesenchymal glioblastoma TPC suppressed their infiltrating capability. Conversely, enforcing high levels of Wnt5a activated an infiltrative, mesenchymal-like program in classical glioblastoma TPC and Wnt5a(Low) mesenchymal TPC. In intracranial mouse xenograft models of glioblastoma, inhibiting Wnt5a activity blocked brain invasion and increased host survival. Overall, our results highlight Wnt5a as a master regulator of brain invasion, specifically TPC, and they provide a therapeutic rationale to target it in patients with glioblastoma. Cancer Res; 77(4); 996-1007. ©2016 AACR. ©2016 American Association for Cancer Research.

  6. Targeting cancer stem-like cells in glioblastoma and colorectal cancer through metabolic pathways.

    PubMed

    Kahlert, U D; Mooney, S M; Natsumeda, M; Steiger, H-J; Maciaczyk, J

    2017-01-01

    Cancer stem-like cells (CSCs) are thought to be the main cause of tumor occurrence, progression and therapeutic resistance. Strong research efforts in the last decade have led to the development of several tailored approaches to target CSCs with some very promising clinical trials underway; however, until now no anti-CSC therapy has been approved for clinical use. Given the recent improvement in our understanding of how onco-proteins can manipulate cellular metabolic networks to promote tumorigenesis, cancer metabolism research may well lead to innovative strategies to identify novel regulators and downstream mediators of CSC maintenance. Interfering with distinct stages of CSC-associated metabolics may elucidate novel, more efficient strategies to target this highly malignant cell population. Here recent discoveries regarding the metabolic properties attributed to CSCs in glioblastoma (GBM) and malignant colorectal cancer (CRC) were summarized. The association between stem cell markers, the response to hypoxia and other environmental stresses including therapeutic insults as well as developmentally conserved signaling pathways with alterations in cellular bioenergetic networks were also discussed. The recent developments in metabolic imaging to identify CSCs were also summarized. This summary should comprehensively update basic and clinical scientists on the metabolic traits of CSCs in GBM and malignant CRC. © 2016 UICC.

  7. Co-amplification of phosphoinositide 3-kinase enhancer A and cyclin-dependent kinase 4 triggers glioblastoma progression | Office of Cancer Genomics

    Cancer.gov

    Glioblastoma (GBM) is the most common primary brain tumor and has a dismal prognosis. Amplification of chromosome 12q13-q15 (Cyclin-dependent kinase 4 (CDK4) amplicon) is frequently observed in numerous human cancers including GBM. Phosphoinositide 3-kinase enhancer (PIKE) is a group of GTP-binding proteins that belong to the subgroup of centaurin GTPase family, encoded by CENTG1 located in CDK4 amplicon. However, the pathological significance of CDK4 amplicon in GBM formation remains incompletely understood.

  8. Differentiation of Glioblastoma from Brain Metastasis: Qualitative and Quantitative Analysis Using Arterial Spin Labeling MR Imaging

    PubMed Central

    Sunwoo, Leonard; You, Sung-Hye; Yoo, Roh-Eul; Kang, Koung Mi; Choi, Seung Hong; Kim, Ji-hoon; Sohn, Chul-Ho; Park, Sun-Won; Jung, Cheolkyu; Park, Chul-Kee

    2016-01-01

    Purpose To evaluate the diagnostic performance of cerebral blood flow (CBF) by using arterial spin labeling (ASL) perfusion magnetic resonance (MR) imaging to differentiate glioblastoma (GBM) from brain metastasis. Materials and Methods The institutional review board of our hospital approved this retrospective study. The study population consisted of 128 consecutive patients who underwent surgical resection and were diagnosed as either GBM (n = 89) or brain metastasis (n = 39). All participants underwent preoperative MR imaging including ASL. For qualitative analysis, the tumors were visually graded into five categories based on ASL-CBF maps by two blinded reviewers. For quantitative analysis, the reviewers drew regions of interest (ROIs) on ASL-CBF maps upon the most hyperperfused portion within the tumor and upon peritumoral T2 hyperintensity area. Signal intensities of intratumoral and peritumoral ROIs for each subject were normalized by dividing the values by those of contralateral normal gray matter (nCBFintratumoral and nCBFperitumoral, respectively). Visual grading scales and quantitative parameters between GBM and brain metastasis were compared. In addition, the area under the receiver-operating characteristic curve was used to evaluate the diagnostic performance of ASL-driven CBF to differentiate GBM from brain metastasis. Results For qualitative analysis, GBM group showed significantly higher grade compared to metastasis group (p = 0.001). For quantitative analysis, both nCBFintratumoral and nCBFperitumoral in GBM were significantly higher than those in metastasis (both p < 0.001). The areas under the curve were 0.677, 0.714, and 0.835 for visual grading, nCBFintratumoral, and nCBFperitumoral, respectively (all p < 0.001). Conclusion ASL perfusion MR imaging can aid in the differentiation of GBM from brain metastasis. PMID:27861605

  9. Multimodal optical coherence tomography for in vivo imaging of brain tissue structure and microvascular network at glioblastoma

    NASA Astrophysics Data System (ADS)

    Yashin, Konstantin S.; Kiseleva, Elena B.; Gubarkova, Ekaterina V.; Matveev, Lev A.; Karabut, Maria M.; Elagin, Vadim V.; Sirotkina, Marina A.; Medyanik, Igor A.; Kravets, L. Y.; Gladkova, Natalia D.

    2017-02-01

    In the case of infiltrative brain tumors the surgeon faces difficulties in determining their boundaries to achieve total resection. The aim of the investigation was to evaluate the performance of multimodal OCT (MM OCT) for differential diagnostics of normal brain tissue and glioma using an experimental model of glioblastoma. The spectral domain OCT device that was used for the study provides simultaneously two modes: cross-polarization and microangiographic OCT. The comparative analysis of the both OCT modalities images from tumorous and normal brain tissue areas concurrently with histologic correlation shows certain difference between when accordingly to morphological and microvascular tissue features.

  10. FMISO-PET-derived brain oxygen tension maps: application to glioblastoma and less aggressive gliomas.

    PubMed

    Chakhoyan, Ararat; Guillamo, Jean-Sebastien; Collet, Solène; Kauffmann, François; Delcroix, Nicolas; Lechapt-Zalcman, Emmanuèle; Constans, Jean-Marc; Petit, Edwige; MacKenzie, Eric T; Barré, Louisa; Bernaudin, Myriam; Touzani, Omar; Valable, Samuel

    2017-08-31

    Quantitative imaging modalities for the analysis of hypoxia in brain tumors are lacking. The objective of this study was to generate absolute maps of tissue ptO2 from [(18)F]-FMISO images in glioblastoma and less aggressive glioma patients in order to quantitatively assess tumor hypoxia. An ancillary objective was to compare estimated ptO2 values to other biomarkers: perfusion weighted imaging (PWI) and tumor metabolism obtained from (1)H-MR mono-voxel spectroscopy (MRS). Ten patients with glioblastoma (GBM) and three patients with less aggressive glioma (nGBM) were enrolled. All patients had [(18)F]-FMISO and multiparametric MRI (anatomic, PWI, MRS) scans. A non-linear regression was performed to generate ptO2 maps based on normal appearing gray (NAGM) and white matter (NAWM) for each patient. As expected, a marked [(18)F]-FMISO uptake was observed in GBM patients. The ptO2 based on patient specific calculations was notably low in this group (4.8 ± 1.9 mmHg, p < 0.001) compared to all other groups (nGBM, NAGM and NAWM). The rCBV was increased in GBM (1.4 ± 0.2 when compared to nGBM tumors 0.8 ± 0.4). Lactate (and lipid) concentration increased in GBM (27.8 ± 13.8%) relative to nGBM (p < 0.01). Linear, nonlinear and ROC curve analyses between ptO2 maps, PWI-derived rCBV maps and MRS-derived lipid and lactate concentration strengthens the robustness of our approaches.

  11. Zika virus has oncolytic activity against glioblastoma stem cells.

    PubMed

    Zhu, Zhe; Gorman, Matthew J; McKenzie, Lisa D; Chai, Jiani N; Hubert, Christopher G; Prager, Briana C; Fernandez, Estefania; Richner, Justin M; Zhang, Rong; Shan, Chao; Tycksen, Eric; Wang, Xiuxing; Shi, Pei-Yong; Diamond, Michael S; Rich, Jeremy N; Chheda, Milan G

    2017-10-02

    Glioblastoma is a highly lethal brain cancer that frequently recurs in proximity to the original resection cavity. We explored the use of oncolytic virus therapy against glioblastoma with Zika virus (ZIKV), a flavivirus that induces cell death and differentiation of neural precursor cells in the developing fetus. ZIKV preferentially infected and killed glioblastoma stem cells (GSCs) relative to differentiated tumor progeny or normal neuronal cells. The effects against GSCs were not a general property of neurotropic flaviviruses, as West Nile virus indiscriminately killed both tumor and normal neural cells. ZIKV potently depleted patient-derived GSCs grown in culture and in organoids. Moreover, mice with glioblastoma survived substantially longer and at greater rates when the tumor was inoculated with a mouse-adapted strain of ZIKV. Our results suggest that ZIKV is an oncolytic virus that can preferentially target GSCs; thus, genetically modified strains that further optimize safety could have therapeutic efficacy for adult glioblastoma patients. © 2017 Zhu et al.

  12. Modeling the Treatment of Glioblastoma Multiforme and Cancer Stem Cells with Ordinary Differential Equations

    PubMed Central

    Abernathy, Kristen; Burke, Jeremy

    2016-01-01

    Despite improvements in cancer therapy and treatments, tumor recurrence is a common event in cancer patients. One explanation of recurrence is that cancer therapy focuses on treatment of tumor cells and does not eradicate cancer stem cells (CSCs). CSCs are postulated to behave similar to normal stem cells in that their role is to maintain homeostasis. That is, when the population of tumor cells is reduced or depleted by treatment, CSCs will repopulate the tumor, causing recurrence. In this paper, we study the application of the CSC Hypothesis to the treatment of glioblastoma multiforme by immunotherapy. We extend the work of Kogan et al. (2008) to incorporate the dynamics of CSCs, prove the existence of a recurrence state, and provide an analysis of possible cancerous states and their dependence on treatment levels. PMID:27022405

  13. Increased level of H19 long noncoding RNA promotes invasion, angiogenesis, and stemness of glioblastoma cells.

    PubMed

    Jiang, Xiaochun; Yan, Yukui; Hu, Minghua; Chen, Xiande; Wang, Yaxian; Dai, Yi; Wu, Degang; Wang, Yongsheng; Zhuang, Zhixiang; Xia, Hongping

    2016-01-01

    OBJECT Increased levels of H19 long noncoding RNA (lncRNA) have been observed in many cancers, suggesting that overexpression of H19 may be important in the development of carcinogenesis. However, the role of H19 in human glioblastoma is still unclear. The object of this study was to examine the level of H19 in glioblastoma samples and investigate the role of H19 in glioblastoma carcinogenesis. METHODS Glioblastoma and nontumor brain tissue specimens were obtained from tissue obtained during tumor resection in 30 patients with glioblastoma. The level of H19 lncRNA was detected by real-time quantitative reverse transcription polymerase chain reaction. The role of H19 in invasion, angiogenesis, and stemness of glioblastoma cells was then investigated using commercially produced cell lines (U87 and U373). The effects of H19 overexpression on glioblastoma cell invasion and angiogenesis were detected by in vitro Matrigel invasion and endothelial tube formation assay. The effects of H19 on glioblastoma cell stemness and tumorigenicity were investigated by neurosphere formation and an in vivo murine xenograft model. RESULTS The authors found that H19 is significantly overexpressed in glioblastoma tissues, and the level of expression was associated with patient survival. In the subsequent investigations, the authors found that overexpression of H19 promotes glioblastoma cell invasion and angiogenesis in vitro. Interestingly, H19 was also significantly overexpressed in CD133(+) glioblastoma cells, and overexpression of H19 was associated with increased neurosphere formation of glioblastoma cells. Finally, stable overexpression of H19 was associated with increased tumor growth in the murine xenograft model. CONCLUSIONS The results of this study suggest that increased expression of H19 lncRNA promotes invasion, angiogenesis, stemness, and tumorigenicity of glioblastoma cells. Taken together, these findings indicate that H19 plays an important role in tumorigenicity and

  14. Aldehyde dehydrogenase 1 positive glioblastoma cells show brain tumor stem cell capacity.

    PubMed

    Rasper, Michael; Schäfer, Andrea; Piontek, Guido; Teufel, Julian; Brockhoff, Gero; Ringel, Florian; Heindl, Stefan; Zimmer, Claus; Schlegel, Jürgen

    2010-10-01

    Glioblastoma (GBM) is the most aggressive primary brain tumor and is resistant to all therapeutic regimens. Relapse occurs regularly and might be caused by a poorly characterized tumor stem cell (TSC) subpopulation escaping therapy. We suggest aldehyde dehydrogenase 1 (ALDH1) as a novel stem cell marker in human GBM. Using the neurosphere formation assay as a functional method to identify brain TSCs, we show that high protein levels of ALDH1 facilitate neurosphere formation in established GBM cell lines. Even single ALDH1 positive cells give rise to colonies and neurospheres. Consequently, the inhibition of ALDH1 in vitro decreases both the number of neurospheres and their size. Cell lines without expression of ALDH1 do not form tumor spheroids under the same culturing conditions. High levels of ALDH1 seem to keep tumor cells in an undifferentiated, stem cell-like state indicated by the low expression of beta-III-tubulin. In contrast, ALDH1 inhibition induces premature cellular differentiation and reduces clonogenic capacity. Primary cell cultures obtained from fresh tumor samples approve the established GBM cell line results.

  15. Casein kinase 2α regulates glioblastoma brain tumor-initiating cell growth through the β-catenin pathway.

    PubMed

    Nitta, R T; Gholamin, S; Feroze, A H; Agarwal, M; Cheshier, S H; Mitra, S S; Li, G

    2015-07-01

    Glioblastoma (GBM) is the most common and fatal primary brain tumor in humans, and it is essential that new and better therapies are developed to treat this disease. Previous research suggests that casein kinase 2 (CK2) may be a promising therapeutic target for GBMs. CK2 has enhanced expression or activity in numerous cancers, including GBM, and it has been demonstrated that inhibitors of CK2 regressed tumor growth in GBM xenograft mouse models. Our studies demonstrate that the CK2 subunit, CK2α, is overexpressed in and has an important role in regulating brain tumor-initiating cells (BTIC) in GBM. Initial studies showed that two GBM cell lines (U87-MG and U138) transduced with CK2α had enhanced proliferation and anchorage-independent growth. Inhibition of CKα using siRNA or small-molecule inhibitors (TBBz, CX-4945) reduced cell growth, decreased tumor size, and increased survival rates in GBM xenograft mouse models. We also verified that inhibition of CK2α decreased the activity of a well-known GBM-initiating cell regulator, β-catenin. Loss of CK2α decreased two β-catenin-regulated genes that are involved in GBM-initiating cell growth, OCT4 and NANOG. To determine the importance of CK2α in GBM stem cell maintenance, we reduced CK2α activity in primary GBM samples and tumor spheres derived from GBM patients. We discovered that loss of CK2α activity reduced the sphere-forming capacity of BTIC and decreased numerous GBM stem cell markers, including CD133, CD90, CD49f and A2B5. Our study suggests that CK2α is involved in GBM tumorigenesis by maintaining BTIC through the regulation of β-catenin.

  16. The potential origin of glioblastoma initiating cells

    PubMed Central

    Chesler, David A.; Berger, Mitchell S.; Quinones-Hinojosa, Alfredo

    2013-01-01

    Despite intensive clinical and laboratory research and effort, Glioblastoma remains the most common and invariably lethal primary cancer of the central nervous system. The identification of stem cell and lineage-restricted progenitor cell populations within the adult human brain in conjunction with the discovery of stem-like cells derived from gliomas which are themselves tumorigenic and have been shown to have properties of self-renewal and multipotency, has led to the hypothesis that this population of cells may represent glioma initiating cells. Extensive research characterizing the anatomic distribution and phenotype of neural stem cells in the adult brain, and the genetic underpinnings needed for malignant transformation may ultimately lead to the identification of the cellular origin for glioblastoma. Defining the cellular origin of this lethal disease may ultimately provide new therapeutic targets and modalities finally altering an otherwise bleak outcome for patients with glioblastoma. PMID:22202053

  17. Probing brain cancer by fiber optic FTIR spectroscopy

    NASA Astrophysics Data System (ADS)

    Steiner, Gerald; Kano, Angelique; Richter, Tom; Bergmann, Ralf; Rodig, Heike; Kobelke, Jens; Johannsen, Bernd; Salzer, Reiner

    2002-03-01

    The use of several silver halide and chalcogenide infrared transmitting fibers in the detection of cancer is investigated. As a test sample for all types of fibers we used a thin section of an entire rat brain with glioblastoma. Moving the sample with an XY stage maps across the whole tissue section with more than 200 spectra were recorded. Data evaluation was performed using Principal Components Analysis (PCA). The silver halide fibers have provided excellent results. The tumor was clearly differentiable from the normal tissue. It wasn't possible to identify the tumor region using chalcogenide fibers because the fiber has a very low transmittance in the important fingerprint region.

  18. Intratumoral heterogeneity in glioblastoma: don't forget the peritumoral brain zone

    PubMed Central

    Lemée, Jean-Michel; Clavreul, Anne; Menei, Philippe

    2015-01-01

    Glioblastoma (GB) is the most frequent and aggressive primary tumor of the central nervous system. Prognosis remains poor despite ongoing progress. In cases where the gadolinium-enhanced portion of the GB is completely resected, 90% of recurrences occur at the margin of surgical resection in the macroscopically normal peritumoral brain zone (PBZ). Intratumoral heterogeneity in GB is currently a hot topic in neuro-oncology, and the GB PBZ may be involved in this phenomenon. Indeed, this region, which possesses specific properties, has been less studied than the core of the GB tumor. The high rate of local recurrence in the PBZ and the limited success of targeted therapies against GB demonstrate the need for a better understanding of the PBZ. We present here a review of the literature on the GB PBZ, focusing on its radiological, cellular, and molecular characteristics. We discuss how intraoperative analysis of the PBZ is important for the optimization of surgical resection and the development of targeted therapies against GB. PMID:26203067

  19. Immunosuppressive mechanisms in glioblastoma.

    PubMed

    Nduom, Edjah K; Weller, Michael; Heimberger, Amy B

    2015-11-01

    Despite maximal surgical and medical therapy, the treatment of glioblastoma remains a seriously vexing problem, with median survival well under 2 years and few long-term survivors. Targeted therapy has yet to produce significant advances in treatment of these lesions in spite of advanced molecular characterization of glioblastoma and glioblastoma cancer stem cells. Recently, immunotherapy has emerged as a promising mode for some of the hardest to treat tumors, including metastatic melanoma. Although immunotherapy has been evaluated in glioblastoma in the past with limited success, better understanding of the failures of these therapies could lead to more successful treatments in the future. Furthermore, there is a persistent challenge for the use of immune therapy to treat glioblastoma secondary to the existence of redundant mechanisms of tumor-mediated immune suppression. Here we will address these mechanisms of immunosuppression in glioblastoma and therapeutic approaches.

  20. MicroRNA-300 inhibited glioblastoma progression through ROCK1.

    PubMed

    Zhou, Fucheng; Li, Yang; Hao, Zhen; Liu, Xuanxi; Chen, Liang; Cao, Yu; Liang, Zuobin; Yuan, Fei; Liu, Jie; Wang, Jianjiao; Zheng, Yongri; Dong, Deli; Bian, Shan; Yang, Baofeng; Jiang, Chuanlu; Li, Qingsong

    2016-06-14

    Glioblastoma is a common type of brain aggressive tumors and has a poor prognosis. MicroRNAs (miRNAs) are a class of small, endogenous and non-coding RNAs that play crucial roles in cell proliferation, survival and invasion. Deregulated expression of miR-300 has been studied in a lot of cancers. However, the role of miR-300 in glioblastoma is still unknown. In this study, we demonstrated that miR-300 expression was downregulated in glioblastoma tissues compared with the normal tissues. Lower expression level of miR-300 was observed in thirty cases (75 %, 30/40) of glioblastoma samples compared with the normal samples. Moreover, the overall survival of glioblastoma patients with lower miR-300 expression level was shorter than those with higher miR-300 expression level. In addition, miR-300 expression was also downregulated in glioblastoma cell lines. Overexpression of miR-300 inhibited cell proliferation, cell cycle and invasion in glioblastoma cell line U87 and U251. Moreover, we identified ROCK1 as a direct target of miR-300 in U87 and U251 cells. Overexpression of ROCK1 partially rescued the miR-300-mediated cell growth. ROCK1 expression levels in glioblastoma tissues were higher than that in normal tissues. ROCK1 expression levels were higher in thirty-one cases of glioblastoma samples than their normal samples. Furthermore, the expression level ROCK1 was inversely correlated with the expression level of miR-300. Importantly, overexpression of miR-300 suppressed glioblastoma progression in an established xenograft model. In conclusion, we revealed that miR-300 might act as a tumor suppressor gene through inhibiting ROCK1 in glioblastoma.

  1. The Cytoskeletal Adapter Protein Spinophilin Regulates Invadopodia Dynamics and Tumor Cell Invasion in Glioblastoma.

    PubMed

    Cheerathodi, Mujeeburahiman; Avci, Naze G; Guerrero, Paola A; Tang, Leung K; Popp, Julia; Morales, John E; Chen, Zhihua; Carnero, Amancio; Lang, Frederick F; Ballif, Bryan A; Rivera, Gonzalo M; McCarty, Joseph H

    2016-12-01

    Glioblastoma is a primary brain cancer that is resistant to all treatment modalities. This resistance is due, in large part, to invasive cancer cells that disperse from the main tumor site, escape surgical resection, and contribute to recurrent secondary lesions. The adhesion and signaling mechanisms that drive glioblastoma cell invasion remain enigmatic, and as a result there are no effective anti-invasive clinical therapies. Here we have characterized a novel adhesion and signaling pathway comprised of the integrin αvβ8 and its intracellular binding partner, Spinophilin (Spn), which regulates glioblastoma cell invasion in the brain microenvironment. We show for the first time that Spn binds directly to the cytoplasmic domain of β8 integrin in glioblastoma cells. Genetically targeting Spn leads to enhanced invasive cell growth in preclinical models of glioblastoma. Spn regulates glioblastoma cell invasion by modulating the formation and dissolution of invadopodia. Spn-regulated invadopodia dynamics are dependent, in part, on proper spatiotemporal activation of the Rac1 GTPase. Glioblastoma cells that lack Spn showed diminished Rac1 activities, increased numbers of invadopodia, and enhanced extracellular matrix degradation. Collectively, these data identify Spn as a critical adhesion and signaling protein that is essential for modulating glioblastoma cell invasion in the brain microenvironment.

  2. Stage-specific embryonic antigen: determining expression in canine glioblastoma, melanoma, and mammary cancer cells

    PubMed Central

    Ito, Daisuke

    2017-01-01

    The expression of stage-specific embryonic antigens (SSEAs) was determined in several types of canine cancer cells. Flow cytometry showed SSEA-1 expression in glioblastoma, melanoma, and mammary cancer cells, although none expressed SSEA-3 or SSEA-4. Expression of SSEA-1 was not detected in lymphoma, osteosarcoma, or hemangiosarcoma cell lines. Relatively stable SSEA-1 expression was observed between 24 and 72 h of culture. After 8 days in culture, sorted SSEA-1− and SSEA-1+ cells re-established SSEA-1 expression to levels comparable to those observed in unsorted cells. Our results document, for the first time, the expression of SSEA-1 in several canine cancer cell lines. PMID:27456773

  3. Whole-brain spectroscopic MRI biomarkers identify infiltrating margins in glioblastoma patients

    PubMed Central

    Cordova, James S.; Shu, Hui-Kuo G.; Liang, Zhongxing; Gurbani, Saumya S.; Cooper, Lee A. D.; Holder, Chad A.; Olson, Jeffrey J.; Kairdolf, Brad; Schreibmann, Eduard; Neill, Stewart G.; Hadjipanayis, Constantinos G.; Shim, Hyunsuk

    2016-01-01

    Background The standard of care for glioblastoma (GBM) is maximal safe resection followed by radiation therapy with chemotherapy. Currently, contrast-enhanced MRI is used to define primary treatment volumes for surgery and radiation therapy. However, enhancement does not identify the tumor entirely, resulting in limited local control. Proton spectroscopic MRI (sMRI), a method reporting endogenous metabolism, may better define the tumor margin. Here, we develop a whole-brain sMRI pipeline and validate sMRI metrics with quantitative measures of tumor infiltration. Methods Whole-brain sMRI metabolite maps were coregistered with surgical planning MRI and imported into a neuronavigation system to guide tissue sampling in GBM patients receiving 5-aminolevulinic acid fluorescence-guided surgery. Samples were collected from regions with metabolic abnormalities in a biopsy-like fashion before bulk resection. Tissue fluorescence was measured ex vivo using a hand-held spectrometer. Tissue samples were immunostained for Sox2 and analyzed to quantify the density of staining cells using a novel digital pathology image analysis tool. Correlations among sMRI markers, Sox2 density, and ex vivo fluorescence were evaluated. Results Spectroscopic MRI biomarkers exhibit significant correlations with Sox2-positive cell density and ex vivo fluorescence. The choline to N-acetylaspartate ratio showed significant associations with each quantitative marker (Pearson's ρ = 0.82, P < .001 and ρ = 0.36, P < .0001, respectively). Clinically, sMRI metabolic abnormalities predated contrast enhancement at sites of tumor recurrence and exhibited an inverse relationship with progression-free survival. Conclusions As it identifies tumor infiltration and regions at high risk for recurrence, sMRI could complement conventional MRI to improve local control in GBM patients. PMID:26984746

  4. Comparative genomic and genetic analysis of glioblastoma-derived brain tumor-initiating cells and their parent tumors.

    PubMed

    Davis, Brad; Shen, Yaoqing; Poon, Candice C; Luchman, H Artee; Stechishin, Owen D; Pontifex, Carly S; Wu, Wei; Kelly, John J; Blough, Michael D

    2016-03-01

    Glioblastoma (GBM) is a fatal cancer that has eluded major therapeutic advances. Failure to make progress may reflect the absence of a human GBM model that could be used to test compounds for anti-GBM activity. In this respect, the development of brain tumor-initiating cell (BTIC) cultures is a step forward because BTICs appear to capture the molecular diversity of GBM better than traditional glioma cell lines. Here, we perform a comparative genomic and genetic analysis of BTICs and their parent tumors as preliminary evaluation of the BTIC model. We assessed single nucleotide polymorphisms (SNPs), genome-wide copy number variations (CNVs), gene expression patterns, and molecular subtypes of 11 established BTIC lines and matched parent tumors. Although CNV differences were noted, BTICs retained the major genomic alterations characteristic of GBM. SNP patterns were similar between BTICs and tumors. Importantly, recurring SNP or CNV alterations specific to BTICs were not seen. Comparative gene expression analysis and molecular subtyping revealed differences between BTICs and GBMs. These differences formed the basis of a 63-gene expression signature that distinguished cells from tumors; differentially expressed genes primarily involved metabolic processes. We also derived a set of 73 similarly expressed genes; these genes were not associated with specific biological functions. Although not identical, established BTIC lines preserve the core molecular alterations seen in their parent tumors, as well as the genomic hallmarks of GBM, without acquiring recurring BTIC-specific changes. © The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  5. A Nanoparticle Carrying the p53 Gene Targets Tumors Including Cancer Stem Cells, Sensitizes Glioblastoma to Chemotherapy and Improves Survival

    PubMed Central

    2015-01-01

    Temozolomide (TMZ)-resistance in glioblastoma multiforme (GBM) has been linked to upregulation of O6-methylguanine-DNA methyltransferase (MGMT). Wild-type (wt) p53 was previously shown to down-modulate MGMT. However, p53 therapy for GBM is limited by lack of efficient delivery across the blood brain barrier (BBB). We have developed a systemic nanodelivery platform (scL) for tumor-specific targeting (primary and metastatic), which is currently in multiple clinical trials. This self-assembling nanocomplex is formed by simple mixing of the components in a defined order and a specific ratio. Here, we demonstrate that scL crosses the BBB and efficiently targets GBM, as well as cancer stem cells (CSCs), which have been implicated in recurrence and treatment resistance in many human cancers. Moreover, systemic delivery of scL-p53 down-modulates MGMT and induces apoptosis in intracranial GBM xenografts. The combination of scL-p53 and TMZ increased the antitumor efficacy of TMZ with enhanced survival benefit in a mouse model of highly TMZ-resistant GBM. scL-p53 also sensitized both CSCs and bulk tumor cells to TMZ, increasing apoptosis. These results suggest that combining scL-p53 with standard TMZ treatment could be a more effective therapy for GBM. PMID:24811110

  6. Toosendanin Exerts an Anti-Cancer Effect in Glioblastoma by Inducing Estrogen Receptor β- and p53-Mediated Apoptosis

    PubMed Central

    Cao, Liang; Qu, Dingding; Wang, Huan; Zhang, Sha; Jia, Chenming; Shi, Zixuan; Wang, Zongren; Zhang, Jian; Ma, Jing

    2016-01-01

    Glioblastoma (GBM) is the most common primary brain tumor with median survival of approximately one year. This dismal poor prognosis is due to resistance to currently available chemotherapeutics; therefore, new cytotoxic agents are urgently needed. In the present study, we reported the cytotoxicity of toosendanin (TSN) in the GBM U87 and C6 cell lines in vitro and in vivo. By using the MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide) assay, flow cytometry analysis, and Western blot, we found that TSN inhibited U87 and C6 cell proliferation and induced apoptosis at a concentration as low as 10 nM. Administration of TSN also reduced tumor burden in a xenograft model of athymic nude mice. Pharmacological and molecular studies suggested that estrogen receptor β (ERβ) and p53 were prominent targets for TSN. GBM cell apoptosis induced by TSN was a stepwise biological event involving the upregulation of ERβ and contextual activation of functional p53. Collectively, our study indicates, for the first time, that TSN is a candidate of novel anti-cancer drugs for GBM. Furthermore, ERβ and p53 could act as predictive biomarkers for the sensitivity of cancer to TSN. PMID:27869737

  7. Tenascin-C: a novel candidate marker for cancer stem cells in glioblastoma identified by tissue microarrays.

    PubMed

    Nie, Song; Gurrea, Mikel; Zhu, Jianhui; Thakolwiboon, Smathorn; Heth, Jason A; Muraszko, Karin M; Fan, Xing; Lubman, David M

    2015-02-06

    Glioblastoma multiforme (GBM) is a highly aggressive brain tumor, with dismal survival outcomes. Recently, cancer stem cells (CSCs) have been demonstrated to play a role in therapeutic resistance and are considered to be the most likely cause of cancer relapse. The identification of CSCs is an important step toward finding new and effective ways to treat GBM. Tenascin-C (TNC) protein has been identified as a potential marker for CSCs in gliomas based on previous work. Here, we have investigated the expression of TNC in tissue microarrays including 17 GBMs, 18 WHO grade III astrocytomas, 15 WHO grade II astrocytomas, 4 WHO grade I astrocytomas, and 7 normal brain tissue samples by immunohistochemical staining. TNC expression was found to be highly associated with the grade of astrocytoma. It has a high expression level in most of the grade III astrocytomas and GBMs analyzed and a very low expression in most grade II astrocytomas, whereas it is undetectable in grade I astrocytomas and normal brain tissues. Double-immunofluorescence staining for TNC and CD133 in GBM tissues revealed that there was a high overlap between theses two positive populations. The results were further confirmed by flow cytometry analysis of TNC and CD133 in GBM-derived stem-like neurospheres in vitro. A limiting dilution assay demonstrated that the sphere formation ability of CD133(+)/TNC(+) and CD133(-)/TNC(+) cell populations is much higher than that of the CD133(+)/TNC(-) and CD133(-)/TNC(-) populations. These results suggest that TNC is not only a potential prognostic marker for GBM but also a potential marker for glioma CSCs, where the TNC(+) population is identified as a CSC population overlapping with part of the CD133(-) cell population.

  8. Diversified expression of NG2/CSPG4 isoforms in glioblastoma and human foetal brain identifies pericyte subsets.

    PubMed

    Girolamo, Francesco; Dallatomasina, Alice; Rizzi, Marco; Errede, Mariella; Wälchli, Thomas; Mucignat, Maria Teresa; Frei, Karl; Roncali, Luisa; Perris, Roberto; Virgintino, Daniela

    2013-01-01

    NG2/CSPG4 is a complex surface-associated proteoglycan (PG) recognized to be a widely expressed membrane component of glioblastoma (WHO grade IV) cells and angiogenic pericytes. To determine the precise expression pattern of NG2/CSPG4 on glioblastoma cells and pericytes, we generated a panel of >60 mouse monoclonal antibodies (mAbs) directed against the ectodomain of human NG2/CSPG4, partially characterized the mAbs, and performed a high-resolution distributional mapping of the PG in human foetal, adult and glioblastoma-affected brains. The reactivity pattern initially observed on reference tumour cell lines indicated that the mAbs recognized 48 immunologically distinct NG2/CSPG4 isoforms, and a total of 14 mAbs was found to identify NG2/CSPG4 isoforms in foetal and neoplastic cerebral sections. These were consistently absent in the adult brain, but exhibited a complementary expression pattern in angiogenic vessels of both tumour and foetal tissues. Considering the extreme pleomorphism of tumour areas, and with the aim of subsequently analysing the distributional pattern of the NG2/CSPG4 isoforms on similar histological vessel typologies, a preliminary study was carried out with endothelial cell and pericyte markers, and with selected vascular basement membrane (VBM) components. On both tumour areas characterized by 'glomeruloid' and 'garland vessels', which showed a remarkably similar cellular and molecular organization, and on developing brain vessels, spatially separated, phenotypically diversified pericyte subsets with a polarized expression of key surface components, including NG2/CSPG4, were disclosed. Interestingly, the majority of the immunolocalized NG2/CSPG4 isoforms present in glioblastoma tissue were present in foetal brain, except for one isoform that seemed to be exclusive of tumour cells, being absent in foetal brain. The results highlight an unprecedented, complex pattern of NG2/CSPG4 isoform expression in foetal and neoplastic CNS, discriminating

  9. SLC7A11 Overexpression in Glioblastoma Is Associated with Increased Cancer Stem Cell-Like Properties.

    PubMed

    Polewski, Monika D; Reveron-Thornton, Rosyli F; Cherryholmes, Gregory A; Marinov, Georgi K; Aboody, Karen S

    2017-09-01

    System xc(-) is a sodium-independent electroneutral transporter, comprising a catalytic subunit xCT (SLC7A11), which is involved in importing cystine. Certain cancers such as gliomas upregulate the expression of system xc(-), which confers a survival advantage against the detrimental effects of reactive oxygen species (ROS) by increasing generation of the antioxidant glutathione. However, ROS have also been shown to function as targeted, intracellular second messengers in an array of physiological processes such as proliferation. Several studies have implicated ROS in important cancer features such as migration, invasion, and contribution to a cancer stem cell (CSC)-like phenotype. The role of system xc(-) in regulating these ROS-sensitive processes in glioblastoma multiforme (GBM), the most aggressive malignant primary brain tumor in adults, remains unknown. Stable SLC7A11 knockdown and overexpressing U251 glioma cells were generated and characterized to understand the role of redox and system xc(-) in glioma progression. SLC7A11 knockdown resulted in higher endogenous ROS levels and enhanced invasive properties. On the contrary, overexpression of SLC7A11 resulted in decreased endogenous ROS levels as well as decreased migration and invasion. However, SLC7A11-overexpressing cells displayed actin cytoskeleton changes reminiscent of epithelial-like cells and exhibited an increased CSC-like phenotype. The enhanced CSC-like phenotype may contribute to increased chemoresistance and suggests that overexpression of SLC7A11 in the context of GBM may contribute to tumor progression. These findings have important implications for cancer management where targeting system xC(-) in combination with other chemotherapeutics can reduce cancer resistance and recurrence and improve GBM patient survival.

  10. Characterization of brain tumours with spin-spin relaxation: pilot case study reveals unique T 2 distribution profiles of glioblastoma, oligodendroglioma and meningioma.

    PubMed

    Laule, Cornelia; Bjarnason, Thorarin A; Vavasour, Irene M; Traboulsee, Anthony L; Wayne Moore, G R; Li, David K B; MacKay, Alex L

    2017-09-11

    Prolonged spin-spin relaxation times in tumour tissue have been observed since some of the earliest nuclear magnetic resonance investigations of the brain. Over the last three decades, numerous studies have sought to characterize tumour morphology and malignancy using quantitative assessment of T 2 relaxation times, although attempts to categorize and differentiate tumours have had limited success. However, previous work must be interpreted with caution as relaxation data were typically acquired using a variety of multiple echo sequences with a range of echoes and T 2 decay curves and were frequently fit with monoexponential analysis. We defined the distribution of T 2 components in three different human brain tumours (glioblastoma, oligodendroglioma, meningioma) using a multi-echo sequence with a greater number of echoes and a longer acquisition window than previously used (48 echoes, data collection out to 1120 ms) with no a priori assumptions about the number of exponential components contributing to the T 2 decay. T 2 relaxation times were increased in tumour tissue and each tumour showed a distinct T 2 distribution profile. Tumours have complex and unique compartmentalization characteristics. Quantitative assessment of T 2 relaxation in brain cancer may be useful in evaluating different grades of brain tumours on the basis of their T 2 distribution profile, and has the potential to be a non-invasive diagnostic tool which may also be useful in monitoring therapy. Further study with a larger sample size and varying grades of tumours is warranted.

  11. Glucose transport: meeting the metabolic demands of cancer, and applications in glioblastoma treatment

    PubMed Central

    Labak, Collin M; Wang, Paul Y; Arora, Rishab; Guda, Maheedhara R; Asuthkar, Swapna; Tsung, Andrew J; Velpula, Kiran K

    2016-01-01

    GLUT1, and to a lesser extent, GLUT3, appear to be interesting targets in the treatment of glioblastoma multiforme. The current review aims to give a brief history of the scientific community’s understanding of these glucose transporters and to relate their importance to the metabolic changes that occur as a result of cancer. One of the primary changes that occurs in cancer, the Warburg Effect, is characterized by an extreme shift toward glycolysis from the usual reliance on oxidative phosphorylation and is currently being investigated to target the upstream and downstream factors responsible for Warburg-induced changes. Further, it aims to explain the differential expression of GLUT1 and GLUT3 in glioblastoma tissue, and how these modulations in expression can serve as targets to restore a more normal metabolism. Additionally, hypoxia-induced factor-1α’s (HIF1α) role in a number of transcriptional changes typical to GBM will be discussed, including its role in GLUT upregulation. Finally, the four known subtypes of GBM [proneural, neural, mesenchymal, and classical] will be characterized in order to discuss how metabolic changes differ in each subtype. These changes have the potential to be selectively targeted in order to provide specificity to the clinical treatment options in GBM. PMID:27648352

  12. Directly visualized glioblastoma-derived extracellular vesicles transfer RNA to microglia/macrophages in the brain.

    PubMed

    van der Vos, Kristan E; Abels, Erik R; Zhang, Xuan; Lai, Charles; Carrizosa, Esteban; Oakley, Derek; Prabhakar, Shilpa; Mardini, Osama; Crommentuijn, Matheus H W; Skog, Johan; Krichevsky, Anna M; Stemmer-Rachamimov, Anat; Mempel, Thorsten R; El Khoury, Joseph; Hickman, Suzanne E; Breakefield, Xandra O

    2016-01-01

    To understand the ability of gliomas to manipulate their microenvironment, we visualized the transfer of vesicles and the effects of tumor-released extracellular RNA on the phenotype of microglia in culture and in vivo. Extracellular vesicles (EVs) released from primary human glioblastoma (GBM) cells were isolated and microRNAs (miRNAs) were analyzed. Primary mouse microglia were exposed to GBM-EVs, and their uptake and effect on proliferation and levels of specific miRNAs, mRNAs, and proteins were analyzed. For in vivo analysis, mouse glioma cells were implanted in the brains of mice, and EV release and uptake by microglia and monocytes/macrophages were monitored by intravital 2-photon microscopy, immunohistochemistry, and fluorescence activated cell sorting analysis, as well as RNA and protein levels. Microglia avidly took up GBM-EVs, leading to increased proliferation and shifting of their cytokine profile toward immune suppression. High levels of miR-451/miR-21 in GBM-EVs were transferred to microglia with a decrease in the miR-451/miR-21 target c-Myc mRNA. In in vivo analysis, we directly visualized release of EVs from glioma cells and their uptake by microglia and monocytes/macrophages in brain. Dissociated microglia and monocytes/macrophages from tumor-bearing brains revealed increased levels of miR-21 and reduced levels of c-Myc mRNA. Intravital microscopy confirms the release of EVs from gliomas and their uptake into microglia and monocytes/macrophages within the brain. Our studies also support functional effects of GBM-released EVs following uptake into microglia, associated in part with increased miRNA levels, decreased target mRNAs, and encoded proteins, presumably as a means for the tumor to manipulate its environs. © The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  13. Cancer around the brain

    PubMed Central

    Grisold, Wolfgang; Grisold, Anna

    2014-01-01

    Background Neuro-oncologists are familiar with primary brain tumors, intracerebral metastases meningeal carcinomatosis and extracerebral intracranial tumors as meningeoma. For these conditions, and also some other rare tumor entities several treatment options exist. Cancer can also involve structures around the brain as the dura, the base of the skull, the cavities of the skull and tissue around the bony skull, the skin, the tissue of the neck. and either compress, invade or spread in the central or peripheral nervous system. Methods A systematic literature research was conducted determining symptoms and signs, tumor sites of nerve invasion, tumor types, diagnostic techniques, mechanisms of nerve invasion, and important differential diagnosis. Additional cases from own experience were added for illustration. Results The mechanisms of tumor invasion of cranial nerves is heterogenous and not only involves several types of invasion, but also spread along the cranial nerves in antero- and retrograde fashion and even spread into different nerve territories via anastomosis. In addition the concept of angiosomas may have an influence on the spread of metastases. Conclusion In addition to the well described tumor spread in meningeal carcinomatosis and base of the skull metastases, dural spread, lesions of the bony skull, the cavities of the skull and skin of the face and tissue of the neck region need to be considered, and have an impact on therapeutic decisions. PMID:26034610

  14. DTI and PWI analysis of peri-enhancing tumoral brain tissue in patients treated for glioblastoma.

    PubMed

    Stecco, Alessandro; Pisani, Carla; Quarta, Raffaella; Brambilla, Marco; Masini, Laura; Beldì, Debora; Zizzari, Sara; Fossaceca, Rita; Krengli, Marco; Carriero, Alessandro

    2011-04-01

    To analyse the role of MR diffusion-tensor imaging (DTI) and perfusion-weighted imaging (PWI) in characterising tumour boundaries in patients with glioblastoma multiforme. Seventeen patients with surgically treated WHO IV grade gliomas who were candidates for adjuvant chemo-radiotherapy were enrolled. Before (T0) and after radiation treatment (T1), they underwent DTI and PWI, and the apparent diffusion coefficient (ADC), fractional anisotropy (FA) and relative cerebral blood volume (rCBV) in the enhancing tumour, the hyperintense tissue adjacent to the enhancing tumour, and the normal-appearing white matter (NAWM) adjacent to the hyperintense areas were analysed. The enhancing tissue at T1 was retrospectively divided on the basis of whether or not it was also enhancing at T0. The controls were the corresponding contralateral areas, on which we normalized the rCBV values, calculating the rCBV ratio. In NAWM, we did not find any significant differences in FA, ADC or rCBV. In the hyperintense perilesional regions, FA was significantly lower and ADC significantly higher than in the unaffected contralateral tissue; there were no significant differences in the rCBV maps. The values of FA, ADC and rCBV in enhancing neoplastic tissue were all significantly different from those observed in the contralateral tissue. There was no significant difference in rCBV values between the areas enhancing at T0 and those not enhancing at T0 but enhancing at T1, which may indicate the neoplastic transformation of apparently normal brain tissue. DTI metrics identify ultrastructural changes in hyperintense perilesional areas, but these are not specific for neoplastic tissue. rCBV seemed to reflect an ultrastructural alteration that was not visible at T0, but became visible (as neoplastic progression) on conventional MR images at T1. These findings could help identify tissue at risk of tumour infiltration.

  15. [Radiation-induces increased tumor cell aggressiveness of tumors of the glioblastomas?].

    PubMed

    Falk, Alexander T; Moncharmont, Coralie; Guilbert, Matthieu; Guy, Jean-Baptiste; Alphonse, Gersende; Trone, Jane-Chloé; Rivoirard, Romain; Gilormini, Marion; Toillon, Robert-Alain; Rodriguez-Lafrasse, Claire; Magné, Nicolas

    2014-09-01

    Glioblastoma multiform is the most common and aggressive brain tumor with a worse prognostic. Ionizing radiation is a cornerstone in the treatment of glioblastome with chemo-radiation association being the actual standard. As a paradoxal effect, it has been suggested that radiotherapy could have a deleterious effect on local recurrence of cancer. In vivo studies have studied the effect of radiotherapy on biological modification and pathogenous effect of cancer cells. It seems that ionizing radiations with photon could activate oncogenic pathways in glioblastoma cell lines. We realized a review of the literature of photon-enhanced effect on invasion and migration of glioblastoma cells by radiotherapy.

  16. A three-dimensional organoid culture system derived from human glioblastomas recapitulates the hypoxic gradients and cancer stem cell heterogeneity of tumors found in vivo

    PubMed Central

    Hubert, Christopher G.; Rivera, Maricruz; Spangler, Lisa C.; Wu, Qiulian; Mack, Stephen C.; Prager, Briana C.; Couce, Marta; McLendon, Roger E.; Sloan, Andrew E.; Rich, Jeremy N.

    2016-01-01

    Many cancers feature cellular hierarchies that are driven by tumor-initiating, cancer stem cells (CSCs) and rely on complex interactions with the tumor microenvironment. Standard cell culture conditions fail to recapitulate the original tumor architecture or microenvironmental gradients, and are not designed to retain the cellular heterogeneity of parental tumors. Here, we describe a three-dimensional culture system that supports the long-term growth and expansion of tumor organoids derived directly from glioblastoma specimens, including patient-derived primary cultures, xenografts, genetically engineered glioma models, or patient samples. Organoids derived from multiple regions of patient tumors retain selective tumorigenic potential. Furthermore, organoids could be established directly from brain metastases not typically amenable to in vitro culture. Once formed, tumor organoids grew for months and displayed regional heterogeneity with a rapidly dividing outer region of SOX2+, OLIG2+, and TLX+ cells surrounding a hypoxic core of primarily non-stem senescent cells and diffuse, quiescent CSCs. Notably, non-stem cells within organoids were sensitive to radiation therapy, whereas adjacent CSCs were radioresistant. Orthotopic transplantation of patient-derived organoids resulted in tumors displayed histological features, including single cell invasiveness, that were more representative of the parental tumor compared with those formed from patient-derived sphere cultures. In conclusion, we present a new ex vivo model in which phenotypically diverse stem and non-stem glioblastoma cell populations can be simultaneously cultured to explore new facets of microenvironmental influences and CSC biology. PMID:26896279

  17. Glycosylation Changes in Brain Cancer.

    PubMed

    Veillon, Lucas; Fakih, Christina; Abou-El-Hassan, Hadi; Kobeissy, Firas; Mechref, Yehia

    2017-10-05

    Protein glycosylation is a posttranslational modification that affects more than half of all known proteins. Glycans covalently bound to biomolecules modulate their functions by both direct interactions, such as the recognition of glycan structures by binding partners, and indirect mechanisms that contribute to the control of protein conformation, stability, and turnover. The focus of this review is the discussion of aberrant glycosylation related to brain cancer. Altered sialylation and fucosylation of N- and O-glycans play a role in the development and progression of brain cancer. Additionally, aberrant O-glycan expression has been implicated in brain cancer. This review also addresses the clinical potential and applications of aberrant glycosylation for the detection and treatment of brain cancer. The viable roles glycans may play in the development of brain cancer therapeutics are addressed as well as cancer-glycoproteomics and personalized medicine. Glycoprotein alterations are considered as a hallmark of cancer while high expression in body fluids represents an opportunity for cancer assessment.

  18. Brain metastasization of breast cancer.

    PubMed

    Custódio-Santos, Tânia; Videira, Mafalda; Brito, Maria Alexandra

    2017-08-01

    Central nervous system metastases have been reported in 15-25% of breast cancer patients, and the incidence is increasing. Moreover, the survival of these patients is generally poor, with reports of a 1-year survival rate of 20%. Therefore, a better knowledge about the determinants of brain metastasization is essential for the improvement of the clinical outcomes. Here, we summarize the current data about the metastatic cascade, ranging from the output of cancer cells from the primary tumour to their colonization in the brain, which involves the epithelial-mesenchymal transition, invasion of mammary tissue, intravasation into circulation, and homing into and extravasation towards the brain. The phenotypic change in malignant cells, and the importance of the microenvironment in the formation of brain metastases are also inspected. Finally, the importance of genetic and epigenetic changes, and the recently disclosed effects of microRNAs in brain metastasization of breast cancer are highlighted. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. Antiglioma activity of curcumin-loaded lipid nanoparticles and its enhanced bioavailability in brain tissue for effective glioblastoma therapy.

    PubMed

    Kundu, Paromita; Mohanty, Chandana; Sahoo, Sanjeeb K

    2012-07-01

    Glioblastoma, the most aggressive form of brain and central nervous system tumours, is characterized by high rates proliferation, migration and invasion. The major road block in the delivery of drugs to the brain is the blood-brain barrier, along with the expression of various multi-drug resistance (MDR) proteins that cause the efflux of a wide range of chemotherapeutic drugs. Curcumin, a herbal drug, is known to inhibit cellular proliferation, migration and invasion and induce apoptosis of glioma cells. It also has the potential to modulate MDR in glioma cells. However, the greatest challenge in the administration of curcumin stems from its low bioavailability and high rate of metabolism. To circumvent the above pitfalls of curcumin we have developed curcumin-loaded glyceryl monooleate (GMO) nanoparticles (NP) coated with the surfactant Pluronic F-68 and vitamin E D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) for brain delivery. We demonstrated that our curcumin-loaded NPs inhibit cellular proliferation, migration and invasion along with a higher percentage of cell cycle arrest and telomerase inhibition, thus leading to a greater percentage apoptotic cell death in glioma cells compared with native curcumin. An in vivo study demonstrated enhanced bioavailability of curcumin in blood serum and brain tissue when delivered by curcumin-loaded GMO NPs compared with native curcumin in a rat model. Thus, curcumin-loaded GMO NPs can be used as an effective delivery system to overcome the challenges of drug delivery to the brain, providing a new approach to glioblastoma therapy. Copyright © 2012 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

  20. Focused ultrasound induced blood-brain barrier disruption to enhance chemotherapeutic drugs (BCNU) delivery for glioblastoma treatment

    NASA Astrophysics Data System (ADS)

    Liu, Hao-Li; Hua, Mu-Yi; Chen, Pin-Yuan; Huang, Chiung-Yin; Wang, Jiun-Jie; Wei, Kuo-Chen

    2010-03-01

    Focused ultrasound has been recently found to capable of temporally and reversibly disrupt local blood-brain barrier (BBB) and opens new frontier in delivering varies type of drugs into brain for central nerve system (CNS) disorder treatment. In this study, we aim to investigate the feasibility of delivering 1, 3-bits (2-chloroethyl) -1-nitrosourea (BCNU) to treat glioblastoma in animal models and evaluate whether this approach would gain treatment efficacy. Under the presence of microbubbles administration, a 400-kHz focused ultrasound was employed to deliver burst-tone ultrasonic energy stimulation to disrupt BBB in animal brains transcranially, and in-vivo monitored by magnetic-resonance imaging (MRI). C6-glioma cells were cultured and implanted into Sprague-Dawley rats as the brain-tumor model. BCNU deposited in brain was quantified by using high-performance liquid chromatography (HPLC), and brain tissues were examined histologically. MRI was employed to longitudinal evaluate the brain tumor treatment including the analysis of tumor progression and animal survival. We confirmed that the focused ultrasound, under the secure ultrasonic energy level, can significantly enhance the BCNU penetration through BBB over 300% than control without cause hemorrhage. Apparent improvement of treatment efficacy achieved by combining focused ultrasound with BCNU delivery, including significant suppression of tumor growth and a prolonged animal survival. This study highly support that this treatment strategy could be clinically-relevant and may help to provide another potential strategy in increasing local chemotherapeutic drugs for brain-tumor treatment.

  1. The Hypoxic Microenvironment Maintains Glioblastoma Stem Cells and Promotes Reprogramming towards a Cancer Stem Cell Phenotype

    PubMed Central

    Heddleston, John M.; Li, Zhizhong; Hjelmeland, Anita B.; Rich, Jeremy N.

    2009-01-01

    Glioblastomas are highly lethal cancers that contain cellular hierarchies with self-renewing cancer stem cells that can propagate tumors in secondary transplant assays. The potential significance of cancer stem cells in cancer biology has been demonstrated by studies showing contributions to therapeutic resistance, angiogenesis, and tumor dispersal. We recently reported that physiologic oxygen levels differentially induce hypoxia inducible factor-2α (HIF2α) levels in cancer stem cells. HIF1α functioned in proliferation and survival of all cancer cells but also was activated in normal neural progenitors suggesting a potentially restricted therapeutic index while HIF2α was essential in only in cancer stem cells and was not expressed by normal neural progenitors demonstrating HIF2α is a cancer stem cell specific target. We now extend these studies to examine the role of hypoxia in regulating tumor cell plasticity. We find that hypoxia promotes the self-renewal capability of the stem and non-stem population as well as promoting a more stem-like phenotype in the non-stem population with increased neurosphere formation as well as upregulation of important stem cell factors, such as OCT4, NANOG, and c-MYC. The importance of HIF2α was further supported as forced expression of non-degradable HIF2α induced a cancer stem cell marker and augmented the tumorigenic potential of the non-stem population. This novel finding may indicate a specific role of HIF2α in promoting glioma tumorigenesis. The unexpected plasticity of the non-stem glioma population and the stem-like phenotype emphasizes the importance of developing therapeutic strategies targeting the microenvironmental influence on the tumor in addition to cancer stem cells. PMID:19770585

  2. Hypoxia in the glioblastoma microenvironment: shaping the phenotype of cancer stem-like cells.

    PubMed

    Colwell, Nicole; Larion, Mioara; Giles, Amber J; Seldomridge, Ashlee N; Sizdahkhani, Saman; Gilbert, Mark R; Park, Deric M

    2017-07-01

    Glioblastoma is the most common and aggressive malignant primary brain tumor. Cellular heterogeneity is a characteristic feature of the disease and contributes to the difficulty in formulating effective therapies. Glioma stem-like cells (GSCs) have been identified as a subpopulation of tumor cells that are thought to be largely responsible for resistance to treatment. Intratumoral hypoxia contributes to maintenance of the GSCs by supporting the critical stem cell traits of multipotency, self-renewal, and tumorigenicity. This review highlights the interaction of GSCs with the hypoxic tumor microenvironment, exploring the mechanisms underlying the contribution of GSCs to tumor vessel dynamics, immune modulation, and metabolic alteration. Published by Oxford University Press on behalf of the Society for Neuro-Oncology 2017. This work is written by (a) US Government employee(s) and is in the public domain in the US.

  3. The ZEB1 pathway links glioblastoma initiation, invasion and chemoresistance

    PubMed Central

    Siebzehnrubl, Florian A; Silver, Daniel J; Tugertimur, Bugra; Deleyrolle, Loic P; Siebzehnrubl, Dorit; Sarkisian, Matthew R; Devers, Kelly G; Yachnis, Antony T; Kupper, Marius D; Neal, Daniel; Nabilsi, Nancy H; Kladde, Michael P; Suslov, Oleg; Brabletz, Simone; Brabletz, Thomas; Reynolds, Brent A; Steindler, Dennis A

    2013-01-01

    Glioblastoma remains one of the most lethal types of cancer, and is the most common brain tumour in adults. In particular, tumour recurrence after surgical resection and radiation invariably occurs regardless of aggressive chemotherapy. Here, we provide evidence that the transcription factor ZEB1 (zinc finger E-box binding homeobox 1) exerts simultaneous influence over invasion, chemoresistance and tumourigenesis in glioblastoma. ZEB1 is preferentially expressed in invasive glioblastoma cells, where the ZEB1-miR-200 feedback loop interconnects these processes through the downstream effectors ROBO1, c-MYB and MGMT. Moreover, ZEB1 expression in glioblastoma patients is predictive of shorter survival and poor Temozolomide response. Our findings indicate that this regulator of epithelial-mesenchymal transition orchestrates key features of cancer stem cells in malignant glioma and identify ROBO1, OLIG2, CD133 and MGMT as novel targets of the ZEB1 pathway. Thus, ZEB1 is an important candidate molecule for glioblastoma recurrence, a marker of invasive tumour cells and a potential therapeutic target, along with its downstream effectors. Glioblastoma have a poor prognosis, mainly due to infiltrating and therapy resistant cells leading to cancer recurrence. Here, tumor formation, invasion and resistance are not independent but intertwined processes regulated by the EMT activator ZEB1. PMID:23818228

  4. Inhibition of Pediatric Glioblastoma Tumor Growth by the Anti-Cancer Agent OKN-007 in Orthotopic Mouse Xenografts

    PubMed Central

    Coutinho de Souza, Patricia; Mallory, Samantha; Smith, Nataliya; Saunders, Debra; Li, Xiao-Nan; McNall-Knapp, Rene Y.; Fung, Kar-Ming; Towner, Rheal A.

    2015-01-01

    Pediatric glioblastomas (pGBM), although rare, are one of the leading causes of cancer-related deaths in children, with tumors essentially refractory to existing treatments. Here, we describe the use of conventional and advanced in vivo magnetic resonance imaging (MRI) techniques to assess a novel orthotopic xenograft pGBM mouse (IC-3752GBM patient-derived culture) model, and to monitor the effects of the anti-cancer agent OKN-007 as an inhibitor of pGBM tumor growth. Immunohistochemistry support data is also presented for cell proliferation and tumor growth signaling. OKN-007 was found to significantly decrease tumor volumes (p<0.05) and increase animal survival (p<0.05) in all OKN-007-treated mice compared to untreated animals. In a responsive cohort of treated animals, OKN-007 was able to significantly decrease tumor volumes (p<0.0001), increase survival (p<0.001), and increase diffusion (p<0.01) and perfusion rates (p<0.05). OKN-007 also significantly reduced lipid tumor metabolism in responsive animals [(Lip1.3 and Lip0.9)-to-creatine ratio (p<0.05)], as well as significantly decrease tumor cell proliferation (p<0.05) and microvessel density (p<0.05). Furthermore, in relationship to the PDGFRα pathway, OKN-007 was able to significantly decrease SULF2 (p<0.05) and PDGFR-α (platelet-derived growth factor receptor-α) (p<0.05) immunoexpression, and significantly increase decorin expression (p<0.05) in responsive mice. This study indicates that OKN-007 may be an effective anti-cancer agent for some patients with pGBMs by inhibiting cell proliferation and angiogenesis, possibly via the PDGFRα pathway, and could be considered as an additional therapy for pediatric brain tumor patients. PMID:26248280

  5. Interrogating Metabolism in Brain Cancer.

    PubMed

    Salzillo, Travis C; Hu, Jingzhe; Nguyen, Linda; Whiting, Nicholas; Lee, Jaehyuk; Weygand, Joseph; Dutta, Prasanta; Pudakalakatti, Shivanand; Millward, Niki Zacharias; Gammon, Seth T; Lang, Frederick F; Heimberger, Amy B; Bhattacharya, Pratip K

    2016-11-01

    This article reviews existing and emerging techniques of interrogating metabolism in brain cancer from well-established proton magnetic resonance spectroscopy to the promising hyperpolarized metabolic imaging and chemical exchange saturation transfer and emerging techniques of imaging inflammation. Some of these techniques are at an early stage of development and clinical trials are in progress in patients to establish the clinical efficacy. It is likely that in vivo metabolomics and metabolic imaging is the next frontier in brain cancer diagnosis and assessing therapeutic efficacy; with the combined knowledge of genomics and proteomics a complete understanding of tumorigenesis in brain might be achieved. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. Simultaneous targeting of Eph receptors in glioblastoma

    PubMed Central

    Ferluga, Sara; Tomé, Carla Maria Lema; Herpai, Denise Mazess; D'Agostino, Ralph; Debinski, Waldemar

    2016-01-01

    Eph tyrosine kinase receptors are frequently overexpressed and functional in many cancers, and they are attractive candidates for targeted therapy. Here, we analyzed the expression of Eph receptor A3, one of the most up-regulated factors in glioblastoma cells cultured under tumorsphere-forming conditions, together with EphA2 and EphB2 receptors. EphA3 was overexpressed in up to 60% of glioblastoma tumors tested, but not in normal brain. EphA3 was localized in scattered areas of the tumor, the invasive ring, and niches near tumor vessels. EphA3 co-localized with macrophage/leukocyte markers, suggesting EphA3 expression on tumor-infiltrating cells of bone marrow origin. We took advantage of the fact that ephrinA5 (eA5) is a ligand that binds EphA3, EphA2 and EphB2 receptors, and used it to construct a novel targeted anti-glioblastoma cytotoxin. The eA5-based cytotoxin potently and specifically killed glioblastoma cells with an IC50 of at least 10−11 M. This and similar cytotoxins will simultaneously target different compartments of glioblastoma tumors while mitigating tumor heterogeneity. PMID:27494882

  7. Advance Care Planning in Glioblastoma Patients

    PubMed Central

    Fritz, Lara; Dirven, Linda; Reijneveld, Jaap C.; Koekkoek, Johan A. F.; Stiggelbout, Anne M.; Pasman, H. Roeline W.; Taphoorn, Martin J. B.

    2016-01-01

    Despite multimodal treatment with surgery, radiotherapy and chemotherapy, glioblastoma is an incurable disease with a poor prognosis. During the disease course, glioblastoma patients may experience progressive neurological deficits, symptoms of increased intracranial pressure such as drowsiness and headache, incontinence, seizures and progressive cognitive dysfunction. These patients not only have cancer, but also a progressive brain disease. This may seriously interfere with their ability to make their own decisions regarding treatment. It is therefore warranted to involve glioblastoma patients early in the disease trajectory in treatment decision-making on their future care, including the end of life (EOL) care, which can be achieved with Advance Care Planning (ACP). Although ACP, by definition, aims at timely involvement of patients and proxies in decision-making on future care, the optimal moment to initiate ACP discussions in the disease trajectory of glioblastoma patients remains controversial. Moreover, the disease-specific content of these ACP discussions needs to be established. In this article, we will first describe the history of patient participation in treatment decision-making, including the shift towards ACP. Secondly, we will describe the possible role of ACP for glioblastoma patients, with the specific aim of treatment of disease-specific symptoms such as somnolence and dysphagia, epileptic seizures, headache, and personality changes, agitation and delirium in the EOL phase, and the importance of timing of ACP discussions in this patient population. PMID:27834803

  8. Nicotinamide metabolism regulates glioblastoma stem cell maintenance

    PubMed Central

    Jung, Jinkyu; Kim, Leo J.Y.; Wang, Xiuxing; Wu, Qiulian; Sanvoranart, Tanwarat; Hubert, Christopher G.; Prager, Briana C.; Wallace, Lisa C.; Jin, Xun; Mack, Stephen C.; Rich, Jeremy N.

    2017-01-01

    Metabolic dysregulation promotes cancer growth through not only energy production, but also epigenetic reprogramming. Here, we report that a critical node in methyl donor metabolism, nicotinamide N-methyltransferase (NNMT), ranked among the most consistently overexpressed metabolism genes in glioblastoma relative to normal brain. NNMT was preferentially expressed by mesenchymal glioblastoma stem cells (GSCs). NNMT depletes S-adenosyl methionine (SAM), a methyl donor generated from methionine. GSCs contained lower levels of methionine, SAM, and nicotinamide, but they contained higher levels of oxidized nicotinamide adenine dinucleotide (NAD+) than differentiated tumor cells. In concordance with the poor prognosis associated with DNA hypomethylation in glioblastoma, depletion of methionine, a key upstream methyl group donor, shifted tumors toward a mesenchymal phenotype and accelerated tumor growth. Targeting NNMT expression reduced cellular proliferation, self-renewal, and in vivo tumor growth of mesenchymal GSCs. Supporting a mechanistic link between NNMT and DNA methylation, targeting NNMT reduced methyl donor availability, methionine levels, and unmethylated cytosine, with increased levels of DNA methyltransferases, DNMT1 and DNMT3A. Supporting the clinical significance of these findings, NNMT portended poor prognosis for glioblastoma patients. Collectively, our findings support NNMT as a GSC-specific therapeutic target in glioblastoma by disrupting oncogenic DNA hypomethylation. PMID:28515364

  9. Synergistic effect of gold nanoparticles and cold plasma on glioblastoma cancer therapy

    NASA Astrophysics Data System (ADS)

    Cheng, Xiaoqian; Murphy, William; Recek, Nina; Yan, Dayun; Cvelbar, Uros; Vesel, Alenka; Mozetič, Miran; Canady, Jerome; Keidar, Michael; Sherman, Jonathan H.

    2014-08-01

    Gold nanoparticles (AuNPs) have been investigated as a promising reagent for cancer therapy in various fields. In the meantime, cold atmospheric plasma has shown exquisite selectivity towards cancer cells. In this paper, we demonstrate that there is a synergy between gold nanoparticles and cold atmospheric plasma in cancer therapy. Specifically, the concentration of AuNPs plays an important role on plasma therapy. At an optimal concentration, gold nanoparticles can significantly induce glioblastoma (U87) cell death up to a 30% overall increase compared to the control group with the same plasma dosage but no AuNPs applied. The reactive oxygen species (ROS) intensity of the corresponding conditions has a reversed trend compared to cell viability. This matches with the theory that intracellular ROS accumulation results in oxidative stress, which further changes the intracellular pathways, causing damage to the proteins, lipids and DNA. Our results show that this synergy has great potential in improving the efficiency of cancer therapy and reducing harm to normal cells.

  10. Restricted delivery of talazoparib across the blood-brain barrier limits the sensitizing effects of poly (ADP-ribose) polymerase inhibition on temozolomide therapy in glioblastoma.

    PubMed

    Kizilbash, Sani H; Gupta, Shiv K; Chang, Kenneth; Kawashima, Ryo; Parrish, Karen E; Carlson, Brett L; Bakken, Katrina K; Mladek, Ann C; Schroeder, Mark A; Decker, Paul A; Kitange, Gaspar J; Shen, Yuqiao; Feng, Ying; Protter, Andrew A; Elmquist, William F; Sarkaria, Jann N

    2017-09-25

    Poly (ADP-ribose) polymerase PARP inhibitors, including talazoparib (TAL), potentiate temozolomide (TMZ) efficacy in multiple tumor types, however TAL-mediated sensitization has not been evaluated in orthotopic glioblastoma (GBM) models. This study evaluates TAL ± TMZ in clinically relevant GBM models. TAL at 1-3 nmol/L sensitized T98G, U251 and GBM12 cells to TMZ, and enhanced DNA damage signaling and G2/M arrest in vitro. In vivo cyclical therapy with TAL (0.15 mg/kg twice daily) combined with low dose TMZ (5 mg/kg daily) was well tolerated. This TAL/TMZ regimen prolonged tumor stasis more than TMZ alone in heterotopic GBM12 xenografts [median time to endpoint: 76 days vs. 50 days TMZ (p=0.005), 11 days placebo (p <0.001)]. However, TAL/TMZ did not accentuate survival beyond that of TMZ alone in corresponding orthotopic xenografts (median survival 37 vs. 30 days with TMZ (p=0.93), 14 days with placebo, p<0.001). Average brain and plasma TAL concentrations at 2 hours after a single dose (0.15 mg/kg) were 0.49±0.07 ng/g and 25.5±4.1 ng/ml, respectively. The brain/plasma distribution of TAL in Bcrp-/- versus WT mice did not differ, while the brain/plasma ratio in Mdr1a/b-/- mice was higher than WT mice (0.23 vs. 0.02, p<0.001). Consistent with the in vivo brain distribution, overexpression of MDR1 decreased TAL accumulation in MDCKII cells. These results indicate that TAL has significant MDR1 efflux liability that may restrict delivery across the blood-brain barrier, and this may explain the loss of TAL-mediated TMZ sensitization in orthotopic versus heterotopic GBM xenografts. Copyright ©2017, American Association for Cancer Research.

  11. Focused ultrasound-induced blood-brain barrier opening to enhance temozolomide delivery for glioblastoma treatment: a preclinical study.

    PubMed

    Wei, Kuo-Chen; Chu, Po-Chun; Wang, Hay-Yan Jack; Huang, Chiung-Yin; Chen, Pin-Yuan; Tsai, Hong-Chieh; Lu, Yu-Jen; Lee, Pei-Yun; Tseng, I-Chou; Feng, Li-Ying; Hsu, Peng-Wei; Yen, Tzu-Chen; Liu, Hao-Li

    2013-01-01

    The purpose of this study is to assess the preclinical therapeutic efficacy of magnetic resonance imaging (MRI)-monitored focused ultrasound (FUS)-induced blood-brain barrier (BBB) disruption to enhance Temozolomide (TMZ) delivery for improving Glioblastoma Multiforme (GBM) treatment. MRI-monitored FUS with microbubbles was used to transcranially disrupt the BBB in brains of Fisher rats implanted with 9L glioma cells. FUS-BBB opening was spectrophotometrically determined by leakage of dyes into the brain, and TMZ was quantitated in cerebrospinal fluid (CSF) and plasma by LC-MS\\MS. The effects of treatment on tumor progression (by MRI), animal survival and brain tissue histology were investigated. Results demonstrated that FUS-BBB opening increased the local accumulation of dyes in brain parenchyma by 3.8-/2.1-fold in normal/tumor tissues. Compared to TMZ alone, combined FUS treatment increased the TMZ CSF/plasma ratio from 22.7% to 38.6%, reduced the 7-day tumor progression ratio from 24.03 to 5.06, and extended the median survival from 20 to 23 days. In conclusion, this study provided preclinical evidence that FUS BBB-opening increased the local concentration of TMZ to improve the control of tumor progression and animal survival, suggesting its clinical potential for improving current brain tumor treatment.

  12. RXFP1 is Targeted by Complement C1q Tumor Necrosis Factor-Related Factor 8 in Brain Cancer

    PubMed Central

    Thanasupawat, Thatchawan; Glogowska, Aleksandra; Burg, Maxwell; Wong, G. William; Hoang-Vu, Cuong; Hombach-Klonisch, Sabine; Klonisch, Thomas

    2015-01-01

    The relaxin-like RXFP1 ligand–receptor system has important functions in tumor growth and tissue invasion. Recently, we have identified the secreted protein, CTRP8, a member of the C1q/tumor necrosis factor-related protein (CTRP) family, as a novel ligand of the relaxin receptor, RXFP1, with functions in brain cancer. Here, we review the role of CTRP members in cancers cells with particular emphasis on CTRP8 in glioblastoma. PMID:26322020

  13. Curcumin for the Treatment of Glioblastoma.

    PubMed

    Sordillo, Laura A; Sordillo, Peter P; Helson, Lawrence

    2015-12-01

    Glioblastoma multiforme is a highly aggressive primary cancer of the brain associated with a poor prognosis. Modest increases in survival can sometimes be achieved with the use of temozolomide and radiation therapy after surgery, but second-line therapy after recurrence has a limited efficacy. Curcumin has demonstrated promising results against this form of cancer in experimental models. The reported activity of curcumin against cancer stem cells, a major cause of glioblastoma resistance to therapy, and its ability to augment the apoptotic effects of ceramides, suggest it would have a synergistic effect with cytotoxic chemotherapy agents currently used in second-line therapy, such as lomustine. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  14. Glioblastoma-associated microglia and macrophages: targets for therapies to improve prognosis.

    PubMed

    Poon, Candice C; Sarkar, Susobhan; Yong, V Wee; Kelly, John J P

    2017-06-01

    Glioblastoma is the most common and most malignant primary adult human brain tumour. Diagnosis of glioblastoma carries a dismal prognosis. Treatment resistance and tumour recurrence are the result of both cancer cell proliferation and their interaction with the tumour microenvironment. A large proportion of the tumour microenvironment consists of an inflammatory infiltrate predominated by microglia and macrophages, which are thought to be subverted by glioblastoma cells for tumour growth. Thus, glioblastoma-associated microglia and macrophages are logical therapeutic targets. Their emerging roles in glioblastoma progression are reflected in the burgeoning research into therapeutics directed at their modification or elimination. Here, we review the biology of glioblastoma-associated microglia and macrophages, and model systems used to study these cells in vitro and in vivo. We discuss translation of results using these model systems and review recent advances in immunotherapies targeting microglia and macrophages in glioblastoma. Significant challenges remain but medications that affect glioblastoma-associated microglia and macrophages hold considerable promise to improve the prognosis for patients with this disease. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  15. Metabolic management of brain cancer.

    PubMed

    Seyfried, Thomas N; Kiebish, Michael A; Marsh, Jeremy; Shelton, Laura M; Huysentruyt, Leanne C; Mukherjee, Purna

    2011-06-01

    Malignant brain tumors are a significant health problem in children and adults. Conventional therapeutic approaches have been largely unsuccessful in providing long-term management. As primarily a metabolic disease, malignant brain cancer can be managed through changes in metabolic environment. In contrast to normal neurons and glia, which readily transition to ketone bodies (β-hydroxybutyrate) for energy under reduced glucose, malignant brain tumors are strongly dependent on glycolysis for energy. The transition from glucose to ketone bodies as a major energy source is an evolutionary conserved adaptation to food deprivation that permits the survival of normal cells during extreme shifts in nutritional environment. Only those cells with a flexible genome and normal mitochondria can effectively transition from one energy state to another. Mutations restrict genomic and metabolic flexibility thus making tumor cells more vulnerable to energy stress than normal cells. We propose an alternative approach to brain cancer management that exploits the metabolic flexibility of normal cells at the expense of the genetically defective and metabolically challenged tumor cells. This approach to brain cancer management is supported from recent studies in mice and humans treated with calorie restriction and the ketogenic diet. Issues of implementation and use protocols are presented for the metabolic management of brain cancer. Copyright © 2010. Published by Elsevier B.V.

  16. Mesenchymal stem cells differentially affect the invasion of distinct glioblastoma cell lines

    PubMed Central

    Breznik, Barbara; Motaln, Helena; Vittori, Miloš; Rotter, Ana; Turnšek, Tamara Lah

    2017-01-01

    Glioblastoma multiforme are an aggressive form of brain tumors that are characterized by distinct invasion of single glioblastoma cells, which infiltrate the brain parenchyma. This appears to be stimulated by the communication between cancer and stromal cells. Mesenchymal stem cells (MSCs) are part of the glioblastoma microenvironment, and their ‘cross-talk’ with glioblastoma cells is still poorly understood. Here, we examined the effects of bone marrow-derived MSCs on two different established glioblastoma cell lines U87 and U373. We focused on mutual effects of direct MSC/glioblastoma contact on cellular invasion in three-dimensional invasion assays in vitro and in a zebrafish embryo model in vivo. This is the first demonstration of glioblastoma cell-type-specific responses to MSCs in direct glioblastoma co-cultures, where MSCs inhibited the invasion of U87 cells and enhanced the invasion of U373. Inversely, direct cross-talk between MSCs and both of glioblastoma cell lines enhanced MSC motility. MSC-enhanced invasion of U373 cells was assisted by overexpression of proteases cathepsin B, calpain1, uPA/uPAR, MMP-2, -9 and -14, and increased activities of some of these proteases, as determined by the effects of their selective inhibitors on invasion. In contrast, these proteases had no effect on U87 cell invasion under MSC co-culturing. Finally, we identified differentially expressed genes, in U87 and U373 cells that could explain different response of these cell lines to MSCs. In conclusion, we demonstrated that MSC/glioblastoma cross-talk is different in the two glioblastoma cell phenotypes, which contributes to tumor heterogeneity. PMID:28424417

  17. Polo-like kinase 1 inhibition kills glioblastoma multiforme brain tumor cells in part through loss of SOX2 and delays tumor progression in mice.

    PubMed

    Lee, Cathy; Fotovati, Abbas; Triscott, Joanna; Chen, James; Venugopal, Chitra; Singhal, Ash; Dunham, Christopher; Kerr, John M; Verreault, Maite; Yip, Stephen; Wakimoto, Hiroaki; Jones, Chris; Jayanthan, Aarthi; Narendran, Aru; Singh, Sheila K; Dunn, Sandra E

    2012-06-01

    Glioblastoma multiforme (GBM) ranks among the deadliest types of cancer and given these new therapies are urgently needed. To identify molecular targets, we queried a microarray profiling 467 human GBMs and discovered that polo-like kinase 1 (PLK1) was highly expressed in these tumors and that it clustered with the proliferative subtype. Patients with PLK1-high tumors were more likely to die from their disease suggesting that current therapies are inactive against such tumors. This prompted us to examine its expression in brain tumor initiating cells (BTICs) given their association with treatment failure. BTICs isolated from patients expressed 110-470 times more PLK1 than normal human astrocytes. Moreover, BTICs rely on PLK1 for survival because the PLK1 inhibitor BI2536 inhibited their growth in tumorsphere cultures. PLK1 inhibition suppressed growth, caused G(2) /M arrest, induced apoptosis, and reduced the expression of SOX2, a marker of neural stem cells, in SF188 cells. Consistent with SOX2 inhibition, the loss of PLK1 activity caused the cells to differentiate based on elevated levels of glial fibrillary acidic protein and changes in cellular morphology. We then knocked glial fibrillary acidic protein (GFAP) down SOX2 with siRNA and showed that it too inhibited cell growth and induced cell death. Likewise, in U251 cells, PLK1 inhibition suppressed cell growth, downregulated SOX2, and induced cell death. Furthermore, BI2536 delayed tumor growth of U251 cells in an orthotopic brain tumor model, demonstrating that the drug is active against GBM. In conclusion, PLK1 level is elevated in GBM and its inhibition restricts the growth of brain cancer cells.

  18. Harnessing nanomedicine for therapeutic intervention in glioblastoma.

    PubMed

    Gutkin, Anna; Cohen, Zvi R; Peer, Dan

    2016-11-01

    Glioblastoma is a type of brain cancer arises from glial cells. Glioblastoma multiforme (GBM), a subtype of glioblastoma, is the most common and most aggressive primary brain tumor. Currently, GBM therapy includes surgery and post-operative high-doses of radiation and chemotherapy. This therapeutic strategy has a limited contribution in extending the survival rate of GBM patients. Areas covered: Herein, we focus on harnessing nanoscale drug delivery strategies to treat brain malignancies. Specifically, we briefly discuss the challenges facing GBM therapy such as restricted passage across the blood-brain barrier (BBB) and low enhanced permeability and retention effect. Next, we describe different pathways to address these challenges. Finally, we discuss the field of nanomedicine, which emerged as a promising platform for drug delivery to brain malignancies. Expert opinion: Countless strategies have been applied in preclinical and clinical settings to treat GBM. Among them is the use of different types of nanoparticles (NPs) and viruses with different approaches to cross or bypass the BBB. We suggest here a paradigm shift in thinking about crossing the BBB and tumor penetration as fundamental issues that need to be address in order to improve the therapeutic outcome in GBM.

  19. Effect and Mechanism of Total Flavonoids Extracted from Cotinus coggygria against Glioblastoma Cancer In Vitro and In Vivo.

    PubMed

    Wang, Gang; Wang, JunJie; Du, Li; Li, Fei

    2015-01-01

    Flavonoids, a major constituent of Cotinus coggygria (CC), have been reported to possess diverse biological activities, including antigenotoxic and hepatoprotective effects; however, few studies have investigated the biological activity of the total flavonoids of Cotinus coggygria, especially in terms of its cytotoxicity in cancer cells. In the present study, the Cotinus coggygria flavonoids (CCF) were extracted from Cotinus coggygria and characterized by HPLC. These results indicated that CCF extracts could inhibit cell proliferation, with IC50 values of 128.49 µg/mL (U87), 107.62 µg/mL (U251), and 93.57 µg/mL (DBTRG-05MG). The current investigation also revealed that CCF induced apoptosis in highly malignant glioblastoma cells, a process that apparently involved the inhibition of Akt coupled with ERK protein expression. This finding suggests that the PI3K/Akt-ERK signaling pathway is regulated by CCF and leads to the inhibition of the glioblastoma cancer cells. Furthermore, a significant antitumor effect of CCF was observed in xenograft animal models of glioblastoma multiforme in vivo. Taken together, these data suggest that CCF is the active component in the Cotinus coggygria plant that offers potential therapeutic modality in the abrogation of cancer cell proliferation, including the induction of apoptosis.

  20. PEITC inhibits human brain glioblastoma GBM 8401 cell migration and invasion through the inhibition of uPA, Rho A, and Ras with inhibition of MMP-2, -7 and -9 gene expression.

    PubMed

    Chou, Yu-Cheng; Chang, Meng-Ya; Wang, Mei-Jen; Yu, Fu-Shun; Liu, Hsin-Chung; Harnod, Tomor; Hung, Chih-Huang; Lee, Hsu-Tung; Chung, Jing-Gung

    2015-11-01

    Glioblastoma is the most aggressive primary brain malignancy, and the efficacy of multimodality treatments remains unsatisfactory. Phenethyl isothiocyanate (PEITC), one member of the isothiocyanate family, was found to inhibit the migration and invasion of many types of human cancer cells. In our previous study, PEITC induced the apoptosis of human brain glioblastoma GBM 8401 cells through the extrinsic and intrinsic signaling pathways. In the present study, we first investigated the effects of PEITC on the migration and invasion of GBM 8401 cells. PEITC decreased the migration of GBM 8401 cells in a dose-dependent manner as determined from scratch wound healing and Transwell migration assays. The percentage of inhibition ranged from 46.89 to 15.75%, and from 27.80 to 7.31% after a 48-h treatment of PEITC as determined from the Transwell migration assay and invasion assay, respectively. The western blot analysis indicated that PEITC decreased the levels of proteins associated with migration and invasion, Ras, uPA, RhoA, GRB2, p-p38, p-JNK, p-ERK, p65, SOS1, MMP-2, MMP-9 and MMP-13, in a dose-dependent manner. Real-time PCR analyses revealed that PEITC reduced the mRNA levels of MMP-2, MMP-7, MMP-9 and RhoA in a dose- and time-dependent manner. PEITC exhibited potent anticancer activities through the inhibition of migration and invasion in the GBM 8401 cells. Our findings elucidate the possible molecular mechanisms and signaling pathways of the anti-metastatic effects of PEITC on human brain glioblastoma cells, and PEITC may be considered as a therapeutic agent.

  1. Metabolic therapy: a new paradigm for managing malignant brain cancer.

    PubMed

    Seyfried, Thomas N; Flores, Roberto; Poff, Angela M; D'Agostino, Dominic P; Mukherjee, Purna

    2015-01-28

    Little progress has been made in the long-term management of glioblastoma multiforme (GBM), considered among the most lethal of brain cancers. Cytotoxic chemotherapy, steroids, and high-dose radiation are generally used as the standard of care for GBM. These procedures can create a tumor microenvironment rich in glucose and glutamine. Glucose and glutamine are suggested to facilitate tumor progression. Recent evidence suggests that many GBMs are infected with cytomegalovirus, which could further enhance glucose and glutamine metabolism in the tumor cells. Emerging evidence also suggests that neoplastic macrophages/microglia, arising through possible fusion hybridization, can comprise an invasive cell subpopulation within GBM. Glucose and glutamine are major fuels for myeloid cells, as well as for the more rapidly proliferating cancer stem cells. Therapies that increase inflammation and energy metabolites in the GBM microenvironment can enhance tumor progression. In contrast to current GBM therapies, metabolic therapy is designed to target the metabolic malady common to all tumor cells (aerobic fermentation), while enhancing the health and vitality of normal brain cells and the entire body. The calorie restricted ketogenic diet (KD-R) is an anti-angiogenic, anti-inflammatory and pro-apoptotic metabolic therapy that also reduces fermentable fuels in the tumor microenvironment. Metabolic therapy, as an alternative to the standard of care, has the potential to improve outcome for patients with GBM and other malignant brain cancers.

  2. Brain Training for Cancer Survivors' Nerve Damage

    MedlinePlus

    ... html Brain Training for Cancer Survivors' Nerve Damage Neurofeedback seems to offers relief from chemo-induced pain, ... brain waves with a type of training called neurofeedback seems to help cancer survivors ease symptoms of ...

  3. Glioblastoma cancer stem cells: role of the microenvironment and therapeutic targeting.

    PubMed

    Persano, Luca; Rampazzo, Elena; Basso, Giuseppe; Viola, Giampietro

    2013-03-01

    It has been recently suggested that many types of cancer, including glioblastoma (GBM), contain functionally subsets of cells with stem-like properties named "cancer stem cells" (CSCs). These are characterized by chemotherapy resistance and considered one of the key determinants driving tumor relapse. Many studies demonstrated that Glioma stem cells (GSCs) reside in particular tumor niches, that are necessary to support their behavior. A hypoxic microenvironment has been reported to play a crucial role in controlling GSC molecular and phenotypic profile and in promoting the recruitment of vascular and stromal cells in order to sustain tumor growth. Recent advances in the field allow researches to generate models able to recapitulate, at least in part, the extreme heterogeneity found within GBM tumors. These models try to account for the presence of GSCs and more differentiated cells, the influence of different microenvironments enclosed within the mass, heterotypic interactions between GBM and stromal cells and genetic aberrations. Understanding the mechanism of action of the microenvironmental signals and the interplay between different cell types within the tumor mass, open new questions on how GSCs modulate GBM aggressiveness and response to therapy. The definition of these tumor features will allow to setup innovative multimodal therapies able to target GBM cells at multiple levels. Here, we will discuss the major advances in the study of GSC role in GBM and the therapeutic implications resulting from them, thus reporting the latest strategies applied to counteract and overcome GBM intrinsic resistance to therapy for a better management of patients.

  4. Optimization of the route of platinum drugs administration to optimize the concomitant treatment with radiotherapy for glioblastoma implanted in the Fischer rat brain.

    PubMed

    Charest, Gabriel; Sanche, Léon; Fortin, David; Mathieu, David; Paquette, Benoit

    2013-12-01

    Treatment of glioblastoma with platinum compounds modestly improves progression-free survival and may cause toxic effects which prevent use at higher dose that would otherwise improve the antineoplastic effect. To reduce toxicity, we propose to encapsulate the platinum drug in a liposome. We have also tested three methods of drug administration (intra-venous, intra-arterial and intra-arterial combined with blood brain barrier disruption) to determine which one optimizes the tumor cell uptake, limits the toxicity and delivers the best concomitance effect with radiotherapy. Cisplatin, oxaliplatin, their respective liposomal formulations, Lipoplatin™ and Lipoxal™, and carboplatin were assessed in F98 glioma, orthotopically implanted in Fischer rats. We found that the modest accumulation of drugs in tumor cells after intra-venous injection was significantly improved when the intra-arterial route was used and further increased after the transient opening of the blood brain barrier with mannitol. The liposomal formulations have largely reduced the toxicity and have allowed a better exploitation of the anti-cancer activity of platinum agent. Although the liposomes Lipoplatin™ and Lipoxal™ have shown a similar ability to that of carboplatin, to accumulate in brain tumors, the highest additive effect with radiotherapy was obtained with carboplatin. We conclude that the intra-arterial infusion of carboplatin or Lipoxal™ in concomitance with radiation therapy leads to the best tumor control as measured by an increase of mean survival time in Fischer rats implanted with the F98 glioma with a benefit in survival time of 13.4 and 6.5 days respectively compared to intra-venous.

  5. Emerging immunotherapies for glioblastoma

    PubMed Central

    Desai, Rupen; Suryadevara, Carter M.; Batich, Kristen A.; Harrison Farber, S.; Sanchez-Perez, Luis; Sampson, John H.

    2016-01-01

    Immunotherapy for brain cancer has evolved dramatically over the past decade, owed in part to our improved understanding of how the immune system interacts with tumors residing within the central nervous system (CNS). Glioblastoma (GBM), the most common brain tumor in adults, carries a poor prognosis (<15 months) and only few advances have been made since the FDA’s approval of temozolomide (TMZ) in 2005. Importantly, several immunotherapies have now entered patient trials based on promising preclinical data, and recent studies have shed light on how GBM employs a slew of immunosuppressive mechanisms which may be targeted for therapeutic gain. Altogether, accumulating evidence suggests immunotherapy may soon earn its keep as a mainstay of clinical management for GBM. Areas Covered Here, we review cancer vaccines, checkpoint inhibitors, T-cell immunotherapy, and oncolytic virotherapy. Expert Opinion Checkpoint blockade induces antitumor activity by preventing negative regulation of T-cell activation. This platform, however, depends on an existing frequency of tumor-reactive T cells, and GBM is weakly immunogenic and GBM patients are typically immunocompromised. Therefore, checkpoint blockade may be most effective when used in combination with a DC vaccine or adoptively transferred tumor-specific T cells generated ex vivo. Both approaches have been shown to induce endogenous immune responses against tumor antigens, providing a rationale for use with checkpoint blockade where both primary and secondary responses may be potentiated. PMID:27223671

  6. Small molecule epigenetic screen identifies novel EZH2 and HDAC inhibitors that target glioblastoma brain tumor-initiating cells

    PubMed Central

    Grinshtein, Natalie; Rioseco, Constanza C.; Marcellus, Richard; Uehling, David; Aman, Ahmed; Lun, Xueqing; Muto, Osamu; Podmore, Lauren; Lever, Jake; Shen, Yaoqing; Blough, Michael D.; Cairncross, Greg J.; Robbins, Stephen M.; Jones, Steven J.; Marra, Marco A.; Al-Awar, Rima; Senger, Donna L.; Kaplan, David R.

    2016-01-01

    Glioblastoma (GBM) is the most lethal and aggressive adult brain tumor, requiring the development of efficacious therapeutics. Towards this goal, we screened five genetically distinct patient-derived brain-tumor initiating cell lines (BTIC) with a unique collection of small molecule epigenetic modulators from the Structural Genomics Consortium (SGC). We identified multiple hits that inhibited the growth of BTICs in vitro, and further evaluated the therapeutic potential of EZH2 and HDAC inhibitors due to the high relevance of these targets for GBM. We found that the novel SAM-competitive EZH2 inhibitor UNC1999 exhibited low micromolar cytotoxicity in vitro on a diverse collection of BTIC lines, synergized with dexamethasone (DEX) and suppressed tumor growth in vivo in combination with DEX. In addition, a unique brain-penetrant class I HDAC inhibitor exhibited cytotoxicity in vitro on a panel of BTIC lines and extended survival in combination with TMZ in an orthotopic BTIC model in vivo. Finally, a combination of EZH2 and HDAC inhibitors demonstrated synergy in vitro by augmenting apoptosis and increasing DNA damage. Our findings identify key epigenetic modulators in GBM that regulate BTIC growth and survival and highlight promising combination therapies. PMID:27449082

  7. Salmonella enterica serovar Enteritidis brain abscess mimicking meningitis after surgery for glioblastoma multiforme: a case report and review of the literature.

    PubMed

    Luciani, Léa; Dubourg, Grégory; Graillon, Thomas; Honnorat, Estelle; Lepidi, Hubert; Drancourt, Michel; Seng, Piseth; Stein, Andreas

    2016-07-07

    Salmonella brain abscess associated with brain tumor is rare. Only 11 cases have been reported to date. Here we report a case of brain abscess caused by Salmonella enterica serovar Enteritidis mimicking post-surgical meningitis in a patient with glioblastoma multiforme. A 60-year-old Algerian woman was admitted through an emergency department for a 4-day history of headache, nausea and vomiting, and behavioral disorders. Surgery for cerebral tumor excision was performed and histopathological analysis revealed glioblastoma multiforme. On the seventh day post-surgery, she presented a sudden neurological deterioration with a meningeal syndrome, confusion, and fever of 39.8°C. Her cerebrospinal fluid sample and blood cultures were positive for S. enterica Enteritidis. She was treated with ceftriaxone and ciprofloxacin. On the 17th day post-surgery, she presented a new neurological disorder and purulent discharge from the surgical wound. Brain computed tomography revealed a large cerebral abscess located at the operative site. Surgical drainage of the abscess was performed and microbial cultures of surgical deep samples were positive for the same S. enterica Enteritidis isolate. She recovered and was discharged 6 weeks after admission. In this case report, a brain abscess was initially diagnosed as Salmonella post-surgical meningitis before the imaging diagnosis of the brain abscess. The diagnosis of brain abscess should be considered in all cases of non-typhoidal Salmonella meningitis after surgery for brain tumor. Surgical brain abscess drainage followed by prolonged antibiotic treatment remains a major therapeutic option.

  8. Metabolic reprogramming in glioblastoma: the influence of cancer metabolism on epigenetics and unanswered questions

    PubMed Central

    Agnihotri, Sameer; Zadeh, Gelareh

    2016-01-01

    A defining hallmark of glioblastoma is altered tumor metabolism. The metabolic shift towards aerobic glycolysis with reprogramming of mitochondrial oxidative phosphorylation, regardless of oxygen availability, is a phenomenon known as the Warburg effect. In addition to the Warburg effect, glioblastoma tumor cells also utilize the tricarboxylic acid cycle/oxidative phosphorylation in a different capacity than normal tissue. Altered metabolic enzymes and their metabolites are oncogenic and not simply a product of tumor proliferation. Here we highlight the advantages of why tumor cells, including glioblastoma cells, require metabolic reprogramming and how tumor metabolism can converge on tumor epigenetics and unanswered questions in the field. PMID:26180081

  9. Molecular analysis of WWOX expression correlation with proliferation and apoptosis in glioblastoma multiforme

    PubMed Central

    Pluciennik, Elzbieta; Kurzyk, Agata; Jesionek-Kupnicka, Dorota; Kordek, Radzislaw; Potemski, Piotr; Bednarek, Andrzej K.

    2010-01-01

    Glioblastoma multiforme is the most common type of primary brain tumor in adults. WWOX is a tumor suppressor gene involved in carcinogenesis and cancer progression in many different neoplasms. Reduced WWOX expression is associated with more aggressive phenotype and poor patient outcome in several cancers. We investigated alternations of WWOX expression and its correlation with proliferation, apoptosis and signal trafficking in 67 glioblastoma multiforme specimens. Moreover, we examined the level of WWOX LOH and methylation status in WWOX promoter region. Our results suggest that loss of heterozygosity (relatively frequent in glioblastoma multiforme) along with promoter methylation may decrease the expression of this tumor suppressor gene. Our experiment revealed positive correlations between WWOX and Bcl2 and between WWOX and Ki67. We also confirmed that WWOX is positively correlated with ErbB4 signaling pathway in glioblastoma multiforme. PMID:20535528

  10. Engineering a Brain Cancer Chip for High-throughput Drug Screening

    PubMed Central

    Fan, Yantao; Nguyen, Duong Thanh; Akay, Yasemin; Xu, Feng; Akay, Metin

    2016-01-01

    Glioblastoma multiforme (GBM) is the most common and malignant of all human primary brain cancers, in which drug treatment is still one of the most effective treatments. However, existing drug discovery and development methods rely on the use of conventional two-dimensional (2D) cell cultures, which have been proven to be poor representatives of native physiology. Here, we developed a novel three-dimensional (3D) brain cancer chip composed of photo-polymerizable poly(ethylene) glycol diacrylate (PEGDA) hydrogel for drug screening. This chip can be produced after a few seconds of photolithography and requires no silicon wafer, replica molding, and plasma bonding like microfluidic devices made of poly(dimethylsiloxane) (PDMS). We then cultured glioblastoma cells (U87), which formed 3D brain cancer tissues on the chip, and used the GBM chip to perform combinatorial treatment of Pitavastatin and Irinotecan. The results indicate that this chip is capable of high-throughput GBM cancer spheroids formation, multiple-simultaneous drug administration, and a massive parallel testing of drug response. Our approach is easily reproducible, and this chip has the potential to be a powerful platform in cases such as high-throughput drug screening and prolonged drug release. The chip is also commercially promising for other clinical applications, including 3D cell culture and micro-scale tissue engineering. PMID:27151082

  11. Heparanase Mechanisms in Brain - Metastatic Breast Cancer

    DTIC Science & Technology

    2012-04-01

    by 74%. These findings introduce a new concept that links microRNA mechanisms with brain metastatic breast cancer by downregulating HPSE, providing...the groundwork for heparanase-based therapeutics in patients with brain metastases, BMBC in particular. MicroRNA , Breast Cancer , Brain...by 74% (Figs. 4B-D). These findings introduce new concepts that links microRNA mechanisms with brain metastatic breast cancer by downregulating

  12. Metformin and Ara-a Effectively Suppress Brain Cancer by Targeting Cancer Stem/Progenitor Cells.

    PubMed

    Mouhieddine, Tarek H; Nokkari, Amaly; Itani, Muhieddine M; Chamaa, Farah; Bahmad, Hisham; Monzer, Alissar; El-Merahbi, Rabih; Daoud, Georges; Eid, Assaad; Kobeissy, Firas H; Abou-Kheir, Wassim

    2015-01-01

    Gliomas and neuroblastomas pose a great health burden worldwide with a poor and moderate prognosis, respectively. Many studies have tried to find effective treatments for these primary malignant brain tumors. Of interest, the AMP-activated protein kinase (AMPK) pathway was found to be associated with tumorigenesis and tumor survival, leading to many studies on AMPK drugs, especially Metformin, and their potential role as anti-cancer treatments. Cancer stem cells (CSCs) are a small population of slowly-dividing, treatment-resistant, undifferentiated cancer cells that are being discovered in a multitude of cancers. They are thought to be responsible for replenishing the tumor with highly proliferative cells and increasing the risk of recurrence. Metformin and 9-β-d-Arabinofuranosyl Adenine (Ara-a) were used to study the role of the AMPK pathway in vitro on U251 (glioblastoma) and SH-SY5Y (neuroblastoma) cell lines. We found that both drugs are able to decrease the survival of U251 and SH-SY5Y cell lines in a 2D as well as a 3D culture model. Metformin and Ara-a significantly decreased the invasive ability of these cancer cell lines. Treatment with these drugs decreased the sphere-forming units (SFU) of U251 cells, with Ara-a being more efficient, signifying the extinction of the CSC population. However, if treatment is withdrawn before all SFUs are extinguished, the CSCs regain some of their sphere-forming capabilities in the case of Metformin but not Ara-a treatment. Metformin and Ara-a have proved to be effective in the treatment of glioblastomas and neuroblastomas, in vitro, by targeting their cancer stem/progenitor cell population, which prevents recurrence.

  13. Metformin and Ara-a Effectively Suppress Brain Cancer by Targeting Cancer Stem/Progenitor Cells

    PubMed Central

    Mouhieddine, Tarek H.; Nokkari, Amaly; Itani, Muhieddine M.; Chamaa, Farah; Bahmad, Hisham; Monzer, Alissar; El-Merahbi, Rabih; Daoud, Georges; Eid, Assaad; Kobeissy, Firas H.; Abou-Kheir, Wassim

    2015-01-01

    Background: Gliomas and neuroblastomas pose a great health burden worldwide with a poor and moderate prognosis, respectively. Many studies have tried to find effective treatments for these primary malignant brain tumors. Of interest, the AMP-activated protein kinase (AMPK) pathway was found to be associated with tumorigenesis and tumor survival, leading to many studies on AMPK drugs, especially Metformin, and their potential role as anti-cancer treatments. Cancer stem cells (CSCs) are a small population of slowly-dividing, treatment-resistant, undifferentiated cancer cells that are being discovered in a multitude of cancers. They are thought to be responsible for replenishing the tumor with highly proliferative cells and increasing the risk of recurrence. Methods: Metformin and 9-β-d-Arabinofuranosyl Adenine (Ara-a) were used to study the role of the AMPK pathway in vitro on U251 (glioblastoma) and SH-SY5Y (neuroblastoma) cell lines. Results: We found that both drugs are able to decrease the survival of U251 and SH-SY5Y cell lines in a 2D as well as a 3D culture model. Metformin and Ara-a significantly decreased the invasive ability of these cancer cell lines. Treatment with these drugs decreased the sphere-forming units (SFU) of U251 cells, with Ara-a being more efficient, signifying the extinction of the CSC population. However, if treatment is withdrawn before all SFUs are extinguished, the CSCs regain some of their sphere-forming capabilities in the case of Metformin but not Ara-a treatment. Conclusion: Metformin and Ara-a have proved to be effective in the treatment of glioblastomas and neuroblastomas, in vitro, by targeting their cancer stem/progenitor cell population, which prevents recurrence. PMID:26635517

  14. Familiality in brain tumors

    PubMed Central

    Blumenthal, Deborah T.; Cannon-Albright, Lisa A.

    2008-01-01

    Background: Familiality in brain tumors is not definitively substantiated. Methods: We used the Utah Population Data Base (UPDB), a genealogy representing the Utah pioneers and their descendants, record-linked to statewide cancer records, to describe the familial nature of primary brain cancer. We examined the familial clustering of primary brain tumors, including subgroups defined by histologic type and age at diagnosis. The UPDB includes 1,401 primary brain tumor cases defined as astrocytoma or glioblastoma, all with at least three generations of genealogy data. We tested the hypothesis of excess relatedness of brain tumor cases using the Genealogical Index of Familiality method. We estimated relative risks for brain tumors in relatives using rates of brain tumors estimated internally. Results: Significant excess relatedness was observed for astrocytomas and glioblastomas considered as a group (n = 1,401), for astrocytomas considered separately (n = 744), but not for glioblastomas considered separately (n = 658). Significantly increased risks to first- and second-degree relatives for astrocytomas were identified for relatives of astrocytomas considered separately. Significantly increased risks to first-degree relatives, but not second degree, were observed for astrocytoma and glioblastoma cases considered together, and for glioblastoma cases considered separately. Conclusions: This study provides strong evidence for a familial contribution to primary brain cancer risk. There is evidence that this familial aspect includes not only shared environment, but also a heritable component. Extended high-risk brain tumor pedigrees identified in the UPDB may provide the opportunity to identify predisposition genes responsible for familial brain tumors. GLOSSARY GBM = glioblastoma; GIF = Genealogical Index of Familiality; HGG = high-grade gliomas; ICD-O = International Classification of Disease–Oncology; LGG = low-grade gliomas; RR = relative risks; SEER = Surveillance

  15. MiRNA203 suppresses the expression of protumorigenic STAT1 in glioblastoma to inhibit tumorigenesis

    PubMed Central

    Yang, Chuan He; Wang, Yinan; Sims, Michelle; Cai, Chun; He, Ping; Yue, Junming; Cheng, Jinjun; Boop, Frederick A.; Pfeffer, Susan R.; Pfeffer, Lawrence M.

    2016-01-01

    MicroRNAs (miRNAs) play critical roles in regulating cancer cell proliferation, migration, survival and sensitivity to chemotherapy. The potential application of using miRNAs for cancer prognosis holds great promise but miRNAs with predictive value remain to be identified and underlying mechanisms of how they promote or suppress tumorigenesis are not completely understood. Here, we show a strong correlation between miR203 expression and brain cancer patient survival. Low miR203 expression is found in subsets of brain cancer patients, especially glioblastoma. Ectopic miR203 expression in glioblastoma cell lines inhibited cell proliferation and migration, increased sensitivity to apoptosis induced by interferon or temozolomide in vitro, and inhibited tumorigenesis in vivo. We further show that STAT1 is a direct functional target of miR203, and miR203 level is negatively correlated with STAT1 expression in brain cancer patients. Knockdown of STAT1 expression mimicked the effect of overexpression of miR203 in glioblastoma cell lines, and inhibited cell proliferation and migration, increased sensitivity to apoptosis induced by IFN or temozolomide in vitro, and inhibited glioblastoma tumorigenesis in vivo. High STAT1 expression significantly correlated with poor survival in brain cancer patients. Mechanistically, we found that enforced miR203 expression in glioblastoma suppressed STAT1 expression directly, as well as that of a number of STAT1 regulated genes. Taken together, our data suggest that miR203 acts as a tumor suppressor in glioblastoma by suppressing the pro-tumorigenic action of STAT1. MiR203 may serve as a predictive biomarker and potential therapeutic target in subsets of cancer patients with low miR203 expression. PMID:27705947

  16. Inhibition of notch signaling in glioblastoma targets cancer stem cells via an endothelial cell intermediate.

    PubMed

    Hovinga, Koos E; Shimizu, Fumiko; Wang, Rong; Panagiotakos, Georgia; Van Der Heijden, Maartje; Moayedpardazi, Hamideh; Correia, Ana Sofia; Soulet, Denis; Major, Tamara; Menon, Jayanthi; Tabar, Viviane

    2010-06-01

    Glioblastoma multiforme (GBM) is a highly heterogeneous malignant tumor. Recent data suggests the presence of a hierarchical organization within the GBM cell population that involves cancer cells with stem-like behavior, capable of repopulating the tumor and contributing to its resistance to therapy. Tumor stem cells are thought to reside within a vascular niche that provides structural and functional support. However, most GBM studies involve isolated tumor cells grown under various culture conditions. Here, we use a novel three-dimensional organotypic "explant" system of surgical GBM specimens that preserves cytoarchitecture and tumor stroma along with tumor cells. Notch inhibition in explants results in decreased proliferation and self-renewal of tumor cells but is also associated with a decrease in endothelial cells. When endothelial cells are selectively eliminated from the explants via a toxin conjugate, we also observed a decrease in self-renewal of tumor stem cells. These findings support a critical role for tumor endothelial cells in GBM stem cell maintenance, mediated at least in part by Notch signaling. The explant system further highlighted differences in the response to radiation between explants and isolated tumor neurospheres. Combination treatment with Notch blockade and radiation resulted in a substantial decrease in proliferation and in self-renewal in tumor explants while radiation alone was less effective. This data suggests that the Notch pathway plays a critical role in linking angiogenesis and cancer stem cell self-renewal and is thus a potential therapeutic target. Three-dimensional explant systems provide a novel approach for the study of tumor and microenvironment interactions.

  17. Intracranial elimination of human glioblastoma brain tumors in nude rats using the bispecific ligand-directed toxin, DTEGF13 and convection enhanced delivery.

    PubMed

    Oh, Seunguk; Ohlfest, John R; Todhunter, Deborah A; Vallera, Vincent D; Hall, Walter A; Chen, Hua; Vallera, Daniel A

    2009-12-01

    A bispecific ligand-directed toxin (BLT) consisting of human interleukin-13, epithelial growth factor, and the first 389 amino acids of diphtheria toxin was assembled in order to target human glioblastoma. In vitro, DTEGF13 selectively killed the human glioblastoma cell line U87-luc as well as other human glioblastomas. DTEGF13 fulfilled the requirement of a successful BLT by having greater activity than either of its monospecific counterparts or their mixture proving it necessary to have both ligands on the same single chain molecule. Aggressive brain tumors established intracranially (IC) in nude rats with U87 glioma genetically marked with a firefly luciferase reporter gene were treated with two injections of DTEGF13 using convection enhanced delivery resulting in tumor eradication in 50% of the rats which survived with tumor free status at least 110 days post tumor inoculation. An irrelevant BLT control did not protect establishing specificity. The bispecific DTEGF13 MTD dose was measured at 2 microg/injection or 0.5 microg/kg and toxicity studies indicated safety in this dose. Combination of monospecific DTEGF and DTIL13 did not inhibit tumor growth. ELISA assay indicated that anti-DT antibodies were not generated in normal immunocompetent rats given identical intracranial DTEGF13 therapy. Thus, DTEGF13 is safe and efficacious as an alternative drug for glioblastoma therapy and warrants further study.

  18. Immune Evasion Strategies of Glioblastoma

    PubMed Central

    Razavi, Seyed-Mostafa; Lee, Karen E.; Jin, Benjamin E.; Aujla, Parvir S.; Gholamin, Sharareh; Li, Gordon

    2016-01-01

    Glioblastoma (GBM) is the most devastating brain tumor, with associated poor prognosis. Despite advances in surgery and chemoradiation, the survival of afflicted patients has not improved significantly in the past three decades. Immunotherapy has been heralded as a promising approach in treatment of various cancers; however, the immune privileged environment of the brain usually curbs the optimal expected response in central nervous system malignancies. In addition, GBM cells create an immunosuppressive microenvironment and employ various methods to escape immune surveillance. The purpose of this review is to highlight the strategies by which GBM cells evade the host immune system. Further understanding of these strategies and the biology of this tumor will pave the way for developing novel immunotherapeutic approaches for treatment of GBM. PMID:26973839

  19. Therapeutic nanomedicine for brain cancer.

    PubMed

    Tzeng, Stephany Y; Green, Jordan J

    2013-06-01

    Malignant brain cancer treatment is limited by a number of barriers, including the blood-brain barrier, transport within the brain interstitium, difficulties in delivering therapeutics specifically to tumor cells, the highly invasive quality of gliomas and drug resistance. As a result, the prognosis for patients with high-grade gliomas is poor and has improved little in recent years. Nanomedicine approaches have been developed in the laboratory, with some technologies being translated to the clinic, in order to address these needs. This review discusses the obstacles to effective treatment that are currently faced in the field, as well as various nanomedicine techniques that have been used or are being explored to overcome them, with a focus on liposomal and polymeric nanoparticles.

  20. Therapeutic nanomedicine for brain cancer

    PubMed Central

    Tzeng, Stephany Y; Green, Jordan J

    2013-01-01

    Malignant brain cancer treatment is limited by a number of barriers, including the blood–brain barrier, transport within the brain interstitium, difficulties in delivering therapeutics specifically to tumor cells, the highly invasive quality of gliomas and drug resistance. As a result, the prognosis for patients with high-grade gliomas is poor and has improved little in recent years. Nanomedicine approaches have been developed in the laboratory, with some technologies being translated to the clinic, in order to address these needs. This review discusses the obstacles to effective treatment that are currently faced in the field, as well as various nanomedicine techniques that have been used or are being explored to overcome them, with a focus on liposomal and polymeric nanoparticles. PMID:23738667

  1. Comprehensive genomic characterization defines human glioblastoma genes and core pathways.

    PubMed

    2008-10-23

    Human cancer cells typically harbour multiple chromosomal aberrations, nucleotide substitutions and epigenetic modifications that drive malignant transformation. The Cancer Genome Atlas (TCGA) pilot project aims to assess the value of large-scale multi-dimensional analysis of these molecular characteristics in human cancer and to provide the data rapidly to the research community. Here we report the interim integrative analysis of DNA copy number, gene expression and DNA methylation aberrations in 206 glioblastomas--the most common type of adult brain cancer--and nucleotide sequence aberrations in 91 of the 206 glioblastomas. This analysis provides new insights into the roles of ERBB2, NF1 and TP53, uncovers frequent mutations of the phosphatidylinositol-3-OH kinase regulatory subunit gene PIK3R1, and provides a network view of the pathways altered in the development of glioblastoma. Furthermore, integration of mutation, DNA methylation and clinical treatment data reveals a link between MGMT promoter methylation and a hypermutator phenotype consequent to mismatch repair deficiency in treated glioblastomas, an observation with potential clinical implications. Together, these findings establish the feasibility and power of TCGA, demonstrating that it can rapidly expand knowledge of the molecular basis of cancer.

  2. A potential non-invasive glioblastoma treatment: Nose-to-brain delivery of farnesylthiosalicylic acid incorporated hybrid nanoparticles.

    PubMed

    Sekerdag, Emine; Lüle, Sevda; Bozdağ Pehlivan, Sibel; Öztürk, Naile; Kara, Aslı; Kaffashi, Abbas; Vural, Imran; Işıkay, Ilkay; Yavuz, Burҫin; Oguz, Kader Karlı; Söylemezoğlu, Figen; Gürsoy-Özdemir, Yasemin; Mut, Melike

    2017-09-10

    New drug delivery systems are highly needed in research and clinical area to effectively treat gliomas by reaching a high antineoplastic drug concentration at the target site without damaging healthy tissues. Intranasal (IN) administration, an alternative route for non-invasive drug delivery to the brain, bypasses the blood-brain-barrier (BBB) and eliminates systemic side effects. This study evaluated the antitumor efficacy of farnesylthiosalicylic acid (FTA) loaded (lipid-cationic) lipid-PEG-PLGA hybrid nanoparticles (HNPs) after IN application in rats. FTA loaded HNPs were prepared, characterized and evaluated for cytotoxicity. Rat glioma 2 (RG2) cells were implanted unilaterally into the right striatum of female Wistar rats. 10days later, glioma bearing rats received either no treatment, or 5 repeated doses of 500μM freshly prepared FTA loaded HNPs via IN or intravenous (IV) application. Pre-treatment and post-treatment tumor sizes were determined with MRI. After a treatment period of 5days, IN applied FTA loaded HNPs achieved a significant decrease of 55.7% in tumor area, equal to IV applied FTA loaded HNPs. Herewith, we showed the potential utility of IN application of FTA loaded HNPs as a non-invasive approach in glioblastoma treatment. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Human alpha-lactalbumin made lethal to tumor cells (HAMLET) kills human glioblastoma cells in brain xenografts by an apoptosis-like mechanism and prolongs survival.

    PubMed

    Fischer, Walter; Gustafsson, Lotta; Mossberg, Ann-Kristin; Gronli, Janne; Mork, Sverre; Bjerkvig, Rolf; Svanborg, Catharina

    2004-03-15

    Malignant brain tumors present a major therapeutic challenge because no selective or efficient treatment is available. Here, we demonstrate that intratumoral administration of human alpha-lactalbumin made lethal to tumor cells (HAMLET) prolongs survival in a human glioblastoma (GBM) xenograft model, by selective induction of tumor cell apoptosis. HAMLET is a protein-lipid complex that is formed from alpha-lactalbumin when the protein changes its tertiary conformation and binds oleic acid as a cofactor. HAMLET induces apoptosis in a wide range of tumor cells in vitro, but the therapeutic effect in vivo has not been examined. In this study, invasively growing human GBM tumors were established in nude rats (Han:rnu/rnu Rowett, n = 20) by transplantation of human GBM biopsy spheroids. After 7 days, HAMLET was administered by intracerebral convection-enhanced delivery for 24 h into the tumor area; and alpha-lactalbumin, the native, folded variant of the same protein, was used as a control. HAMLET reduced the intracranial tumor volume and delayed the onset of pressure symptoms in the tumor-bearing rats. After 8 weeks, all alpha-lactalbumin-treated rats had developed pressure symptoms, but the HAMLET-treated rats remained asymptomatic. Magnetic resonance imaging scans revealed large differences in tumor volume (456 versus 63 mm(3)). HAMLET caused apoptosis in vivo in the tumor but not in adjacent intact brain tissue or in nontransformed human astrocytes, and no toxic side effects were observed. The results identify HAMLET as a new candidate in cancer therapy and suggest that HAMLET should be additionally explored as a novel approach to controlling GBM progression.

  4. MNK Inhibition Disrupts Mesenchymal Glioma Stem Cells and Prolongs Survival in a Mouse Model of Glioblastoma.

    PubMed

    Bell, Jonathan B; Eckerdt, Frank D; Alley, Kristen; Magnusson, Lisa P; Hussain, Hridi; Bi, Yingtao; Arslan, Ahmet Dirim; Clymer, Jessica; Alvarez, Angel A; Goldman, Stewart; Cheng, Shi-Yuan; Nakano, Ichiro; Horbinski, Craig; Davuluri, Ramana V; James, C David; Platanias, Leonidas C

    2016-10-01

    Glioblastoma multiforme remains the deadliest malignant brain tumor, with glioma stem cells (GSC) contributing to treatment resistance and tumor recurrence. We have identified MAPK-interacting kinases (MNK) as potential targets for the GSC population in glioblastoma multiforme. Isoform-level subtyping using The Cancer Genome Atlas revealed that both MNK genes (MKNK1 and MKNK2) are upregulated in mesenchymal glioblastoma multiforme as compared with other subtypes. Expression of MKNK1 is associated with increased glioma grade and correlated with the mesenchymal GSC marker, CD44, and coexpression of MKNK1 and CD44 predicts poor survival in glioblastoma multiforme. In established and patient-derived cell lines, pharmacologic MNK inhibition using LY2801653 (merestinib) inhibited phosphorylation of the eukaryotic translation initiation factor 4E, a crucial effector for MNK-induced mRNA translation in cancer cells and a marker of transformation. Importantly, merestinib inhibited growth of GSCs grown as neurospheres as determined by extreme limiting dilution analysis. When the effects of merestinib were assessed in vivo using an intracranial xenograft mouse model, improved overall survival was observed in merestinib-treated mice. Taken together, these data provide strong preclinical evidence that pharmacologic MNK inhibition targets mesenchymal glioblastoma multiforme and its GSC population. These findings raise the possibility of MNK inhibition as a viable therapeutic approach to target the mesenchymal subtype of glioblastoma multiforme. Mol Cancer Res; 14(10); 984-93. ©2016 AACR. ©2016 American Association for Cancer Research.

  5. Encapsulation of temozolomide in a tumor-targeting nanocomplex enhances anti-cancer efficacy and reduces toxicity in a mouse model of glioblastoma

    PubMed Central

    Kim, Sang-Soo; Rait, Antonina; Kim, Eric; DeMarco, James; Pirollo, Kathleen F.; Chang, Esther H.

    2015-01-01

    Although temozolomide (TMZ) is the current first-line chemotherapy for glioblastoma multiforme (GBM), most patients either do not respond or ultimately fail TMZ treatment. Both intrinsic tumor resistance and limited access of TMZ to brain tumors as a result of the blood-brain barrier (BBB) contribute to poor response and ultimately to poor prognosis for GBM patients. We have developed a "dual-targeting" nanomedicine that both actively crosses the BBB and actively targets cancer cells once in the brain parenchyma. This nanomedicine (termed scL-TMZ) is sized ~40 nm and comprised of a cationic liposome (DOTAP:DOPE) encapsulating TMZ. The surface of liposome is decorated with anti-transferrin receptor single-chain antibody fragments to facilitate the crossing of the BBB by the scL-TMZ in addition to targeting GBM in the brain. This novel formulation was found to be markedly more effective than standard TMZ in both TMZ-resistant and TMZ-sensitive GBM. Encapsulation of TMZ also markedly enhanced its efficacy in killing a variety of non-GBM tumor cells. The scL-TMZ nanocomplex was shown to target cancer stem cells, which have been linked to both drug resistance and recurrence in GBM. Most significantly, systemically administered scL-TMZ significantly prolonged survival in mice bearing intracranial GBM tumors. The improved efficacy of scL-TMZ compared to standard TMZ was accompanied by reduced toxicity, so we conclude that the scL-TMZ nanomedicine holds great promise as a more effective therapy for GBM and other tumor types. PMID:26325605

  6. Comparative expression study of the endo-G protein coupled receptor (GPCR) repertoire in human glioblastoma cancer stem-like cells, U87-MG cells and non malignant cells of neural origin unveils new potential therapeutic targets.

    PubMed

    Fève, Marie; Saliou, Jean-Michel; Zeniou, Maria; Lennon, Sarah; Carapito, Christine; Dong, Jihu; Van Dorsselaer, Alain; Junier, Marie-Pierre; Chneiweiss, Hervé; Cianférani, Sarah; Haiech, Jacques; Kilhoffer, Marie-Claude

    2014-01-01

    Glioblastomas (GBMs) are highly aggressive, invasive brain tumors with bad prognosis and unmet medical need. These tumors are heterogeneous being constituted by a variety of cells in different states of differentiation. Among these, cells endowed with stem properties, tumor initiating/propagating properties and particularly resistant to chemo- and radiotherapies are designed as the real culprits for tumor maintenance and relapse after treatment. These cells, termed cancer stem-like cells, have been designed as prominent targets for new and more efficient cancer therapies. G-protein coupled receptors (GPCRs), a family of membrane receptors, play a prominent role in cell signaling, cell communication and crosstalk with the microenvironment. Their role in cancer has been highlighted but remains largely unexplored. Here, we report a descriptive study of the differential expression of the endo-GPCR repertoire in human glioblastoma cancer stem-like cells (GSCs), U-87 MG cells, human astrocytes and fetal neural stem cells (f-NSCs). The endo-GPCR transcriptome has been studied using Taqman Low Density Arrays. Of the 356 GPCRs investigated, 138 were retained for comparative studies between the different cell types. At the transcriptomic level, eight GPCRs were specifically expressed/overexpressed in GSCs. Seventeen GPCRs appeared specifically expressed in cells with stem properties (GSCs and f-NSCs). Results of GPCR expression at the protein level using mass spectrometry and proteomic analysis are also presented. The comparative GPCR expression study presented here gives clues for new pathways specifically used by GSCs and unveils novel potential therapeutic targets.

  7. A Metabolic Inhibitory Cocktail for Grave Cancers: Metformin, Pioglitazone and Lithium Combination in Treatment of Pancreatic Cancer and Glioblastoma Multiforme.

    PubMed

    Elmaci, İlhan; Altinoz, Meric A

    2016-10-01

    Pancreatic cancer (PC) and glioblastoma multiforme (GBM) are among the human cancers with worst prognosis which require an urgent need for efficient therapies. Here, we propose to apply to treat both malignancies with a triple combination of drugs, which are already in use for different indications. Recent studies demonstrated a considerable link between risk of PC and diabetes. In experimental models, anti-diabetogenic agents suppress growth of PC, including metformin (M), pioglitazone (P) and lithium (L). L is used in psychiatric practice, yet also bears anti-diabetic potential and selectively inhibits glycogen synthase kinase-3 beta (GSK-3β). M, a biguanide class anti-diabetic agent shows anticancer activity via activating AMP-activated protein kinase (AMPK). Glitazones bind to PPAR-γ and inhibit NF-κB, triggering cell proliferation, apoptosis resistance and synthesis of inflammatory cytokines in cancer cells. Inhibition of inflammatory cytokines could simultaneously decrease tumor growth and alleviate cancer cachexia, having a major role in PC mortality. Furthermore, mutual synergistic interactions exist between PPAR-γ and GSK-3β, between AMPK and GSK-3β and between AMPK and PPAR-γ. In GBM, M blocks angiogenesis and migration in experimental models. Very noteworthy, among GBM patients with type 2 diabetes, usage of M significantly correlates with better survival while reverse is true for sulfonylureas. In experimental models, P synergies with ligands of RAR, RXR and statins in reducing growth of GBM. Further, usage of P was found to be lesser in anaplastic astrocytoma and GBM patients, indicating a protective effect of P against high-grade gliomas. L is accumulated in GBM cells faster and higher than in neuroblastoma cells, and its levels further increase with chronic exposure. Recent studies revealed anti-invasive potential of L in GBM cell lines. Here, we propose that a triple-agent regime including drugs already in clinical usage may provide a

  8. Intra-operative probe for brain cancer: feasibility study

    NASA Astrophysics Data System (ADS)

    Vu Thi, M. H.; Charon, Y.; Duval, M. A.; Lefebvre, F.; Menard, L.; Pitre, S.; Pinot, L.; Siebert, R.

    2007-07-01

    The present work aims a new medical probe for surgeons devoted to brain cancers, in particular glioblastoma multiforme. Within the last years, our group has started the development of a new intra-operative beta imaging probe. More recently, we took an alternative approach for the same application: a fluorescence probe. In both cases the purpose is to differentiate normal from tumor brain tissue. In a first step, we developed set-ups capable to measure autofluorescence. They are based on a dedicated epi-fluorescence design and on specific fiber optic probes. Relative signal amplitude, spectral shape and fluorescence lifetime measurements are foreseen to distinguish normal and cancer tissue by analyzing fluorophores like NADH, lipopigments and porphyrines. The autofluorescence spectra are recorded in the 460-640 nm range with a low resolution spectrometer. For lifetime measurements a fast detector (APD) is used together with a TCSPC-carte. Intrinsic wavelength- and time-resolutions are a few nm and 200 ps, respectively. Different samples have been analyzed to validate our new detection system and to allow a first configuration of our medical fluorescence probe. First results from the tissue measurements are shown.

  9. STAT3 Regulation of Glioblastoma Pathogenesis

    PubMed Central

    de la Iglesia, Núria; Puram, Sidharth V.; Bonni, Azad

    2009-01-01

    Malignant gliomas are the most common primary brain tumors. Despite efforts to find effective treatments, these tumors remain incurable. The failure of malignant gliomas to respond to conventional cancer therapies may reflect the unique biology of these tumors, underscoring the need for new approaches in their investigation. Recently, progress has been made in characterization of the molecular pathogenesis of glioblastoma using a developmental neurobiological perspective, by exploring the role of signaling pathways that control the differentiation of neural stem cells along the glial lineage. The transcription factor STAT3, which has an established function in neural stem cell and astrocyte development, has been found to play dual tumor suppressive and oncogenic roles in glial malignancy depending on the mutational profile of the tumor. These findings establish a novel developmental paradigm in the study of glioblastoma pathogenesis and provide the rationale for patient-tailored therapy in the treatment of this devastating disease. PMID:19601808

  10. Glioblastoma: changing expectations?

    PubMed

    Arribas Alpuente, Leoncio; Menéndez López, Antonio; Yayá Tur, Ricardo

    2011-04-01

    Glioblastoma (GB) represents the most aggressive glioma in the adult population. Despite recent research efforts, the prognosis of patients with GB has remained dismal. Lately, the knowledge of genetic information about gliomagenesis has increased; we even have a classification of the genetic expression of the tumour. The main problem is that at the moment we do not have any therapeutical resources to help us better treat these tumours, as we can do, with others tumours like breast, lung and colorectal cancer. We have also improved on diagnostic imaging, especially with the new MRI sequences; we can now better define the characteristics of the tumour area and the surrounding brain structures, allowing us to adjust resections. Thanks to the most advanced surgery techniques, such as neuronavigation, intraoperative control of the nervous function and the tumour volume, the neurosurgeon is able to complete tumour exeresis with less morbidity. These imaging techniques allow the radiation oncologist to better contour the irradiation target volume, the structures and the organs at risk, to diminish the irradiation of apparently healthy tissue. Nowadays, knowledge of brain stem cells provides new expectations for future treatments. Novel targeted agents such as bevacizumab, imatinib, erlotinib, temsirolimus, immunotherapy, cilengitide, talampanel, etc. are helping classical chemotherapeutic agents, like temozolomide, to achieve an increase in overall survival. The main objective is to improve median overall survival, which is currently between 9 and 12 months, with a good quality of life, measured by the ability to carry out daily life activities.

  11. Selection of DNA Aptamers against Glioblastoma Cells with High Affinity and Specificity

    PubMed Central

    Kang, Dezhi; Wang, Jiangjie; Zhang, Weiyun; Song, Yanling; Li, Xilan; Zou, Yuan; Zhu, Mingtao; Zhu, Zhi; Chen, Fuyong; Yang, Chaoyong James

    2012-01-01

    Background Glioblastoma is the most common and most lethal form of brain tumor in human. Unfortunately, there is still no effective therapy to this fatal disease and the median survival is generally less than one year from the time of diagnosis. Discovery of ligands that can bind specifically to this type of tumor cells will be of great significance to develop early molecular imaging, targeted delivery and guided surgery methods to battle this type of brain tumor. Methodology/Principal Findings We discovered two target-specific aptamers named GBM128 and GBM131 against cultured human glioblastoma cell line U118-MG after 30 rounds selection by a method called cell-based Systematic Evolution of Ligands by EXponential enrichment (cell-SELEX). These two aptamers have high affinity and specificity against target glioblastoma cells. They neither recognize normal astraglial cells, nor do they recognize other normal and cancer cell lines tested. Clinical tissues were also tested and the results showed that these two aptamers can bind to different clinical glioma tissues but not normal brain tissues. More importantly, binding affinity and selectivity of these two aptamers were retained in complicated biological environment. Conclusion/Significance The selected aptamers could be used to identify specific glioblastoma biomarkers. Methods of molecular imaging, targeted drug delivery, ligand guided surgery can be further developed based on these ligands for early detection, targeted therapy, and guided surgery of glioblastoma leading to effective treatment of glioblastoma. PMID:23056171

  12. Laser light induced modulations in metabolic activities in human brain cancer

    NASA Astrophysics Data System (ADS)

    Tata, Darrell B.; Waynant, Ronald W.

    2008-03-01

    The role of low visible or near infra-red laser intensity in suppressing metabolic activity of malignant human brain cancer (glioblastoma) cells was investigated through the application of either a continuous wave 633nm HeNe or a pulsed picosecond 1,552nm wavelength laser. Human glioblastomas were exposed in their growth culture medium with serum for several energy doses. For both types of laser exposures the glioblastomas exhibited a maximal decline in the metabolic activity relative to their respective sham control counterparts at 10 J/cm2. The cellular metabolic activities for various treatment doses were measured through the colorimetric MTS metabolic assay after the laser exposure. Interestingly, addition of (the enzyme) catalase in the growth medium prior to the laser exposure was found to diminish the laser induced metabolic suppression for all fluence treatment conditions, thus suggesting a functional role of H IIO II in the metabolic suppression. Taken together, our findings reveal that visible or near infra-red low level light exposures could potentially be a viable tool in reducing the metabolic activity of cancers; evidence at hand implicates a role of light induced H IIO II in bringing about in part, suppression in the metabolic activity. Due to the cellular "biphasic" response to the laser exposure, further research needs to be undertaken to determine exposure parameters which would optimize metabolic and cellular growth suppression in-vivo.

  13. Analysis of angiogenesis related factors in glioblastoma, peritumoral tissue and their derived cancer stem cells

    PubMed Central

    D'Alessio, Alessio; Proietti, Gabriella; Lama, Gina; Biamonte, Filippo; Lauriola, Libero; Moscato, Umberto; Vescovi, Angelo; Mangiola, Annunziato; Angelucci, Cristiana; Sica, Gigliola

    2016-01-01

    The formation of new blood vessels represents a crucial event under both physiological and pathological circumstances. In this study, we evaluated by immunohistochemistry, and/or Western blotting and/or quantitative real time-PCR the expression of HIF1α, HIF2α, VEGF, VEGFR1 and VEGFR2 in surgical glioblastoma multiforme (GBM) and peritumoral tissue samples obtained from 50 patients as well as in cancer stem cells (CSCs) isolated from GBM (GCSCs) and peritumoral tissue (PCSCs) of 5 patients. We also investigated the contribution of both GCSCs and PCSCs on the behavior of endothelial cells (ECs) in vitro. Immunohistochemistry demonstrated the expression of angiogenesis markers in both GBM and peritumoral tissue. In addition, in vitro tube formation assay indicated that both GCSCs and PCSCs stimulate EC proliferation as well as tube-like vessel formation. An increased migration aptitude was mainly observed when ECs were cultured in the presence of GCSCs rather than in the presence of PCSCs. These findings suggest that relevant neoangiogenetic events may occur in GBM. In particular, VEGF/VEGFR co-expression in PCSCs leads to hypothesize the involvement of an autocrine signaling. Moreover, our results suggest that both GCSCs and PCSCs own the skill of activating the “angiogenic switch” and the capability of modulating EC behavior, indicating that both cell types are either responsive to angiogenic stimuli or able to trigger angiogenic response. Together with our previous findings, this study adds a further piece to the challenging puzzle of the characterization of peritumoral tissue and of the definition of its real role in GBM pathophysiology. PMID:27705944

  14. Analysis of angiogenesis related factors in glioblastoma, peritumoral tissue and their derived cancer stem cells.

    PubMed

    D'Alessio, Alessio; Proietti, Gabriella; Lama, Gina; Biamonte, Filippo; Lauriola, Libero; Moscato, Umberto; Vescovi, Angelo; Mangiola, Annunziato; Angelucci, Cristiana; Sica, Gigliola

    2016-11-29

    The formation of new blood vessels represents a crucial event under both physiological and pathological circumstances. In this study, we evaluated by immunohistochemistry, and/or Western blotting and/or quantitative real time-PCR the expression of HIF1α, HIF2α, VEGF, VEGFR1 and VEGFR2 in surgical glioblastoma multiforme (GBM) and peritumoral tissue samples obtained from 50 patients as well as in cancer stem cells (CSCs) isolated from GBM (GCSCs) and peritumoral tissue (PCSCs) of 5 patients. We also investigated the contribution of both GCSCs and PCSCs on the behavior of endothelial cells (ECs) in vitro. Immunohistochemistry demonstrated the expression of angiogenesis markers in both GBM and peritumoral tissue. In addition, in vitro tube formation assay indicated that both GCSCs and PCSCs stimulate EC proliferation as well as tube-like vessel formation. An increased migration aptitude was mainly observed when ECs were cultured in the presence of GCSCs rather than in the presence of PCSCs. These findings suggest that relevant neoangiogenetic events may occur in GBM. In particular, VEGF/VEGFR co-expression in PCSCs leads to hypothesize the involvement of an autocrine signaling. Moreover, our results suggest that both GCSCs and PCSCs own the skill of activating the "angiogenic switch" and the capability of modulating EC behavior, indicating that both cell types are either responsive to angiogenic stimuli or able to trigger angiogenic response. Together with our previous findings, this study adds a further piece to the challenging puzzle of the characterization of peritumoral tissue and of the definition of its real role in GBM pathophysiology.

  15. Genomic understanding of glioblastoma expanded

    Cancer.gov

    Glioblastoma multiforme (GBM) was the first cancer type to be systematically studied by TCGA in 2008. In a new, complementary report, TCGA experts examined more than 590 GBM samples--the largest to date utilizing genomic characterization techniques and ne

  16. Prostate specific membrane antigen (PSMA) expression in primary gliomas and breast cancer brain metastases

    PubMed Central

    2014-01-01

    Background Primary and secondary brain cancers are highly treatment resistant, and their marked angiogenesis attracts interest as a potential therapeutic target. Recent observations reveal that the microvascular endothelium of primary high-grade gliomas expresses prostate specific membrane antigen (PSMA). Breast cancers express PSMA and they frequently form secondary brain tumors. Hence we report here our pilot study addressing the feasibility of PSMA targeting in brain and metastatic breast tumors, by examining PSMA levels in all glioma grades (19 patients) and in breast cancer brain metastases (5 patients). Methods Tumor specimens were acquired from archival material and normal brain tissues from autopsies. Tissue were stained and probed for PSMA, and the expression levels imaged and quantified using automated hardware and software. PSMA staining intensities of glioma subtypes, breast tumors, and breast tumor brain metastases were compared statistically versus normals. Results Normal brain microvessels (4 autopsies) did not stain for PSMA, while a small proportion (<5%) of healthy neurons stained, and were surrounded by an intact blood brain barrier. Tumor microvessels of the highly angiogenic grade IV gliomas showed intense PSMA staining which varied between patients and was significantly higher (p < 0.05) than normal brain. Grade I gliomas showed moderate vessel staining, while grade II and III gliomas had no vessel staining, but a few (<2%) of the tumor cells stained. Both primary breast cancer tissues and the associated brain metastases exhibited vascular PSMA staining, although the intensity of staining was generally less for the metastatic lesions. Conclusions Our results align with and extend previous data showing PSMA expression in blood vessels of gliomas and breast cancer brain metastases. These results provide a rationale for more comprehensive studies to explore PSMA targeted agents for treating secondary brain tumors with PSMA expressing

  17. Metabolomic signature of brain cancer.

    PubMed

    Pandey, Renu; Caflisch, Laura; Lodi, Alessia; Brenner, Andrew J; Tiziani, Stefano

    2017-06-15

    Despite advances in surgery and adjuvant therapy, brain tumors represent one of the leading causes of cancer-related mortality and morbidity in both adults and children. Gliomas constitute about 60% of all cerebral tumors, showing varying degrees of malignancy. They are difficult to treat due to dismal prognosis and limited therapeutics. Metabolomics is the untargeted and targeted analyses of endogenous and exogenous small molecules, which charact erizes the phenotype of an individual. This emerging "omics" science provides functional readouts of cellular activity that contribute greatly to the understanding of cancer biology including brain tumor biology. Metabolites are highly informative as a direct signature of biochemical activity; therefore, metabolite profiling has become a promising approach for clinical diagnostics and prognostics. The metabolic alterations are well-recognized as one of the key hallmarks in monitoring disease progression, therapy, and revealing new molecular targets for effective therapeutic intervention. Taking advantage of the latest high-throughput analytical technologies, that is, nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS), metabolomics is now a promising field for precision medicine and drug discovery. In the present report, we review the application of metabolomics and in vivo metabolic profiling in the context of adult gliomas and paediatric brain tumors. Analytical platforms such as high-resolution (HR) NMR, in vivo magnetic resonance spectroscopic imaging and high- and low-resolution MS are discussed. Moreover, the relevance of metabolic studies in the development of new therapeutic strategies for treatment of gliomas are reviewed. © 2017 Wiley Periodicals, Inc.

  18. Glioblastoma-synthesized G-CSF and GM-CSF contribute to growth and immunosuppression: Potential therapeutic benefit from dapsone, fenofibrate, and ribavirin.

    PubMed

    Kast, Richard E; Hill, Quentin A; Wion, Didier; Mellstedt, Håkan; Focosi, Daniele; Karpel-Massler, Georg; Heiland, Tim; Halatsch, Marc-Eric

    2017-05-01

    Increased ratio of circulating neutrophils to lymphocytes is a common finding in glioblastoma and other cancers. Data reviewed establish that any damage to brain tissue tends to cause an increase in G-CSF and/or GM-CSF (G(M)-CSF) synthesized by the brain. Glioblastoma cells themselves also synthesize G(M)-CSF. G(M)-CSF synthesized by brain due to damage by a growing tumor and by the tumor itself stimulates bone marrow to shift hematopoiesis toward granulocytic lineages away from lymphocytic lineages. This shift is immunosuppressive and generates the relative lymphopenia characteristic of glioblastoma. Any trauma to brain-be it blunt, sharp, ischemic, infectious, cytotoxic, tumor encroachment, or radiation-increases brain synthesis of G(M)-CSF. G(M)-CSF are growth and motility enhancing factors for glioblastomas. High levels of G(M)-CSF contribute to the characteristic neutrophilia and lymphopenia of glioblastoma. Hematopoietic bone marrow becomes entrained with, directed by, and contributes to glioblastoma pathology. The antibiotic dapsone, the lipid-lowering agent fenofibrate, and the antiviral drug ribavirin are Food and Drug Administration- and European Medicines Agency-approved medicines that have potential to lower synthesis or effects of G(M)-CSF and thus deprive a glioblastoma of some of the growth promoting contributions of bone marrow and G(M)-CSF.

  19. Endothelial cells create a stem cell niche in glioblastoma by providing NOTCH ligands that nurture self-renewal of cancer stem-like cells.

    PubMed

    Zhu, Thant S; Costello, Mark A; Talsma, Caroline E; Flack, Callie G; Crowley, Jessica G; Hamm, Lisa L; He, Xiaobing; Hervey-Jumper, Shawn L; Heth, Jason A; Muraszko, Karin M; DiMeco, Francesco; Vescovi, Angelo L; Fan, Xing

    2011-09-15

    One important function of endothelial cells in glioblastoma multiforme (GBM) is to create a niche that helps promote self-renewal of cancer stem-like cells (CSLC). However, the underlying molecular mechanism for this endothelial function is not known. Since activation of NOTCH signaling has been found to be required for propagation of GBM CSLCs, we hypothesized that the GBM endothelium may provide the source of NOTCH ligands. Here, we report a corroboration of this concept with a demonstration that NOTCH ligands are expressed in endothelial cells adjacent to NESTIN and NOTCH receptor-positive cancer cells in primary GBMs. Coculturing human brain microvascular endothelial cells (hBMEC) or NOTCH ligand with GBM neurospheres promoted GBM cell growth and increased CSLC self-renewal. Notably, RNAi-mediated knockdown of NOTCH ligands in hBMECs abrogated their ability to induce CSLC self-renewal and GBM tumor growth, both in vitro and in vivo. Thus, our findings establish that NOTCH activation in GBM CSLCs is driven by juxtacrine signaling between tumor cells and their surrounding endothelial cells in the tumor microenvironment, suggesting that targeting both CSLCs and their niche may provide a novel strategy to deplete CSLCs and improve GBM treatment.

  20. Targeting SOX2 as a Therapeutic Strategy in Glioblastoma

    PubMed Central

    Garros-Regulez, Laura; Garcia, Idoia; Carrasco-Garcia, Estefania; Lantero, Aquilino; Aldaz, Paula; Moreno-Cugnon, Leire; Arrizabalaga, Olatz; Undabeitia, Jose; Torres-Bayona, Sergio; Villanua, Jorge; Ruiz, Irune; Egaña, Larraitz; Sampron, Nicolas; Matheu, Ander

    2016-01-01

    Glioblastoma is the most common and malignant brain cancer in adults. Current therapy consisting of surgery followed by radiation and temozolomide has a moderate success rate and the tumor reappears. Among the features that a cancer cell must have to survive the therapeutic treatment and reconstitute the tumor is the ability of self-renewal. Therefore, it is vital to identify the molecular mechanisms that regulate this activity. Sex-determining region Y (SRY)-box 2 (SOX2) is a transcription factor whose activity has been associated with the maintenance of the undifferentiated state of cancer stem cells in several tissues, including the brain. Several groups have detected increased SOX2 levels in biopsies of glioblastoma patients, with the highest levels associated with poor outcome. Therefore, SOX2 silencing might be a novel therapeutic approach to combat cancer and particularly brain tumors. In this review, we will summarize the current knowledge about SOX2 in glioblastoma and recapitulate several strategies that have recently been described targeting SOX2 in this malignancy. PMID:27822457

  1. Brain Stem and Entire Spinal Leptomeningeal Dissemination of Supratentorial Glioblastoma Multiforme in a Patient during Postoperative Radiochemotherapy

    PubMed Central

    Kong, Xiangyi; Wang, Yu; Liu, Shuai; Chen, Keyin; Zhou, Qiangyi; Yan, Chengrui; He, Huayu; Gao, Jun; Guan, Jian; Yang, Yi; Li, Yongning; Xing, Bing; Wang, Renzhi; Ma, Wenbin

    2015-01-01

    Abstract Glioblastoma multiforme (GBM) is the most common primary malignancy of the central nervous system in adults. Macroscopically evident and symptomatic spinal metastases occur rarely. Autopsy series suggest that approximately 25% of patients with intracranial GBM have evidence of spinal subarachnoid seeding, although the exact incidence is not known as postmortem examination of the spine is not routinely performed.1–3 Herein, we present a rare case of symptomatic brain stem and entire spinal dissemination of GBM in a 36-year-old patient during postoperative adjuvant radiochemotherapy with temozolomide and cisplatin. Visual deterioration, intractable stomachache, and limb paralysis were the main clinical features. The results of cytological and immunohistochemical tests on the cerebrospinal fluid cells were highly suggestive of spinal leptomeningeal dissemination. After 1 month, the patient's overall condition deteriorated and succumbed to his disease. To the best of our knowledge, this is the first reported case of GBM dissemination presenting in this manner. Because GBM extracranial dissemination is rare, we also reviewed pertinent literature regarding this uncommon entity. Although metastases to spinal cord from GBM are uncommon, it is always important to have in mind when patients with a history of GBM present with symptoms that do not correlate with the primary disease pattern. PMID:26091464

  2. miR-124 suppresses glioblastoma growth and potentiates chemosensitivity by inhibiting AURKA.

    PubMed

    Qiao, Wanchen; Guo, Beisong; Zhou, Haichun; Xu, Wanzhen; Chen, Yongjie; Liang, Yanchao; Dong, Baijing

    2017-04-22

    Glioblastoma (GBM) accounts for about half of all malignant brain cancers. Although the treatment strategies for glioblastoma develop rapidly, a considerable number of patients could not benefit from temozolomide (TMZ)-based chemotherapy. Here, we revealed a miR-124-AURKA axis that regulated glioblastoma growth and chemosensitivity. Mechanistically, AURKA was up-regulated in glioblastoma tissues and associated with poor overall survival. While overexpression of AURKA enhanced tumor growth, genetic or pharmacological inhibition of AURKA led to growth-inhibitory and chemopotentiating effects in glioblastoma. AURKA was further identified as a target of miR-124. Furthermore, our data showed that miR-124 down-regulated AURKA expression and subsequently suppressed cell growth. Re-expression of AURKA significantly rescued miR124-mediated proliferation repression and chemosensitivity. In conclusion, our results demonstrated that miR-124 inhibited glioblastoma growth and potentiated chemosensitivity by targeting AURKA, which may represent promising targets and rational therapeutic options for glioblastoma. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. Highly efficient radiosensitization of human glioblastoma and lung cancer cells by a G-quadruplex DNA binding compound

    PubMed Central

    Merle, Patrick; Gueugneau, Marine; Teulade-Fichou, Marie-Paule; Müller-Barthélémy, Mélanie; Amiard, Simon; Chautard, Emmanuel; Guetta, Corinne; Dedieu, Véronique; Communal, Yves; Mergny, Jean-Louis; Gallego, Maria; White, Charles; Verrelle, Pierre; Tchirkov, Andreï

    2015-01-01

    Telomeres are nucleoprotein structures at the end of chromosomes which stabilize and protect them from nucleotidic degradation and end-to-end fusions. The G-rich telomeric single-stranded DNA overhang can adopt a four-stranded G-quadruplex DNA structure (G4). Stabilization of the G4 structure by binding of small molecule ligands enhances radiosensitivity of tumor cells, and this combined treatment represents a novel anticancer approach. We studied the effect of the platinum-derived G4-ligand, Pt-ctpy, in association with radiation on human glioblastoma (SF763 and SF767) and non-small cell lung cancer (A549 and H1299) cells in vitro and in vivo. Treatments with submicromolar concentrations of Pt-ctpy inhibited tumor proliferation in vitro with cell cycle alterations and induction of apoptosis. Non-toxic concentrations of the ligand were then combined with ionizing radiation. Pt-ctpy radiosensitized all cell lines with dose-enhancement factors between 1.32 and 1.77. The combined treatment led to increased DNA breaks. Furthermore, a significant radiosensitizing effect of Pt-ctpy in mice xenografted with glioblastoma SF763 cells was shown by delayed tumor growth and improved survival. Pt-ctpy can act in synergy with radiation for efficient killing of cancer cells at concentrations at which it has no obvious toxicity per se, opening perspectives for future therapeutic applications. PMID:26542881

  4. [Nutritional status in patients with recurrent glioblastoma].

    PubMed

    Gokcek, D; Tran, J-D; Gonzalez-Aguilar, A; Alentorn, A; Liou, A; Delattre, J-Y; Idbaih, A

    2013-11-01

    Nutritional status is a major clinical parameter in multiple cancers. Indeed, nutritional status is a prognostic factor and a predictor of response and toxicity to treatments in breast and lung cancers for instance. To our knowledge, in patients suffering from malignant primary brain tumors, nutritional status has been poorly investigated. Nutritional status of 26 glioblastoma patients relapsing after a first line of treatment was studied. The body mass index (BMI), the prognostic inflammatory and nutritional index (PINI) and the instant nutritional score (INS) were assessed. The BMI was abnormal in 12 patients, two were malnourished while 10 were overweight. The BMI was not correlated to age of patients. Overweight status did not impact patient survival but it was associated with reduced performance status. The PINI was abnormal in three patients. Finally, the INS was abnormal in 24 patients, noted 2 (n=22) or 4 (n=4). Our results were not in favor of systematic nutritional support in patients with recurrent glioblastoma after a first line of treatment. Being overweight does not influence prognosis but may influence performance status. Steroid therapy and chemotherapy (inducing sodium and water retention and lymphopenia) weaken the relevance of BMI and INS for nutritional assessment in patients with recurrent glioblastoma. Further studies using additional nutritional tests in larger, independent and prospective cohorts of patients are warranted to obtain more details. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  5. Inflammatory landscape of human brain tumors reveals an NFκB dependent cytokine pathway associated with mesenchymal glioblastoma.

    PubMed

    Zanotto-Filho, Alfeu; Gonçalves, Rosângela Mayer; Klafke, Karina; de Souza, Priscila Oliveira; Dillenburg, Fabiane Cristine; Carro, Luigi; Gelain, Daniel Pens; Moreira, José Cláudio Fonseca

    2017-04-01

    The tumor microenvironment is being increasingly recognized as a key factor in cancer aggressiveness. In this study, we characterized the inflammatory gene signatures altered in glioma cell lines and tumor specimens of differing histological and molecular subtypes. The results showed that glioblastoma multiforme (GBM) shows upregulation of a subset of inflammatory genes when compared to astrocytomas and oligodendrogliomas. With molecular subtypes of GBM, the expression of inflammatory genes is heterogeneous, being enriched in mesenchymal and downregulated in Proneural/GCIMP. Other inflammation-associated processes such as tumor-associated macrophage (TAM) signatures are upregulated in mesenchymal, and a subset of 33 mesenchymal-enriched inflammatory and TAM markers showed correlation with poor survival. We found that various GBM tumor-upregulated genes such as IL6, IL8 and CCL2 are also actively expressed in glioma cell lines, playing differential and cooperative roles in promoting proliferation, invasion, angiogenesis and macrophage polarization in vitro. These genes can be stimulated by pathways typically altered in GBM, including the EGFR, PDGFR, MEK1/2-ERK1/2, PI3K/Akt and NFκB cascades. Taken together, the results presented herein depict some inflammatory pathways altered in gliomas and highlight potentially relevant targets to therapy improvement.

  6. Multispectral opto-acoustic tomography (MSOT) of the brain and glioblastoma characterization.

    PubMed

    Burton, Neal C; Patel, Manishkumar; Morscher, Stefan; Driessen, Wouter H P; Claussen, Jing; Beziere, Nicolas; Jetzfellner, Thomas; Taruttis, Adrian; Razansky, Daniel; Bednar, Bohumil; Ntziachristos, Vasilis

    2013-01-15

    Brain research depends strongly on imaging for assessing function and disease in vivo. We examine herein multispectral opto-acoustic tomography (MSOT), a novel technology for high-resolution molecular imaging deep inside tissues. MSOT illuminates tissue with light pulses at multiple wavelengths and detects the acoustic waves generated by the thermoelastic expansion of the environment surrounding absorbing molecules. Using spectral unmixing analysis of the data collected, MSOT can then differentiate the spectral signatures of oxygenated and deoxygenated hemoglobin and of photo-absorbing agents and quantify their concentration. By being able to detect absorbing molecules up to centimeters deep in the tissue it represents an ideal modality for small animal brain imaging, simultaneously providing anatomical, hemodynamic, functional, and molecular information. In this work we examine the capacity of MSOT in cross-sectional brain imaging of mice. We find unprecedented optical imaging performance in cross-sectional visualization of anatomical and physiological parameters of the mouse brain. For example, the potential of MSOT to characterize ischemic brain areas was demonstrated through the use of a carbon dioxide challenge. In addition, indocyanine green (ICG) was injected intravenously, and the kinetics of uptake and clearance in the vasculature of the brain was visualized in real-time. We further found that multiparameter, multispectral imaging of the growth of U87 tumor cells injected into the brain could be visualized through the intact mouse head, for example through visualization of deoxygenated hemoglobin in the growing tumor. We also demonstrate how MSOT offers several compelling features for brain research and allows time-dependent detection and quantification of brain parameters that are not available using other imaging methods without invasive procedures. Copyright © 2012. Published by Elsevier Inc.

  7. Classification of glioblastoma and metastasis for neuropathology intraoperative diagnosis: a multi-resolution textural approach to model the background

    NASA Astrophysics Data System (ADS)

    Ahmad Fauzi, Mohammad Faizal; Gokozan, Hamza Numan; Elder, Brad; Puduvalli, Vinay K.; Otero, Jose J.; Gurcan, Metin N.

    2014-03-01

    Brain cancer surgery requires intraoperative consultation by neuropathology to guide surgical decisions regarding the extent to which the tumor undergoes gross total resection. In this context, the differential diagnosis between glioblastoma and metastatic cancer is challenging as the decision must be made during surgery in a short time-frame (typically 30 minutes). We propose a method to classify glioblastoma versus metastatic cancer based on extracting textural features from the non-nuclei region of cytologic preparations. For glioblastoma, these regions of interest are filled with glial processes between the nuclei, which appear as anisotropic thin linear structures. For metastasis, these regions correspond to a more homogeneous appearance, thus suitable texture features can be extracted from these regions to distinguish between the two tissue types. In our work, we use the Discrete Wavelet Frames to characterize the underlying texture due to its multi-resolution capability in modeling underlying texture. The textural characterization is carried out in primarily the non-nuclei regions after nuclei regions are segmented by adapting our visually meaningful decomposition segmentation algorithm to this problem. k-nearest neighbor method was then used to classify the features into glioblastoma or metastasis cancer class. Experiment on 53 images (29 glioblastomas and 24 metastases) resulted in average accuracy as high as 89.7% for glioblastoma, 87.5% for metastasis and 88.7% overall. Further studies are underway to incorporate nuclei region features into classification on an expanded dataset, as well as expanding the classification to more types of cancers.

  8. Clinical trial explores new glioblastoma treatment regimen | Center for Cancer Research

    Cancer.gov

    On average, a patient with glioblastoma lives for only about a year after diagnosis. In a new clinical trial, CCR researchers will test whether a combination of a vaccine made from the patient’s tumor with another immunotherapy treatment can increase survival rates. Read more...  

  9. Human brain cancer studied by resonance Raman spectroscopy

    NASA Astrophysics Data System (ADS)

    Zhou, Yan; Liu, Cheng-Hui; Sun, Yi; Pu, Yang; Boydston-White, Susie; Liu, Yulong; Alfano, Robert R.

    2012-11-01

    The resonance Raman (RR) spectra of six types of human brain tissues are examined using a confocal micro-Raman system with 532-nm excitation in vitro. Forty-three RR spectra from seven subjects are investigated. The spectral peaks from malignant meningioma, stage III (cancer), benign meningioma (benign), normal meningeal tissues (normal), glioblastoma multiforme grade IV (cancer), acoustic neuroma (benign), and pituitary adenoma (benign) are analyzed. Using a 532-nm excitation, the resonance-enhanced peak at 1548 cm-1 (amide II) is observed in all of the tissue specimens, but is not observed in the spectra collected using the nonresonance Raman system. An increase in the intensity ratio of 1587 to 1605 cm-1 is observed in the RR spectra collected from meningeal cancer tissue as compared with the spectra collected from the benign and normal meningeal tissue. The peak around 1732 cm-1 attributed to fatty acids (lipids) are diminished in the spectra collected from the meningeal cancer tumors as compared with the spectra from normal and benign tissues. The characteristic band of spectral peaks observed between 2800 and 3100 cm-1 are attributed to the vibrations of methyl (-CH3) and methylene (-CH2-) groups. The ratio of the intensities of the spectral peaks of 2935 to 2880 cm-1 from the meningeal cancer tissues is found to be lower in comparison with that of the spectral peaks from normal, and benign tissues, which may be used as a distinct marker for distinguishing cancerous tissues from normal meningeal tissues. The statistical methods of principal component analysis and the support vector machine are used to analyze the RR spectral data collected from meningeal tissues, yielding a diagnostic sensitivity of 90.9% and specificity of 100% when two principal components are used.

  10. Arsenic trioxide depletes cancer stem-like cells and inhibits repopulation of neurosphere derived from glioblastoma by downregulation of Notch pathway.

    PubMed

    Wu, Jianing; Ji, Zhiyong; Liu, Huailei; Liu, Yaohua; Han, Dayong; Shi, Chen; Shi, Changbin; Wang, Chunlei; Yang, Guang; Chen, Xiaofeng; Shen, Chen; Li, Huadong; Bi, Yunke; Zhang, Dongzhi; Zhao, Shiguang

    2013-06-20

    Notch signaling has been demonstrated to have a central role in cancer stem-like cells (CSLCs) in glioblastoma multiforme (GBM). We have recently demonstrated the inhibitory effect of arsenic trioxide (ATO) on CSLCs in glioblastoma cell lines. In this study we used neurosphere recovery assay that measured neurosphere formation at three time points to assess the capacity of the culture to repopulate after ATO treatment. Our results provided strong evidence that ATO depleted CSLCs in GBM, and inhibited neurosphere recovery and secondary neurosphere formation. ATO inhibited the phosphorylation and activation of AKT and STAT3 through Notch signaling blockade. These data show that the ATO is a promising new approach to decrease glioblastoma proliferation and recurrence by downregulation of Notch pathway.

  11. Advances in Immunotherapy for Glioblastoma Multiforme

    PubMed Central

    Huang, Boyuan; Zhang, Hongbo; Ye, Bainxin

    2017-01-01

    Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults. Patients with GBM have poor outcomes, even with the current gold-standard first-line treatment: maximal safe resection combined with radiotherapy and temozolomide chemotherapy. Accumulating evidence suggests that advances in antigen-specific cancer vaccines and immune checkpoint blockade in other advanced tumors may provide an appealing promise for immunotherapy in glioma. The future of therapy for GBM will likely incorporate a combinatorial, personalized approach, including current conventional treatments, active immunotherapeutics, plus agents targeting immunosuppressive checkpoints. PMID:28299344

  12. Cell-based therapy using miR-302-367 expressing cells represses glioblastoma growth.

    PubMed

    Fareh, Mohamed; Almairac, Fabien; Turchi, Laurent; Burel-Vandenbos, Fanny; Paquis, Philippe; Fontaine, Denys; Lacas-Gervais, Sandra; Junier, Marie-Pierre; Chneiweiss, Hervé; Virolle, Thierry

    2017-03-30

    Glioblastomas are incurable primary brain tumors that affect patients of all ages. The aggressiveness of this cancer has been attributed in part to the persistence of treatment-resistant glioblastoma stem-like cells. We have previously discovered the tumor-suppressor properties of the microRNA cluster miR-302-367, representing a potential treatment for glioblastoma. Here, we attempted to develop a cell-based therapy by taking advantage of the capability of glioma cells to secrete exosomes that enclose small RNA molecules. We engineered primary glioma cells to stably express the miR-302-367. Remarkably, these cells altered, in a paracrine-dependent manner, the expression of stemness markers, the proliferation and the tumorigenicity of neighboring glioblastoma cells. Further characterization of the secretome derived from miR-302-367 expressing cells showed that a large amount of miR-302-367 was enclosed in exosomes, which were internalized by the neighboring glioblastoma cells. This miR-302-367 cell-to-cell transfer resulted in the inhibition of its targets such as CXCR4/SDF1, SHH, cyclin D, cyclin A and E2F1. Orthotopic xenograft of miR-302-367-expressing cells together with glioblastoma stem-like cells efficiently altered the tumor development in mice brain.

  13. A Zebrafish Live Imaging Model Reveals Differential Responses of Microglia Toward Glioblastoma Cells In Vivo

    PubMed Central

    Hamilton, Lloyd; Astell, Katy R.; Velikova, Gergana

    2016-01-01

    Abstract Glioblastoma multiforme is the most common and deadliest form of brain cancer. Glioblastomas are infiltrated by a high number of microglia, which promote tumor growth and surrounding tissue invasion. However, it is unclear how microglia and glioma cells physically interact and if there are differences, depending on glioma cell type. Hence, we have developed a novel live imaging assay to study microglia–glioma interactions in vivo in the zebrafish brain. We transplanted well-established human glioblastoma cell lines, U87 and U251, into transgenic zebrafish lines with labelled macrophages/microglia. Our confocal live imaging results show distinct interactions between microglia and U87, as well as U251 glioblastoma cells that differ in number and nature. Importantly these interactions do not appear to be antitumoral as zebrafish microglia do not engulf and phagocytose the human glioblastoma cells. Finally, xenotransplants into the irf8−/− zebrafish mutant that lacks microglia, as well as pharmacological inhibition of the CSF-1 receptor (CSF-1R) on microglia, confirm a prominent role for zebrafish microglia in promoting human glioblastoma cell growth. This new model will be an important tool for drug screening and the development of future immunotherapeutics targeting microglia within glioma. PMID:27779463

  14. Isolation of cancer stem cells from three human glioblastoma cell lines: characterization of two selected clones.

    PubMed

    Iacopino, Fortunata; Angelucci, Cristiana; Piacentini, Roberto; Biamonte, Filippo; Mangiola, Annunziato; Maira, Giulio; Grassi, Claudio; Sica, Gigliola

    2014-01-01

    Cancer stem cells (CSC) were isolated via a non-adherent neurosphere assay from three glioma cell lines: LI, U87, and U373. Using a clonal assay, two clones (D2 and F11) were selected from spheres derived from LI cells and were characterized for the: expression of stem cell markers (CD133, Nestin, Musashi-1 and Sox2); proliferation; differentiation capability (determined by the expression of GalC, βIII-Tubulin and GFAP); Ca(2+) signaling and tumorigenicity in nude mice. Both D2 and F11 clones expressed higher levels of all stem cell markers with respect to the parental cell line. Clones grew more slowly than LI cells with a two-fold increase in duplication time. Markers of differentiation (βIII-Tubulin and GFAP) were expressed at high levels in both LI cells and in neurospheres. The expression of Nestin, Sox2, and βIII-Tubulin was down-regulated in D2 and F11 when cultured in serum-containing medium, whereas Musashi-1 was increased. In this condition, duplication time of D2 and F11 increased without reaching that of LI cells. D2, F11 and parental cells did not express voltage-dependent Ca(2+)-channels but they exhibited increased intracellular Ca(2+) levels in response to ATP. These Ca(2+) signals were larger in LI cells and in spheres cultured in serum-containing medium, while they were smaller in serum-free medium. The ATP treatment did not affect cell proliferation. Both D2 and F11 induced the appearance of tumors when ortotopically injected in athymic nude mice at a density 50-fold lower than that of LI cells. All these data indicate that both clones have characteristics of CSC and share the same stemness properties. The findings regarding the expression of differentiation markers and Ca(2+)-channels show that both clones are unable to reach the terminal differentiation. Both D2 and F11 might represent a good model to improve the knowledge on CSC in glioblastoma and to identify new therapeutic approaches.

  15. Simulation Predicts IGFBP2-HIF1α Interaction Drives Glioblastoma Growth

    PubMed Central

    Lin, Ka Wai; Liao, Angela; Qutub, Amina A.

    2015-01-01

    Tremendous strides have been made in improving patients’ survival from cancer with one glaring exception: brain cancer. Glioblastoma is the most common, aggressive and highly malignant type of primary brain tumor. The average overall survival remains less than 1 year. Notably, cancer patients with obesity and diabetes have worse outcomes and accelerated progression of glioblastoma. The root cause of this accelerated progression has been hypothesized to involve the insulin signaling pathway. However, while the process of invasive glioblastoma progression has been extensively studied macroscopically, it has not yet been well characterized with regards to intracellular insulin signaling. In this study we connect for the first time microscale insulin signaling activity with macroscale glioblastoma growth through the use of computational modeling. Results of the model suggest a novel observation: feedback from IGFBP2 to HIF1α is integral to the sustained growth of glioblastoma. Our study suggests that downstream signaling from IGFI to HIF1α, which has been the target of many insulin signaling drugs in clinical trials, plays a smaller role in overall tumor growth. These predictions strongly suggest redirecting the focus of glioma drug candidates on controlling the feedback between IGFBP2 and HIF1α. PMID:25884993

  16. Expression of Cancer-Testis Genes in Brain Tumors

    PubMed Central

    Lee, Myoung-Hee; Kim, Ealmaan; Kim, In-Soo; Yim, Man-Bin; Kim, Sang-Pyo

    2008-01-01

    Objective Cancer-testis (CT) genes are considered promising candidates for immunotherapeutic approaches. The aim of this study was to investigate which CT genes should be targeted in immunotherapy for brain tumors. Methods We investigated the expression of 6 CT genes (MAGE-E1, SOX-6, SCP-1, SSX-2, SSX-4, and HOM-TES-85) using reverse-transcription polymerase chain reaction in 26 meningiomas and 32 other various brain tumor specimens, obtained from the patients during tumor surgery from 2000 to 2005. Results The most frequently expressed CT genes of meningiomas were MAGE-E1, which were found in 22/26 (85%) meningioma samples, followed by SOX-6 (9/26 or 35%). Glioblastomas were most frequently expressed SOX-6 (6/7 or 86%), MAGE-E1 (5/7 or 71%), followed by SSX-2 (2/7 or 29%) and SCP-1 (1/7 or 14%). However, 4 astrocytomas, 3 anaplastic astrocytomas, and 3 oligodendroglial tumors only expressed MAGE-E1 and SOX-6. Schwannomas also expressed SOX-6 (5/6 or 83%), MAGE-E1 (4/6 or 67%), and SCP-1 (2/6 or 33%). Conclusion The data presented here suggest that MAGE-E1 and SOX-6 genes are expressed in a high percentage of human central nervous system tumors, which implies the CT genes could be the potential targets of immunotherapy for human central nervous system tumors. PMID:19096642

  17. Combined Proteomic-Molecular Epidemiology Approach to Identify Precision Targets in Brain Cancer.

    PubMed

    Mostovenko, Ekaterina; Liu, Yanhong; Amirian, E Susan; Tsavachidis, Spiridon; Armstrong, Georgina N; Bondy, Melissa L; Nilsson, Carol L

    2017-07-11

    Primary brain tumors are predominantly malignant gliomas. Grade IV astrocytomas (glioblastomas, GBM) are among the most deadly of all tumors; most patients will succumb to their disease within 2 years of diagnosis despite standard of care. The grim outlook for brain tumor patients indicates that novel precision therapeutic targets must be identified. Our hypothesis is that the cancer proteomes of glioma tumors may contain protein variants that are linked to the aggressive pathology of the disease. To this end, we devised a novel workflow that combined variant proteomics with molecular epidemiological mining of public cancer data sets to identify 10 previously unrecognized variants linked to the risk of death in low grade glioma or GBM. We hypothesize that a subset of the protein variants may be successfully developed in the future as novel targets for malignant gliomas.

  18. Pharmacological inhibition of lipid droplet formation enhances the effectiveness of curcumin in glioblastoma.

    PubMed

    Zhang, Issan; Cui, Yiming; Amiri, Abdolali; Ding, Yidan; Campbell, Robert E; Maysinger, Dusica

    2016-03-01

    Increased lipid droplet number and fatty acid synthesis allow glioblastoma multiforme, the most common and aggressive type of brain cancer, to withstand accelerated metabolic rates and resist therapeutic treatments. Lipid droplets are postulated to sequester hydrophobic therapeutic agents, thereby reducing drug effectiveness. We hypothesized that the inhibition of lipid droplet accumulation in glioblastoma cells using pyrrolidine-2, a cytoplasmic phospholipase A2 alpha inhibitor, can sensitize cancer cells to the killing effect of curcumin, a promising anticancer agent isolated from the turmeric spice. We observed that curcumin localized in the lipid droplets of human U251N glioblastoma cells. Reduction of lipid droplet number using pyrrolidine-2 drastically enhanced the therapeutic effect of curcumin in both 2D and 3D glioblastoma cell models. The mode of cell death involved was found to be mediated by caspase-3. Comparatively, the current clinical chemotherapeutic standard, temozolomide, was significantly less effective in inducing glioblastoma cell death. Together, our results suggest that the inhibition of lipid droplet accumulation is an effective way to enhance the chemotherapeutic effect of curcumin against glioblastoma multiforme.

  19. Stereotactic Radiosurgery for Glioblastoma

    PubMed Central

    Mehta, Minesh

    2015-01-01

    Glioblastoma (GBM) is the most common primary malignant brain tumor in adults and one of the most aggressive of all human cancers. GBM tumors are highly infiltrative and relatively resistant to conventional therapies. Aggressive management of GBM using a combination of surgical resection, followed by fractionated radiotherapy and chemotherapy has been shown to improve overall survival; however, GBM tumors recur in the majority of patients and the disease is most often fatal. There is a need to develop new treatment regimens and technological innovations to improve the overall survival of GBM patients. The role of stereotactic radiosurgery (SRS) for the treatment of GBM has been explored and is controversial. SRS utilizes highly precise radiation techniques to allow dose escalation and delivery of ablative radiation doses to the tumor while minimizing dose to the adjacent normal structures. In some studies, SRS with concurrent chemotherapy has shown improved local control with acceptable toxicities in select GBM patients. However, because GBM is a highly infiltrative disease, skeptics argue that local therapies, such as SRS, do not improve overall survival. The purpose of this article is to review the literature regarding SRS in both newly diagnosed and recurrent GBM, to describe SRS techniques, potential eligible SRS candidates, and treatment-related toxicities. In addition, this article will propose promising areas for future research for SRS in the treatment of GBM. PMID:26848407

  20. A phase 2 trial of verubulin for recurrent glioblastoma: a prospective study by the Brain Tumor Investigational Consortium (BTIC).

    PubMed

    Chamberlain, Marc C; Grimm, Sean; Phuphanich, Surasak; Recht, Larry; Zhu, Jay Z; Kim, Lyndon; Rosenfeld, Steve; Fadul, Camilo E

    2014-06-01

    Treatment options are limited for recurrent glioblastoma (GBM). Verubulin is a microtubule destabilizer and vascular disrupting agent that achieve high brain concentration relative to plasma in animals. Adults with recurrent GBM who failed prior standard therapy were eligible. The primary endpoint was 1-month progression-free survival (PFS-1) for bevacizumab refractory (Group 2) and 6-month progression-free survival (PFS-6) for bevacizumab naïve patients (Group 1). Verubulin was administered at 3.3 mg/m(2) as a 2-h intravenous infusion once weekly for 3 consecutive weeks in a 4-week cycle. The planned sample size was 34 subjects per cohort. 56 patients (37 men, 19 women) were enrolled, 31 in Group 1 and 25 in Group 2. The PFS-6 for Group 1 was 14% and the PFS-1 for Group 2 was 20%. Median survival from onset of treatment was 9.5 months in Group 1 and 3.4 months in Group 2. Best overall response was partial response (n = 3; 10% in Group 1; n = 1; 4.2% in Group 2) and stable disease (n = 7; 23% in Group 1; n = 5; 21% in Group 2). In Group 1, 38.7% of patients experienced a serious adverse event; however only 3.2% were potentially attributable to study drug. In Group 2, 44% of patients experienced a serious adverse event although none were attributable to study drug. Accrual was terminated early for futility. Single agent verubulin, in this dose and schedule, is well tolerated, associated with moderate but tolerable toxicity but has limited activity in either bevacizumab naïve or refractory recurrent GBM.

  1. NT113, a pan-ERBB Inhibitor with High Brain Penetrance, Inhibits the Growth of Glioblastoma Xenografts with EGFR Amplification

    PubMed Central

    Yoshida, Yasuyuki; Ozawa, Tomoko; Yao, Tsun-Wen; Shen, Wang; Brown, Dennis; Parsa, Andrew T.; Raizer, Jeffrey J.; Cheng, Shi-Yuan; Stegh, Alexander H.; Mazar, Andrew P.; Giles, Francis J.; Sarkaria, Jann N.; Butowski, Nicholas; Nicolaides, Theodore; James, C. David

    2014-01-01

    This report describes results from our analysis of the activity and biodistribution of a novel pan-ERBB inhibitor, NT113, when used in treating mice with intracranial glioblastoma (GBM) xenografts. Approaches used in this investigation include: bioluminescence imaging (BLI) for monitoring intracranial tumor growth and response to therapy; determination of survival benefit from treatment; analysis of tumor immunohistochemical (IHC) reactivity for indication of treatment effect on proliferation and apoptotic response; western blot for determination of effects of treatment on ERBB and ERBB signaling mediator activation; and high performance liquid chromatography for determination of NT113 concentration in tissue extracts from animals receiving oral administration of inhibitor. Our results show that NT113 is active against GBM xenografts in which wild-type EGFR or EGFRvIII is highly expressed. In experiments including lapatinib and/or erlotinib, NT113 treatment was associated with the most substantial improvement in survival, as well as the most substantial tumor growth inhibition, as indicated by BLI and IHC results. Western blot results indicated that NT113 has inhibitory activity, both in vivo and in vitro, on ERBB family member phosphorylation, as well as on the phosphorylation of downstream signaling mediator Akt. Results from the analysis of animal tissues revealed significantly higher NT113 normal brain-to-plasma and intracranial tumor-to-plasma ratios for NT113, relative to erlotinib, indicating superior NT113 partitioning to intracranial tissue compartments. These data provide a strong rationale for the clinical investigation of NT113, a novel ERBB inhibitor, in treating patients with GBM. PMID:25313012

  2. Nanoparticles for imaging and treating brain cancer

    PubMed Central

    Meyers, Joseph D; Doane, Tennyson; Burda, Clemens; Basilion, James P

    2013-01-01

    Brain cancer tumors cause disruption of the selective properties of vascular endothelia, even causing disruptions in the very selective blood–brain barrier, which are collectively referred to as the blood–brain–tumor barrier. Nanoparticles (NPs) have previously shown great promise in taking advantage of this increased vascular permeability in other cancers, which results in increased accumulation in these cancers over time due to the accompanying loss of an effective lymph system. NPs have therefore attracted increased attention for treating brain cancer. While this research is just beginning, there have been many successes demonstrated thus far in both the laboratory and clinical setting. This review serves to present the reader with an overview of NPs for treating brain cancer and to provide an outlook on what may come in the future. For NPs, just like the blood–brain–tumor barrier, the future is wide open. PMID:23256496

  3. Comparison of microRNA expression levels between initial and recurrent glioblastoma specimens.

    PubMed

    Ilhan-Mutlu, Aysegül; Wöhrer, Adelheid; Berghoff, Anna Sophie; Widhalm, Georg; Marosi, Christine; Wagner, Ludwig; Preusser, Matthias

    2013-05-01

    Glioblastoma is the most frequent primary brain tumour in adults. Recent therapeutic advances increased patient's survival, but tumour recurrence inevitably occurs. The pathobiological mechanisms involved in glioblastoma recurrence are still unclear. MicroRNAs are small RNAs proposed o have important roles for cancer including proliferation, aggressiveness and metastases development. There exist only few data on the involvement of microRNAs in glioblastoma recurrence. We selected the following 7 microRNAs with potential relevance for glioblastoma pathobiology by means of a comprehensive literature search: microRNA-10b, microRNA-21, microRNA-181b, microRNA-181c, microRNA-195, microRNA-221 and microRNA-222. We further selected 15 primary glioblastoma patients, of whom formalin fixed and paraffin embedded tissue (FFPE) of the initial and recurrence surgery were available. All patients had received first line treatment consisting of postoperative combined radiochemotherapy with temozolomide (n = 15). Non-neoplastic brain tissue samples from 3 patients with temporal lobe epilepsy served as control. The expression of the microRNAs were analysed by RT-qPCR. These were correlated with each other and with clinical parameters. All microRNAs showed detectable levels of expressions in glioblastoma group, whereas microRNA-10b was not detectable in epilepsy patients. MicroRNAs except microRNA-21 showed significantly higher levels in epilepsy patients when compared to the levels of first resection of glioblastoma. Comparison of microRNA levels between first and second resections revealed no significant change. Cox regression analyses showed no significant association of microRNA expression levels in the tumor tissue with progression free survival times. Expression levels of microRNA-10b, microRNA-21, microRNA-181b, microRNA-181c, microRNA-195, microRNA-221 and microRNA-222 do not differ significantly between initial and recurrent glioblastoma.

  4. Inhibition of the Ca2+ release channel, IP3R subtype 3 by caffeine slows glioblastoma invasion and migration and extends survival

    PubMed Central

    Kang, Sang Soo; Han, Kyung-Seok; Ku, Bo Mi; Lee, Yeon Kyung; Hong, Jinpyo; Shin, Hye Young; Almonte, Antoine G.; Woo, Dong Ho; Brat, Daniel J.; Hwang, Eun Mi; Yoo, Seung Hyun; Chung, Chun Kee; Park, Sung-Hye; Paek, Sun Ha; Roh, Eun Joo; Lee, Sung joong; Park, Jae-Yong; Traynelis, Stephen F.; Lee, C. Justin

    2009-01-01

    Ca2+ signaling is an important determining factor in many cellular processes, especially in cancer cell proliferation, motility and invasion. Glioblastoma is the deadliest brain cancer with its average survival time of less than a year, with the most prominent cellular feature being the ability of these cells to migrate to and invade the neighboring tissue. We hypothesized that disturbing the Ca2+ signaling pathway would decrease the propensity for these cells to migrate. Thus, we investigated the detailed Ca2+ signaling pathway of the glioblastoma cells in response to various receptor tyrosine kinases (RTK) and G-protein coupled receptor (GPCR) agonists. Here we report that caffeine, which is a well-known activator of ryanodine receptors (RyRs), paradoxically inhibits inositol-1, 4, 5-triphospate receptor(IP3R)-mediated Ca2+ increase by selectively targeting IP3R subtype 3(IP3R3), whose mRNA expression is significantly increased in glioblastoma cells. Consequently, by inhibiting IP3R3-mediated Ca2+ release, caffeine was found to inhibit the invasion and migration of various glioblastoma cell lines in scrape motility, Matrigel invasion, soft agar, and brain slice implantation assays. In a mouse xenograft model of glioblastoma, caffeine intake via drinking water greatly increased mean survival duration of subject animals. These findings propose IP3R3 as a novel target for glioblastoma treatment and that caffeine may be a useful adjunct therapy that slows glioblastoma invasion and migration by selectively targeting IP3R3. PMID:20103623

  5. Benzyl isothiocyanate (BITC) induces apoptosis of GBM 8401 human brain glioblastoma multiforms cells via activation of caspase-8/Bid and the reactive oxygen species-dependent mitochondrial pathway.

    PubMed

    Shang, Hung-Sheng; Shih, Yung-Luen; Lu, Tai-Jung; Lee, Ching-Hsiao; Hsueh, Shu-Ching; Chou, Yu-Cheng; Lu, Hsu-Feng; Liao, Nien-Chieh; Chung, Jing-Gung

    2016-12-01

    Benzyl isothiocyanate (BITC) is one of member of the isothiocyanate family which has been shown to induce cancer cell apoptosis in many human cancer cells. In the present study, we investigated the effects of BITC on the growth of GBM 8401 human brain glioblastoma multiforms cells. Results indicated that BITC-induced cell morphological changes decreased in the percentage of viable GBM8401 cells and these effects are dose-dependent manners. Results from flow cytometric assay indicated that BITC induced sub-G1 phase and induction of apoptosis of GBM 8401 cells. Furthermore, results also showed that BITC promoted the production of reactive oxygen species (ROS) and Ca(2+) release, but decreased the mitochondrial membrane potential (ΔΨm ) and promoted caspase-8, -9, and -3 activates. After cells were pretreated with Z-IETD-FMK, Z-LEHD-FMK, and Z-DEVD-FMK (caspase-8, -9, and -3 inhibitors, respectively) led to decrease in the activities of caspase-8, -9, and -3 and increased the percentage of viable GBM 8401 cells that indicated which BITC induced cell apoptosis through caspase-dependent pathways. Western blotting indicated that BITC induced Fas, Fas-L, FADD, caspase-8, caspase -3, and pro-apoptotic protein (Bax, Bid, and Bak), but inhibited the ant-apoptotic proteins (Bcl-2 and Bcl-x) in GBM 8401 cells. Furthermore, BITC increased the release of cytochrome c, AIF, and Endo G from mitochondria that led to cell apoptosis. Results also showed that BITC increased GADD153, GRP 78, XBP-1, and ATF-6β, IRE-1α, IRE-1β, Calpain 1 and 2 in GBM 8401 cells, which is associated with ER stress. Based on these observations, we may suggest that BITC-induced apoptosis might be through Fas receptor, ROS induced ER stress, caspase-3, and mitochondrial signaling pathways. Taken together, these molecular alterations and signaling pathways offer an insight into BITC-caused growth inhibition and induced apoptotic cell death of GBM 8401 cells. © 2015 Wiley Periodicals, Inc. Environ

  6. Robust discrimination of glioblastomas from metastatic brain tumors on the basis of single-voxel (1)H MRS.

    PubMed

    Vellido, A; Romero, E; Julià-Sapé, M; Majós, C; Moreno-Torres, Á; Pujol, J; Arús, C

    2012-06-01

    This article investigates methods for the accurate and robust differentiation of metastases from glioblastomas on the basis of single-voxel (1)H MRS information. Single-voxel (1)H MR spectra from a total of 109 patients (78 glioblastomas and 31 metastases) from the multicenter, international INTERPRET database, plus a test set of 40 patients (30 glioblastomas and 10 metastases) from three different centers in the Barcelona (Spain) metropolitan area, were analyzed using a robust method for feature (spectral frequency) selection coupled with a linear-in-the-parameters single-layer perceptron classifier. For the test set, a parsimonious selection of five frequencies yielded an area under the receiver operating characteristic curve of 0.86, and an area under the convex hull of the receiver operating characteristic curve of 0.91. Moreover, these accurate results for the discrimination between glioblastomas and metastases were obtained using a small number of frequencies that are amenable to metabolic interpretation, which should ease their use as diagnostic markers. Importantly, the prediction can be expressed as a simple formula based on a linear combination of these frequencies. As a result, new cases could be straightforwardly predicted by integrating this formula into a computer-based medical decision support system. This work also shows that the combination of spectra acquired at different TEs (short TE, 20-32 ms; long TE, 135-144 ms) is key to the successful discrimination between glioblastomas and metastases from single-voxel (1)H MRS.

  7. Glioblastoma Cancer Stem Cells Evade Innate Immune Suppression of Self-Renewal through Reduced TLR4 Expression.

    PubMed

    Alvarado, Alvaro G; Thiagarajan, Praveena S; Mulkearns-Hubert, Erin E; Silver, Daniel J; Hale, James S; Alban, Tyler J; Turaga, Soumya M; Jarrar, Awad; Reizes, Ofer; Longworth, Michelle S; Vogelbaum, Michael A; Lathia, Justin D

    2016-12-27

    Tumors contain hostile inflammatory signals generated by aberrant proliferation, necrosis, and hypoxia. These signals are sensed and acted upon acutely by the Toll-like receptors (TLRs) to halt proliferation and activate an immune response. Despite the presence of TLR ligands within the microenvironment, tumors progress, and the mechanisms that permit this growth remain largely unknown. We report that self-renewing cancer stem cells (CSCs) in glioblastoma have low TLR4 expression that allows them to survive by disregarding inflammatory signals. Non-CSCs express high levels of TLR4 and respond to ligands. TLR4 signaling suppresses CSC properties by reducing retinoblastoma binding protein 5 (RBBP5), which is elevated in CSCs. RBBP5 activates core stem cell transcription factors, is necessary and sufficient for self-renewal, and is suppressed by TLR4 overexpression in CSCs. Our findings provide a mechanism through which CSCs persist in hostile environments because of an inability to respond to inflammatory signals.

  8. Targeting ROR1 inhibits the self-renewal and invasive ability of glioblastoma stem cells.

    PubMed

    Jung, Eun-Hwa; Lee, Han-Na; Han, Gi-Yeon; Kim, Min-Jung; Kim, Chan-Wha

    2016-04-01

    Glioblastoma is the most malignant of brain tumours and is difficult to cure because of interruption of drug delivery by the blood-brain barrier system, its high metastatic capacity and the existence of cancer stem cells (CSCs). Although CSCs are present as a small population in malignant tumours, CSCs have been studied as they are responsible for causing recurrence, metastasis and resistance to chemotherapy and radiotherapy for cancer. CSCs have self-renewal characteristics like normal stem cells. The aim of this study was to investigate whether receptor tyrosine kinase-like orphan receptor 1 (ROR1) is involved in stem cell maintenance and malignant properties in human glioblastoma. Knockdown of ROR1 caused reduction of stemness and sphere formation capacity. Moreover, down-regulation of ROR1 suppressed the expression of epithelial-mesenchymal transition-related genes and the tumour migratory and invasive abilities. The results of this study indicate that targeting ROR1 can induce differentiation of CSCs and inhibit metastasis in glioblastoma. In addition, ROR1 may be used as a potential marker for glioblastoma stem cells as well as a potential target for glioblastoma stem cell therapy.

  9. Analysis of Chemopredictive Assay for Targeting Cancer Stem Cells in Glioblastoma Patients.

    PubMed

    Howard, Candace M; Valluri, Jagan; Alberico, Anthony; Julien, Terrence; Mazagri, Rida; Marsh, Robert; Alastair, Hoyt; Cortese, Antonio; Griswold, Michael; Wang, Wanmei; Denning, Krista; Brown, Linda; Claudio, Pier Paolo

    2017-04-01

    The prognosis of glioblastoma (GBM) treated with standard-of-care maximal surgical resection and concurrent adjuvant temozolomide (TMZ)/radiotherapy remains very poor (less than 15 months). GBMs have been found to contain a small population of cancer stem cells (CSCs) that contribute to tumor propagation, maintenance, and treatment resistance. The highly invasive nature of high-grade gliomas and their inherent resistance to therapy lead to very high rates of recurrence. For these reasons, not all patients with similar diagnoses respond to the same chemotherapy, schedule, or dose. Administration of ineffective anticancer therapy is not only costly but more importantly burdens the patient with unnecessary toxicity and selects for the development of resistant cancer cell clones. We have developed a drug response assay (ChemoID) that identifies the most effective chemotherapy against CSCs and bulk of tumor cells from of a panel of potential treatments, offering great promise for individualized cancer management. Providing the treating physician with drug response information on a panel of approved drugs will aid in personalized therapy selections of the most effective chemotherapy for individual patients, thereby improving outcomes. A prospective study was conducted evaluating the use of the ChemoID drug response assay in GBM patients treated with standard of care. Forty-one GBM patients (mean age 54 years, 59% male), all eligible for a surgical biopsy, were enrolled in an Institutional Review Board-approved protocol, and fresh tissue samples were collected for drug sensitivity testing. Patients were all treated with standard-of-care TMZ plus radiation with or without maximal surgery, depending on the status of the disease. Patients were prospectively monitored for tumor response, time to recurrence, progression-free survival (PFS), and overall survival (OS). Odds ratio (OR) associations of 12-month recurrence, PFS, and OS outcomes were estimated for CSC, bulk tumor

  10. Role of key genetic mutations on increasing migration of brain cancer cells through confinement.

    PubMed

    Bui, Loan; Bhuiyan, Sayem H; Hendrick, Alissa; Chuong, Cheng-Jen; Kim, Young-Tae

    2017-09-01

    Uncontrolled invasive cancer cell migration is among the major challenges for the treatment and management of brain cancer. Although the genetic profiles of brain cancer cells have been well characterized, the relationship between the genetic mutations and the cells' mobility has not been clearly understood. In this study, using microfluidic devices that provide a wide range of physical confinements from 20 × 5 μm(2) to 3 × 5 μm(2) in cross sections, we studied the effect of physical confinement on the migratory capacity of cell lines with different types of mutations. Human glioblastoma and genetically modified mouse astrocytes were used. Human glioblastoma cells with EGFRvIII mutation were found to exhibit high degree of migratory capacity in narrow confinement. From mouse astrocytes, cells with triple mutations (p53-/- PTEN-/- BRAF) were found to exhibit the highest level of migratory capacity in narrow confinement compared to both double (p53-/- PTEN-/-) and single (p53-/-) mutant cells. Furthermore, when treating the triple mutant astrocytes with AZD-6244, an inhibitor of the RAF/MEK/ERK pathway, we found significant reduction in migration through the confined channels when compared to that of controls (83% decrease in 5 × 5 μm(2) and 86% in 3 × 5 μm(2) channels). Our data correlate genetic mutations from different cell lines to their motility in different degrees of confinement. Our results also suggest a potential therapeutic target such as BRAF oncogene for inhibition of brain cancer invasion.

  11. Quantitating Cell-Cell Interaction Functions, with Applications to Glioblastoma Multiforme Cancer Cells

    PubMed Central

    Wang, Jun; Tham, Douglas; Wei, Wei; Shin, Young Shik; Ma, Chao; Ahmad, Habib; Shi, Qihui; Yu, Jenkan; Levine, Raphael D.; Heath, James R.

    2013-01-01

    We report on a method for quantitating the distance dependence of cell-cell interactions. We employ a microchip design that permits a multiplex, quantitative protein assay from statistical numbers of cell pairs, as a function of cell separation, with a 0.15 nanoliter volume microchamber. We interrogate interactions between pairs of model brain cancer cells by assaying for 6 functional proteins associated with PI3k signaling. At short incubation times, cells do not appear to influence each other, regardless of cell separation. For 6 hour incubation times, the cells exert an inhibiting influence on each other at short separations, and a predominately activating influence at large separation. Protein-specific cell-cell interaction functions are extracted, and by assuming pairwise additivity of those interactions, the functions are shown to correctly predict the results from 3-cell experiments carried out under the identical conditions. PMID:23130660

  12. Treatment of brain metastasis from lung cancer.

    PubMed

    Kawabe, Takuya; Phi, Ji Hoon; Yamamoto, Masaaki; Kim, Dong Gyu; Barfod, Bierta E; Urakawa, Yoichi

    2012-01-01

    Brain metastasis from lung cancer occupies a significant portion of all brain metastases. About 15-20% of patients with non-small cell lung cancer (NSCLC) develop brain metastasis during the course of the disease. The prognosis of brain metastasis is poor with median survival of less than 1 year. Whole-brain radiation therapy (WBRT) is widely used for the treatment of brain metastasis. WBRT can also be used as adjuvant treatment along with surgery and stereotactic radiosurgery (SRS).Surgery provides a rapid relief of mass effects and may be the best choice for a large single metastasis. SRS confers local control rates comparable to those for surgery with minimal toxicities and versatility that makes it applicable to multiple lesions, deep-seated lesions, and to patients with poor medical conditions. Recursive partitioning analysis (RPA) classes are widely used for prognostic stratification. However, the validity of RPA classes, especially for NSCLC, has been questioned and other scoring systems are being developed. Synchronous presentation of primary NSCLC and brain metastases is a special situation in which surgery for the lung lesion and surgery or SRS for brain lesions are recommended if the thoracic disease is in early stages. Small cell lung cancer (SCLC) has a higher likelihood for brain metastasis than NSCLC and prophylactic cranial irradiation and subsequent WBRT are usually recommended. Recently, SRS for brain metastasis from SCLC has been tried, but requires further verification.

  13. Raising the standard of brain cancer care.

    PubMed

    Mason, Mary-Claire

    2015-04-15

    Survival rates for people with brain cancer are poor, and some patients do not receive the specialist support they need. Nurse specialist Ingela Oberg calls for earlier diagnosis and improved access to nurse-led clinics and rehabilitation services.

  14. Environmental effects on molecular biomarkers expression in pancreatic and brain cancer

    NASA Astrophysics Data System (ADS)

    Mensah, Lawrence; Mallidi, Srivalleesha; Massodi, Iqbal; Anbil, Sriram; Mai, Zhiming; Hasan, Tayyaba

    2013-03-01

    A complete understanding of the biological mechanisms regulating devastating disease such as cancer remains elusive. Pancreatic and brain cancers are primary among the cancer types with poor prognosis. Molecular biomarkers have emerged as group of proteins that are preferentially overexpressed in cancers and with a key role in driving disease progression and resistance to chemotherapy. The epidermal growth factor receptor (EGFR), a cell proliferative biomarker is particularly highly expressed in most cancers including brain and pancreatic cancers. The ability of EGFR to sustain prolong cell proliferation is augmented by biomarkers such as Bax, Bcl-XL and Bcl-2, proteins regulating the apoptotic process. To better understand the role and effect of the microenvironment on these biomarkers in pancreatic cancer (PaCa); we analysed two pancreatic tumor lines (AsPc-1 and MiaPaCa-2) in 2D, 3D in-vitro cultures and in orthotopic tumors at different growth stages. We also investigated in patient derived glioblastoma (GBM) tumor cultures, the ability to utilize the EGFR expression to specifically deliver photosensitizer to the cells for photodynamic therapy. Overall, our results suggest that (1) microenvironment changes affect biomarker expression; thereby it is critical to understand these effects prior to designing combination therapies and (2) EGFR expression in tumor cells indeed could serve as a reliable and a robust biomarker that could be used to design targeted and image-guided photodynamic therapy.

  15. Integrated Cox's model for predicting survival time of glioblastoma multiforme.

    PubMed

    Ai, Zhibing; Li, Longti; Fu, Rui; Lu, Jing-Min; He, Jing-Dong; Li, Sen

    2017-04-01

    Glioblastoma multiforme is the most common primary brain tumor and is highly lethal. This study aims to figure out signatures for predicting the survival time of patients with glioblastoma multiforme. Clinical information, messenger RNA expression, microRNA expression, and single-nucleotide polymorphism array data of patients with glioblastoma multiforme were retrieved from The Cancer Genome Atlas. Patients were separated into two groups by using 1 year as a cutoff, and a logistic regression model was used to figure out any variables that can predict whether the patient was able to live longer than 1 year. Furthermore, Cox's model was used to find out features that were correlated with the survival time. Finally, a Cox model integrated the significant clinical variables, messenger RNA expression, microRNA expression, and single-nucleotide polymorphism was built. Although the classification method failed, signatures of clinical features, messenger RNA expression levels, and microRNA expression levels were figured out by using Cox's model. However, no single-nucleotide polymorphisms related to prognosis were found. The selected clinical features were age at initial diagnosis, Karnofsky score, and race, all of which had been suggested to correlate with survival time. Both of the two significant microRNAs, microRNA-221 and microRNA-222, were targeted to p27(Kip1) protein, which implied the important role of p27(Kip1) on the prognosis of glioblastoma multiforme patients. Our results suggested that survival modeling was more suitable than classification to figure out prognostic biomarkers for patients with glioblastoma multiforme. An integrated model containing clinical features, messenger RNA levels, and microRNA expression levels was built, which has the potential to be used in clinics and thus to improve the survival status of glioblastoma multiforme patients.

  16. Breast Cancer Cells May Change When They Spread to Brain

    MedlinePlus

    ... Cancer Cells May Change When They Spread to Brain: Study Finding might lead to better treatment, researchers ... HealthDay News) -- When breast cancer spreads to the brain, important molecular changes may occur in the cancer, ...

  17. The SOX2-interactome in brain cancer cells identifies the requirement of MSI2 and USP9X for the growth of brain tumor cells.

    PubMed

    Cox, Jesse L; Wilder, Phillip J; Gilmore, Joshua M; Wuebben, Erin L; Washburn, Michael P; Rizzino, Angie

    2013-01-01

    Medulloblastomas and glioblastomas, the most common primary brain tumors in children and adults, respectively, are extremely difficult to treat. Efforts to identify novel proteins essential for the growth of these tumors may help to further our understanding of the biology of these tumors, as well as, identify targets for future therapies. The recent identification of multiple transcription factor-centric protein interaction landscapes in embryonic stem cells has identified numerous understudied proteins that are essential for the self-renewal of these stem cells. To identify novel proteins essential for the fate of brain tumor cells, we examined the protein interaction network of the transcription factor, SOX2, in medulloblastoma cells. For this purpose, Multidimensional Protein Identification Technology (MudPIT) identified >280 SOX2-associated proteins in the medulloblastoma cell line DAOY. To begin to understand the roles of SOX2-associated proteins in brain cancer, we focused on two SOX2-associated proteins, Musashi 2 (MSI2) and Ubiquitin Specific Protease 9x (USP9X). Recent studies have implicated MSI2, a putative RNA binding protein, and USP9X, a deubiquitinating enzyme, in several cancers, but not brain tumors. We demonstrate that knockdown of MSI2 significantly reduces the growth of DAOY cells as well as U87 and U118 glioblastoma cells. We also demonstrate that the knockdown of USP9X in DAOY, U87 and U118 brain tumor cells strongly reduces their growth. Together, our studies identify a large set of SOX2-associated proteins in DAOY medulloblastoma cells and identify two proteins, MSI2 and USP9X, that warrant further investigation to determine whether they are potential therapeutic targets for brain cancer.

  18. PINK1 Is a Negative Regulator of Growth and the Warburg Effect in Glioblastoma.

    PubMed

    Agnihotri, Sameer; Golbourn, Brian; Huang, Xi; Remke, Marc; Younger, Susan; Cairns, Rob A; Chalil, Alan; Smith, Christian A; Krumholtz, Stacey-Lynn; Mackenzie, Danielle; Rakopoulos, Patricia; Ramaswamy, Vijay; Taccone, Michael S; Mischel, Paul S; Fuller, Gregory N; Hawkins, Cynthia; Stanford, William L; Taylor, Michael D; Zadeh, Gelareh; Rutka, James T

    2016-08-15

    Proliferating cancer cells are characterized by high rates of glycolysis, lactate production, and altered mitochondrial metabolism. This metabolic reprogramming provides important metabolites for proliferation of tumor cells, including glioblastoma. These biological processes, however, generate oxidative stress that must be balanced through detoxification of reactive oxygen species (ROS). Using an unbiased retroviral loss-of-function screen in nontransformed human astrocytes, we demonstrate that mitochondrial PTEN-induced kinase 1 (PINK1) is a regulator of the Warburg effect and negative regulator of glioblastoma growth. We report that loss of PINK1 contributes to the Warburg effect through ROS-dependent stabilization of hypoxia-inducible factor-1A and reduced pyruvate kinase muscle isozyme 2 activity, both key regulators of aerobic glycolysis. Mechanistically, PINK1 suppresses ROS and tumor growth through FOXO3a, a master regulator of oxidative stress and superoxide dismutase 2. These findings highlight the importance of PINK1 and ROS balance in normal and tumor cells. PINK1 loss was observed in a significant number of human brain tumors including glioblastoma (n > 900) and correlated with poor patient survival. PINK1 overexpression attenuates in vivo glioblastoma growth in orthotopic mouse xenograft models and a transgenic glioblastoma model in Drosophila Cancer Res; 76(16); 4708-19. ©2016 AACR. ©2016 American Association for Cancer Research.

  19. Inhibition of FoxO1 nuclear exclusion prevents metastasis of glioblastoma.

    PubMed

    Chen, Jin; Huang, Qin; Wang, Feng

    2014-07-01

    Glioblastoma is the most aggressive malignant primary brain tumor in humans, with extremely poor patient survival. Although previous studies have demonstrated that expression of matrix metalloproteinase-9 (MMP9) in glioblastoma promotes cancer metastasis, the upstream molecular signaling cascades that control activation of MMP9 remain largely unknown. Here, we used a human glioblastoma line, A-172, to examine molecular signaling to activate MMP9. We found that epidermal growth factor (EGF)-induced activation of epidermal growth factor receptor (EGFR) in A-172 cells activated MMP9, resulting in an increase in cancer invasiveness. A specific inhibitor for EGFR efficiently blocked EGF-induced activation of MMP9 and then cancer invasiveness. Moreover, an inhibitor for phosphatidylinositol 3-kinase (PI-3 K)/protein kinase B (Akt) significantly inhibited the EGF-induced activation of MMP9. Furthermore, nuclear exclusion of a major Akt downstream target, Forkhead box protein O1 (FoxO1), was induced by Akt activation, which could be inhibited by either an EGFR inhibitor or by PI-3 K/Akt inhibitor. An expression of a constitutive nuclear form of FoxO1 significantly inhibited MMP9 activation induced by EGF. Taken together, these findings suggest that EGF/EGFR signaling activates downstream PI-3 K/Akt to induce FoxO1 nuclear exclusion, which activates MMP9 to promote glioblastoma invasiveness. Thus, FoxO1 appears to be a novel therapeutic target for inhibiting metastasis of glioblastoma.

  20. Ion channel expression patterns in glioblastoma stem cells with functional and therapeutic implications for malignancy

    PubMed Central

    Pollak, Julia; Rai, Karan G.; Funk, Cory C.; Arora, Sonali; Lee, Eunjee; Zhu, Jun; Price, Nathan D.; Paddison, Patrick J.; Ramirez, Jan-Marino; Rostomily, Robert C.

    2017-01-01

    Ion channels and transporters have increasingly recognized roles in cancer progression through the regulation of cell proliferation, migration, and death. Glioblastoma stem-like cells (GSCs) are a source of tumor formation and recurrence in glioblastoma multiforme, a highly aggressive brain cancer, suggesting that ion channel expression may be perturbed in this population. However, little is known about the expression and functional relevance of ion channels that may contribute to GSC malignancy. Using RNA sequencing, we assessed the enrichment of ion channels in GSC isolates and non-tumor neural cell types. We identified a unique set of GSC-enriched ion channels using differential expression analysis that is also associated with distinct gene mutation signatures. In support of potential clinical relevance, expression of selected GSC-enriched ion channels evaluated in human glioblastoma databases of The Cancer Genome Atlas and Ivy Glioblastoma Atlas Project correlated with patient survival times. Finally, genetic knockdown as well as pharmacological inhibition of individual or classes of GSC-enriched ion channels constrained growth of GSCs compared to normal neural stem cells. This first-in-kind global examination characterizes ion channels enriched in GSCs and explores their potential clinical relevance to glioblastoma molecular subtypes, gene mutations, survival outcomes, regional tumor expression, and experimental responses to loss-of-function. Together, the data support the potential biological and therapeutic impact of ion channels on GSC malignancy and provide strong rationale for further examination of their mechanistic and therapeutic importance. PMID:28264064

  1. Ion channel expression patterns in glioblastoma stem cells with functional and therapeutic implications for malignancy.

    PubMed

    Pollak, Julia; Rai, Karan G; Funk, Cory C; Arora, Sonali; Lee, Eunjee; Zhu, Jun; Price, Nathan D; Paddison, Patrick J; Ramirez, Jan-Marino; Rostomily, Robert C

    2017-01-01

    Ion channels and transporters have increasingly recognized roles in cancer progression through the regulation of cell proliferation, migration, and death. Glioblastoma stem-like cells (GSCs) are a source of tumor formation and recurrence in glioblastoma multiforme, a highly aggressive brain cancer, suggesting that ion channel expression may be perturbed in this population. However, little is known about the expression and functional relevance of ion channels that may contribute to GSC malignancy. Using RNA sequencing, we assessed the enrichment of ion channels in GSC isolates and non-tumor neural cell types. We identified a unique set of GSC-enriched ion channels using differential expression analysis that is also associated with distinct gene mutation signatures. In support of potential clinical relevance, expression of selected GSC-enriched ion channels evaluated in human glioblastoma databases of The Cancer Genome Atlas and Ivy Glioblastoma Atlas Project correlated with patient survival times. Finally, genetic knockdown as well as pharmacological inhibition of individual or classes of GSC-enriched ion channels constrained growth of GSCs compared to normal neural stem cells. This first-in-kind global examination characterizes ion channels enriched in GSCs and explores their potential clinical relevance to glioblastoma molecular subtypes, gene mutations, survival outcomes, regional tumor expression, and experimental responses to loss-of-function. Together, the data support the potential biological and therapeutic impact of ion channels on GSC malignancy and provide strong rationale for further examination of their mechanistic and therapeutic importance.

  2. Systemic approaches identify a garlic-derived chemical, Z-ajoene, as a glioblastoma multiforme cancer stem cell-specific targeting agent.

    PubMed

    Jung, Yuchae; Park, Heejoo; Zhao, Hui-Yuan; Jeon, Raok; Ryu, Jae-Ha; Kim, Woo-Young

    2014-07-01

    Glioblastoma multiforme (GBM) is one of the most common brain malignancies and has a very poor prognosis. Recent evidence suggests that the presence of cancer stem cells (CSC) in GBM and the rare CSC subpopulation that is resistant to chemotherapy may be responsible for the treatment failure and unfavorable prognosis of GBM. A garlic-derived compound, Z-ajoene, has shown a range of biological activities, including anti-proliferative effects on several cancers. Here, we demonstrated for the first time that Z-ajoene specifically inhibits the growth of the GBM CSC population. CSC sphere-forming inhibition was achieved at a concentration that did not exhibit a cytotoxic effect in regular cell culture conditions. The specificity of this inhibitory effect on the CSC population was confirmed by detecting CSC cell surface marker CD133 expression and biochemical marker ALDH activity. In addition, stem cell-related mRNA profiling and real-time PCR revealed the differential expression of CSC-specific genes, including Notch, Wnt, and Hedgehog, upon treatment with Z-ajoene. A proteomic approach, i.e., reverse-phase protein array (RPPA) and Western blot analysis, showed decreased SMAD4, p-AKT, 14.3.3 and FOXO3A expression. The protein interaction map (http://string-db.org/) of the identified molecules suggested that the AKT, ERK/p38 and TGFβ signaling pathways are key mediators of Z-ajoene's action, which affects the transcriptional network that includes FOXO3A. These biological and bioinformatic analyses collectively demonstrate that Z-ajoene is a potential candidate for the treatment of GBM by specifically targeting GBM CSCs. We also show how this systemic approach strengthens the identification of new therapeutic agents that target CSCs.

  3. Systemic Approaches Identify a Garlic-Derived Chemical, Z-ajoene, as a Glioblastoma Multiforme Cancer Stem Cell-Specific Targeting Agent

    PubMed Central

    Jung, Yuchae; Park, Heejoo; Zhao, Hui-Yuan; Jeon, Raok; Ryu, Jae-Ha; Kim, Woo-Young

    2014-01-01

    Glioblastoma multiforme (GBM) is one of the most common brain malignancies and has a very poor prognosis. Recent evidence suggests that the presence of cancer stem cells (CSC) in GBM and the rare CSC subpopulation that is resistant to chemotherapy may be responsible for the treatment failure and unfavorable prognosis of GBM. A garlic-derived compound, Z-ajoene, has shown a range of biological activities, including anti-proliferative effects on several cancers. Here, we demonstrated for the first time that Z-ajoene specifically inhibits the growth of the GBM CSC population. CSC sphere-forming inhibition was achieved at a concentration that did not exhibit a cytotoxic effect in regular cell culture conditions. The specificity of this inhibitory effect on the CSC population was confirmed by detecting CSC cell surface marker CD133 expression and biochemical marker ALDH activity. In addition, stem cell-related mRNA profiling and real-time PCR revealed the differential expression of CSC-specific genes, including Notch, Wnt, and Hedgehog, upon treatment with Z-ajoene. A proteomic approach, i.e., reverse-phase protein array (RPPA) and Western blot analysis, showed decreased SMAD4, p-AKT, 14.3.3 and FOXO3A expression. The protein interaction map (http://string-db.org/) of the identified molecules suggested that the AKT, ERK/p38 and TGFβ signaling pathways are key mediators of Z–ajoene’s action, which affects the transcriptional network that includes FOXO3A. These biological and bioinformatic analyses collectively demonstrate that Z-ajoene is a potential candidate for the treatment of GBM by specifically targeting GBM CSCs. We also show how this systemic approach strengthens the identification of new therapeutic agents that target CSCs. PMID:25078449

  4. Comparative Expression Study of the Endo–G Protein Coupled Receptor (GPCR) Repertoire in Human Glioblastoma Cancer Stem-like Cells, U87-MG Cells and Non Malignant Cells of Neural Origin Unveils New Potential Therapeutic Targets

    PubMed Central

    Lennon, Sarah; Carapito, Christine; Dong, Jihu; Van Dorsselaer, Alain; Junier, Marie-Pierre; Chneiweiss, Hervé; Cianférani, Sarah; Haiech, Jacques; Kilhoffer, Marie-Claude

    2014-01-01

    Glioblastomas (GBMs) are highly aggressive, invasive brain tumors with bad prognosis and unmet medical need. These tumors are heterogeneous being constituted by a variety of cells in different states of differentiation. Among these, cells endowed with stem properties, tumor initiating/propagating properties and particularly resistant to chemo- and radiotherapies are designed as the real culprits for tumor maintenance and relapse after treatment. These cells, termed cancer stem-like cells, have been designed as prominent targets for new and more efficient cancer therapies. G-protein coupled receptors (GPCRs), a family of membrane receptors, play a prominent role in cell signaling, cell communication and crosstalk with the microenvironment. Their role in cancer has been highlighted but remains largely unexplored. Here, we report a descriptive study of the differential expression of the endo-GPCR repertoire in human glioblastoma cancer stem-like cells (GSCs), U-87 MG cells, human astrocytes and fetal neural stem cells (f-NSCs). The endo-GPCR transcriptome has been studied using Taqman Low Density Arrays. Of the 356 GPCRs investigated, 138 were retained for comparative studies between the different cell types. At the transcriptomic level, eight GPCRs were specifically expressed/overexpressed in GSCs. Seventeen GPCRs appeared specifically expressed in cells with stem properties (GSCs and f-NSCs). Results of GPCR expression at the protein level using mass spectrometry and proteomic analysis are also presented. The comparative GPCR expression study presented here gives clues for new pathways specifically used by GSCs and unveils novel potential therapeutic targets. PMID:24662753

  5. Phase II study of thalidomide and radiation in children with newly diagnosed brain stem gliomas and glioblastoma multiforme.

    PubMed

    Turner, Christopher D; Chi, Susan; Marcus, Karen J; MacDonald, Tobey; Packer, Roger J; Poussaint, Tina Young; Vajapeyam, Sridhar; Ullrich, Nicole; Goumnerova, Liliana C; Scott, R Michael; Briody, Caitlin; Chordas, Christine; Zimmerman, Mary Ann; Kieran, Mark W

    2007-03-01

    A phase II study was conducted to assess the efficacy of administering daily thalidomide concomitantly with radiation and continuing for up to 1 year following radiation in children with brain stem gliomas (BSG) or glioblastoma multiforme (GBM). Secondary objectives were to obtain preliminary evidence of biologic activity of thalidomide and to evaluate toxicities from chronic administration of thalidomide in this population. Thirteen patients (2-14 years old) with newly diagnosed BSG (12 patients) or GBM (one patient) were enrolled between July 1999 and June 2000. All patients received focal radiotherapy to a total dose of 5,580 cGy. Thalidomide was administered once daily beginning on the first day of radiation and continued for 12 months or until the patient came off study. The starting dose was 12 mg/kg (rounded down to the nearest 50 mg) and was increased by 20% weekly, if tolerated, to 24 mg/kg or 1,000 mg (whichever was lower). Advanced imaging techniques and urine and serum analysis for anti-angiogenic markers were performed in some patients in an attempt to correlate changes with clinical effect of therapy. No patients completed the planned 12 months of thalidomide therapy and all have since died of disease progression. The median duration of therapy was 5 months (range 2-11 months). Nine patients came off study for progressive disease (PD), three patients due to toxicity and one patient withdrew consent. Several patients on this study required more extended courses of high dose steroids than would have been otherwise expected for this population due to significant peritumoral edema and necrosis. No consistent pattern emerged from the biologic correlative studies from 11 patients. However, advanced imaging with techniques such as MR spectroscopy, MR perfusion and 18-fluorodeoxyglucose positron emission tomography (FDG-PET) were helpful in distinguishing growing tumor from treatment effect and necrosis in some patients. The median time to progression (TTP

  6. Canadian brain cancer survival rates by tumour type and region: 1992-2008.

    PubMed

    Yuan, Yan; Shi, Qian; Li, Maoji; Nagamuthu, Chenthila; Andres, Ellie; Davis, Faith G

    2016-06-27

    To investigate patterns of survival among brain cancer patients in Canada. Canadian Cancer Registry data were obtained for all patients with first-ever primary malignant brain tumours diagnosed between 1992 and 2008 (n = 38,095). Follow-up ended with patient death or December 31, 2008, whichever occurred first. Crude Kaplan-Meier estimates were calculated at one, two and five years post-diagnosis. Cox proportional hazard models were used to obtain adjusted hazard ratios by region for major histology types. A time-specific generalized linear model was used to obtain 5-year survival estimates for specific age group, sex and region for major histology types. The overall five-year survival rate was 27%. No significant difference in survival rate over time is observed. The highest 5-year survival rate was 65% (95% CI: 62.5%-67.4%) for oligodendrogliomas and the lowest was 4.0% (95% CI: 3.7%-4.3%) for glioblastomas. Compared to Ontario, the adjusted 5-year glioblastoma survival estimates were lower in British Columbia, Alberta and the Prairie provinces (Manitoba and Saskatchewan), while the survival estimates were lower in all other regions for diffuse astrocytoma, and lower in Manitoba and Saskatchewan for anaplastic astrocytomas. Estimates were significantly higher for oligodendrogliomas in Alberta, and for anaplastic oligodendrogliomas in Alberta and Quebec (p < 0.05). These data are consistent with previous literature in observing higher survival rates at younger ages, in female patients and for tumours with mixed oligo components. There is a need to further explore the underlying reasons for the observed variation in survival rates by region in an effort to improve the prognosis of brain cancer in the Canadian patient population.

  7. Brain Exposure of Two Selective Dual CDK4 and CDK6 Inhibitors and the Antitumor Activity of CDK4 and CDK6 Inhibition in Combination with Temozolomide in an Intracranial Glioblastoma Xenograft.

    PubMed

    Raub, Thomas J; Wishart, Graham N; Kulanthaivel, Palaniappan; Staton, Brian A; Ajamie, Rose T; Sawada, Geri A; Gelbert, Lawrence M; Shannon, Harlan E; Sanchez-Martinez, Concepcion; De Dios, Alfonso

    2015-09-01

    Effective treatments for primary brain tumors and brain metastases represent a major unmet medical need. Targeting the CDK4/CDK6-cyclin D1-Rb-p16/ink4a pathway using a potent CDK4 and CDK6 kinase inhibitor has potential for treating primary central nervous system tumors such as glioblastoma and some peripheral tumors with high incidence of brain metastases. We compared central nervous system exposures of two orally bioavailable CDK4 and CDK6 inhibitors: abemaciclib, which is currently in advanced clinical development, and palbociclib (IBRANCE; Pfizer), which was recently approved by the U.S. Food and Drug Administration. Abemaciclib antitumor activity was assessed in subcutaneous and orthotopic glioma models alone and in combination with standard of care temozolomide (TMZ). Both inhibitors were substrates for xenobiotic efflux transporters P-glycoprotein and breast cancer resistant protein expressed at the blood-brain barrier. Brain Kp,uu values were less than 0.2 after an equimolar intravenous dose indicative of active efflux but were approximately 10-fold greater for abemaciclib than palbociclib. Kp,uu increased 2.8- and 21-fold, respectively, when similarly dosed in P-gp-deficient mice. Abemaciclib had brain area under the curve (0-24 hours) Kp,uu values of 0.03 in mice and 0.11 in rats after a 30 mg/kg p.o. dose. Orally dosed abemaciclib significantly increased survival in a rat orthotopic U87MG xenograft model compared with vehicle-treated animals, and efficacy coincided with a dose-dependent increase in unbound plasma and brain exposures in excess of the CDK4 and CDK6 Ki values. Abemaciclib increased survival time of intracranial U87MG tumor-bearing rats similar to TMZ, and the combination of abemaciclib and TMZ was additive or greater than additive. These data show that abemaciclib crosses the blood-brain barrier and confirm that both CDK4 and CDK6 inhibitors reach unbound brain levels in rodents that are expected to produce enzyme inhibition; however

  8. Lipoprotein-biomimetic nanostructure enables efficient targeting delivery of siRNA to Ras-activated glioblastoma cells via macropinocytosis

    NASA Astrophysics Data System (ADS)

    Huang, Jia-Lin; Jiang, Gan; Song, Qing-Xiang; Gu, Xiao; Hu, Meng; Wang, Xiao-Lin; Song, Hua-Hua; Chen, Le-Pei; Lin, Ying-Ying; Jiang, Di; Chen, Jun; Feng, Jun-Feng; Qiu, Yong-Ming; Jiang, Ji-Yao; Jiang, Xin-Guo; Chen, Hong-Zhuan; Gao, Xiao-Ling

    2017-05-01

    Hyperactivated Ras regulates many oncogenic pathways in several malignant human cancers including glioblastoma and it is an attractive target for cancer therapies. Ras activation in cancer cells drives protein internalization via macropinocytosis as a key nutrient-gaining process. By utilizing this unique endocytosis pathway, here we create a biologically inspired nanostructure that can induce cancer cells to `drink drugs' for targeting activating transcription factor-5 (ATF5), an overexpressed anti-apoptotic transcription factor in glioblastoma. Apolipoprotein E3-reconstituted high-density lipoprotein is used to encapsulate the siRNA-loaded calcium phosphate core and facilitate it to penetrate the blood-brain barrier, thus targeting the glioblastoma cells in a macropinocytosis-dependent manner. The nanostructure carrying ATF5 siRNA exerts remarkable RNA-interfering efficiency, increases glioblastoma cell apoptosis and inhibits tumour cell growth both in vitro and in xenograft tumour models. This strategy of targeting the macropinocytosis caused by Ras activation provides a nanoparticle-based approach for precision therapy in glioblastoma and other Ras-activated cancers.

  9. Lipoprotein-biomimetic nanostructure enables efficient targeting delivery of siRNA to Ras-activated glioblastoma cells via macropinocytosis

    PubMed Central

    Huang, Jia-Lin; Jiang, Gan; Song, Qing-Xiang; Gu, Xiao; Hu, Meng; Wang, Xiao-Lin; Song, Hua-Hua; Chen, Le-Pei; Lin, Ying-Ying; Jiang, Di; Chen, Jun; Feng, Jun-Feng; Qiu, Yong-Ming; Jiang, Ji-Yao; Jiang, Xin-Guo; Chen, Hong-Zhuan; Gao, Xiao-Ling

    2017-01-01

    Hyperactivated Ras regulates many oncogenic pathways in several malignant human cancers including glioblastoma and it is an attractive target for cancer therapies. Ras activation in cancer cells drives protein internalization via macropinocytosis as a key nutrient-gaining process. By utilizing this unique endocytosis pathway, here we create a biologically inspired nanostructure that can induce cancer cells to ‘drink drugs' for targeting activating transcription factor-5 (ATF5), an overexpressed anti-apoptotic transcription factor in glioblastoma. Apolipoprotein E3-reconstituted high-density lipoprotein is used to encapsulate the siRNA-loaded calcium phosphate core and facilitate it to penetrate the blood–brain barrier, thus targeting the glioblastoma cells in a macropinocytosis-dependent manner. The nanostructure carrying ATF5 siRNA exerts remarkable RNA-interfering efficiency, increases glioblastoma cell apoptosis and inhibits tumour cell growth both in vitro and in xenograft tumour models. This strategy of targeting the macropinocytosis caused by Ras activation provides a nanoparticle-based approach for precision therapy in glioblastoma and other Ras-activated cancers. PMID:28489075

  10. Integrin αvβ3-Targeted IRDye 800CW Near-Infrared Imaging of Glioblastoma

    PubMed Central

    Huang, Ruimin; Vider, Jelena; Kovar, Joy L.; Olive, D. Michael; Mellinghoff, Ingo K.; Mayer-Kuckuk, Philipp; Kircher, Moritz F.; Blasberg, Ronald G.

    2013-01-01

    Purpose Integrin αvβ3 plays an important role in tumor angiogenesis, growth and metastasis. We have tested a targeted probe to visualize integrin receptor expression in glioblastomas using near-infrared fluorescent (NIRF) imaging. Experimental design A transgenic glioblastoma mouse model (RCAS-PDGF-driven/tv-a glioblastoma, which mimics the infiltrative growth pattern of human glioblastomas), and two human orthotopic glioblastoma models, (U-87 MG with high integrin β3 expression and TS543 with low integrin β3 expression), were studied. An integrin-targeting NIRF probe, IRDye 800CW-cyclic-RGD peptide (IRDye 800CW-RGD), was tested by in vivo and ex vivo NIRF imaging. Results We demonstrate that the IRDye 800CW-RGD peptide: 1) specifically binds to integrin receptors, 2) is selectively localized to glioblastoma tissue with overexpressed integrin receptors and is retained over prolonged periods of time, 3) is associated with minimal autofluorescence and photobleaching due to imaging at 800 nm, 4) provides delineation of tumor tissue with high precision due to a high tumor-to-normal brain fluorescence ratio (79.7±6.9, 31.2±2.8, and 16.3±1.3) in the U-87 MG, RCAS-PDGF, and TS543 models, respectively; p<0.01) and 5) enables fluorescence-guided glioblastoma resection. Importantly, small foci of residual fluorescence were observed after resection was completed using white light imaging alone, and these fluorescent foci were shown to represent residual tumor tissue by histology. Conclusions NIRF imaging with the IRDye 800CW-RGD probe provides a simple, rapid, low-cost, non-radioactive and highly translatable approach for improved intraoperative glioblastoma visualization and resection. It also has the potential to serve as an imaging platform for noninvasive cancer detection and drug efficacy evaluation studies. PMID:22914772

  11. High expression of TIG3 predicts poor survival in patients with primary glioblastoma.

    PubMed

    Wang, Hongxiang; Xu, Hanchong; Xu, Tao; Tan, Cong; Jiang, Mei; Chen, Yihong; Hu, Xinyu; Zhou, Jinxu; Shen, Junyan; Qin, Rong; Hu, Daiyu; Huang, Qilin; Wang, Min; Wang, Lian; Duan, Dongxia; Yan, Yong; Chen, Juxiang

    2017-06-01

    TIG3 (tazarotene-induced gene 3) has been reported to suppress the progression of several malignancies, where this gene is universally downregulated. However, the expression of TIG3 in primary glioblastoma and its relevance to patient's prognosis have not been elaborated. Thus, this study was aimed to evaluate TIG3 expression level in primary glioblastoma and investigate the prognostic value of TIG3 for patients. The Cancer Genome Atlas database was first utilized to analyze the expression and prognostic potential of TIG3 in 528 glioblastoma cases. Compared with control group, glioblastoma showed significantly elevated TIG3 expression (p < 0.001). Log-rank analysis revealed that higher expression of TIG3 was associated with shorter overall survival (358vs 383 days, p = 0.039). Furthermore, TIG3 protein expression detected by immunohistochemistry confirmed positive correlation of TIG3 expression and glioma grade and upregulation of TIG3 in our cohort of 101 primary glioblastoma patients compared to 16 normal brains. Finally, Kaplan-Meier analysis and Cox regression analysis identified high TIG3 expression as an independent risk factor for overall survival of primary glioblastoma patients (overall survival, 10 vs 13 months, p = 0.033; hazard ratio = 1.542, p = 0.046). Together, this study indicated that increased expression of TIG3 in primary glioblastoma is a novel biomarker for predicting poor outcome of patients. We then hypothesize that TIG3 may function in a different pattern in glioblastoma.

  12. KLRC3, a Natural Killer receptor gene, is a key factor involved in glioblastoma tumourigenesis and aggressiveness.

    PubMed

    Cheray, Mathilde; Bessette, Barbara; Lacroix, Aurélie; Mélin, Carole; Jawhari, Soha; Pinet, Sandra; Deluche, Elise; Clavère, Pierre; Durand, Karine; Sanchez-Prieto, Ricardo; Jauberteau, Marie-Odile; Battu, Serge; Lalloué, Fabrice

    2017-02-01

    Glioblastoma is the most lethal brain tumour with a poor prognosis. Cancer stem cells (CSC) were proposed to be the most aggressive cells allowing brain tumour recurrence and aggressiveness. Current challenge is to determine CSC signature to characterize these cells and to develop new therapeutics. In a previous work, we achieved a screening of glycosylation-related genes to characterize specific genes involved in CSC maintenance. Three genes named CHI3L1, KLRC3 and PRUNE2 were found overexpressed in glioblastoma undifferentiated cells (related to CSC) compared to the differentiated ones. The comparison of their roles suggest that KLRC3 gene coding for NKG2E, a protein initially identified in NK cells, is more important than both two other genes in glioblastomas aggressiveness. Indeed, KLRC3 silencing decreased self-renewal capacity, invasion, proliferation, radioresistance and tumourigenicity of U87-MG glioblastoma cell line. For the first time we report that KLRC3 gene expression is linked to glioblastoma aggressiveness and could be a new potential therapeutic target to attenuate glioblastoma. © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  13. Restricted calorie ketogenic diet for the treatment of glioblastoma multiforme.

    PubMed

    Maroon, Joseph; Bost, Jeffrey; Amos, Austin; Zuccoli, Giulio

    2013-08-01

    Glioblastoma multiforme is the most common malignant primary brain tumor in adults and generally considered to be universally fatal. Glioblastoma multiforme accounts for 12% to 15% of all intracranial neoplasms and affects 2 to 3 adults per every 100,000 in the United States annually. In children glioblastoma multiforme accounts for only approximately 7% to 9% of central nervous system tumors. The mean survival rate in adults after diagnosis ranges from 12 to 18 months with standard therapy and 3 to 6 months without therapy. The prognosis in children is better compared to adult tumor onset with a mean survival of approximately 4 years following gross total surgical resection and chemotherapy. There have been few advances in the treatment of glioblastoma multiforme in the past 40 years beyond surgery, radiotherapy, chemotherapy, and corticosteroids. For this reason a restrictive calorie ketogenic diet, similar to that used in children to control drug resistant seizure activity, has been advanced as an alternative adjunctive treatment to help prolonged survival. This article reviews the science of tumor metabolism and discusses the mechanism of calorie restriction, cellular energy metabolism, and how dietary induced ketosis can inhibit cancer cell's energy supply to slow tumor growth.

  14. Effects of Flavonoids from Food and Dietary Supplements on Glial and Glioblastoma Multiforme Cells.

    PubMed

    Vidak, Marko; Rozman, Damjana; Komel, Radovan

    2015-10-23

    Quercetin, catechins and proanthocyanidins are flavonoids that are prominently featured in foodstuffs and dietary supplements, and may possess anti-carcinogenic activity. Glioblastoma multiforme is the most dangerous form of glioma, a malignancy of the brain connective tissue. This review assesses molecular structures of these flavonoids, their importance as components of diet and dietary supplements, their bioavailability and ability to cross the blood-brain barrier, their reported beneficial health effects, and their effects on non-malignant glial as well as glioblastoma tumor cells. The reviewed flavonoids appear to protect glial cells via reduction of oxidative stress, while some also attenuate glutamate-induced excitotoxicity and reduce neuroinflammation. Most of the reviewed flavonoids inhibit proliferation of glioblastoma cells and induce their death. Moreover, some of them inhibit pro-oncogene signaling pathways and intensify the effect of conventional anti-cancer therapies. However, most of these anti-glioblastoma effects have only been observed in vitro or in animal models. Due to limited ability of the reviewed flavonoids to access the brain, their normal dietary intake is likely insufficient to produce significant anti-cancer effects in this organ, and supplementation is needed.

  15. Evaluation of the cytotoxic activity of Hypericum spp. on human glioblastoma A1235 and breast cancer MDA MB-231 cells.

    PubMed

    Madunić, Josip; Matulić, Maja; Friščić, Maja; Pilepić, Kroata Hazler

    2016-11-09

    Cytotoxic activity of 16 Hypericum ethanolic extracts was evaluated by MTT assay on two human cancer cell lines: glioblastoma A1235 and breast cancer MDA MB-231. Morphology and the type of induced cell death were determined using light and fluorescence microscopy. The majority of Hypericum extracts had no significant cytotoxic effect on MDA MB-231 cells. Eight extracts exhibited mild cytotoxic effect on A1235 cells after 24 h incubation, ranging from 8.0% (H. patulum) to 21.7% (H. oblongifolium). After 72 h of treatment, the strongest inhibition of A1235 viability was observed for extracts of H. androsaemum (26.4-43.9%), H. balearicum (25.8-36.3%), H. delphicum (14.8-27.4%) and H. densiflorum (11.2-24.1%). Micro-scopic examination of cells showed apoptosis as the dominant type of cell death. Due to observed high viability of treated cells, we propose that cytotoxic effects of Hypericum extracts could be related to alternations/interruptions in the cell cycle.

  16. Phenotypic and functional characterization of Glioblastoma cancer stem cells identified through 5-aminolevulinic acid-assisted surgery [corrected].

    PubMed

    Rampazzo, Elena; Della Puppa, Alessandro; Frasson, Chiara; Battilana, Giusy; Bianco, Sara; Scienza, Renato; Basso, Giuseppe; Persano, Luca

    2014-02-01

    5-aminolevulinic acid (5-ALA) introduction in the surgical management of Glioblastoma (GBM) enables the intra-operatively identification of cancer cells in the mass by means of fluorescence. Here, we analyzed the phenotype of GBM cells isolated from distinct tumour areas determined by 5-ALA (tumour core, 5-ALA intense and vague layers) and the potency of 5-ALA labelling in identifying GBM cells and cancer stem cells (CSCs) in the mass. 5-ALA identified distinct layers in the mass, with less differentiated cells residing in the core of the tumour. 5-ALA was able to stain up to 68.5% of CD133(+) cells in the 5-ALA intense layer and, although 5-ALA(+) cells retrieved from different tumour areas contained a similar proportion of CD133(+) cells (range 27.5-35.6%), those from the vague layer displayed the lowest ability to self-renew. In conclusion, our data demonstrate that a substantial amount of GBM cells and CSCs in the mass are able to avoid 5-ALA labelling and support the presence of heterogenic CSC populations in the GBM mass.

  17. Elucidating the cancer-specific genetic alteration spectrum of glioblastoma derived cell lines from whole exome and RNA sequencing

    PubMed Central

    Somasundaram, Kumaravel

    2015-01-01

    Cell lines derived from tumor tissues have been used as a valuable system to study gene regulation and cancer development. Comprehensive characterization of the genetic background of cell lines could provide clues on novel genes responsible for carcinogenesis and help in choosing cell lines for particular studies. Here, we have carried out whole exome and RNA sequencing of commonly used glioblastoma (GBM) cell lines (U87, T98G, LN229, U343, U373 and LN18) to unearth single nucleotide variations (SNVs), indels, differential gene expression, gene fusions and RNA editing events. We obtained an average of 41,071 SNVs out of which 1,594 (3.88%) were potentially cancer-specific. The cell lines showed frequent SNVs and indels in some of the genes that are known to be altered in GBM- EGFR, TP53, PTEN, SPTA1 and NF1. Chromatin modifying genes- ATRX, MLL3, MLL4, SETD2 and SRCAP also showed alterations. While no cell line carried IDH1 mutations, five cell lines showed hTERT promoter activating mutations with a concomitant increase in hTERT transcript levels. Five significant gene fusions were found of which NUP93-CYB5B was validated. An average of 18,949 RNA editing events was also obtained. Thus we have generated a comprehensive catalogue of genetic alterations for six GBM cell lines. PMID:26496030

  18. Therapeutic potential of cyclooxygenase-3 inhibitors in the management of glioblastoma.

    PubMed

    Oksuz, Ersoy; Atalar, Fatmahan; Tanırverdi, Gamze; Bilir, Ayahan; Shahzadi, Andleeb; Yazici, Zeliha

    2016-01-01

    In this study we investigated the expression of COX-1, COX-2 and COX-3 mRNA in C6 glioblastoma and normal brain tissues and the effects of acetaminophen, indomethacin or metamizole treatments on the development of C6 glioblastoma in relation with COX inhibition. Glioblastoma cells were inoculated intracerebrally into frontal lobe of adult male Wistar albino rats. 10 days after inoculation, rats were treated with 150 mg/kg acetaminophen, 10 mg/kg indomethacin or 150 mg/kg metamizole. The tumor size was measured histologically and total RNA was isolated from tumor or normal brain tissue and mRNA levels of COX isoforms were determined by qRT-PCR. Our results showed the presence of COX-1, COX-2 and COX-3 expressions in both C6 glioblastoma and normal brain tissues. In tumor tissues COX-3 expression was significantly higher than normal brain tissue (p < 0.05) while there was no significant difference in COX-1 and COX-2 expressions. Acetaminophen and indomethacin decreased the tumor size by 71 and 43 % by inhibiting COX-3 mRNA expression around 87 and 91 % respectively. For the first time our study proposes a possible relationship between COX-3 mRNA expression and C6 glioblastoma development. We also suggested that the inhibition of COX-3 enzyme may be responsible for decrease in tumor size in part, the mechanism by which acetaminophen and indomethacin decreased rat C6 glioblastoma growth. However, the molecular events responsible for COX-3 effects on tumor development are still unresolved as these drugs exert their anti-cancer effect via both COX-3 dependent and independent mechanisms.

  19. Radiation-induced glioblastoma signaling cascade regulates viability, apoptosis and differentiation of neural stem cells (NSC).

    PubMed

    Ivanov, Vladimir N; Hei, Tom K

    2014-12-01

    summary, intercellular communication between glioblastoma cells and bystander NSC/NPC could be involved in the amplification of cancer pathology in the brain.

  20. Radiation-induced glioblastoma signaling cascade regulates viability, apoptosis and differentiation of neural stem cells (NSC)

    PubMed Central

    Ivanov, Vladimir N.; Hei, Tom K.

    2015-01-01

    , intercellular communication between glioblastoma cells and bystander NSC/NPC could be involved in the amplification of cancer pathology in the brain. PMID:25273222

  1. Proscillaridin A is cytotoxic for glioblastoma cell lines and controls tumor xenograft growth in vivo

    PubMed Central

    Tchoghandjian, Aurélie; Carré, Manon; Colin, Carole; Jiglaire, Carine Jiguet; Mercurio, Sandy; Beclin, Christophe; Figarella-Branger, Dominique

    2014-01-01

    Glioblastoma is the most frequent primary brain tumor in adults. Because of molecular and cellular heterogeneity, high proliferation rate and significant invasive ability, prognosis of patients is poor. Recent therapeutic advances increased median overall survival but tumor recurrence remains inevitable. In this context, we used a high throughput screening approach to bring out novel compounds with anti-proliferative and anti-migratory properties for glioblastoma treatment. Screening of the Prestwick chemical library® of 1120 molecules identified proscillaridin A, a cardiac glycoside inhibitor of the Na+/K+ ATPase pump, with most significant effects on glioblastoma cell lines. In vitro effects of proscillaridin A were evaluated on GBM6 and GBM9 stem-like cell lines and on U87-MG and U251-MG cell lines. We showed that proscillaridin A displayed cytotoxic properties, triggered cell death, induced G2/M phase blockade in all the glioblastoma cell lines and impaired GBM stem self-renewal capacity even at low concentrations. Heterotopic and orthotopic xenotransplantations were used to confirm in vivo anticancer effects of proscillaridin A that both controls xenograft growth and improves mice survival. Altogether, results suggest that proscillaridin A is a promising candidate as cancer therapies in glioblastoma. This sustains previous reports showing that cardiac glycosides act as anticancer drugs in other cancers. PMID:25400117

  2. Hematopoietic stem cells as a tool for the treatment of glioblastoma multiforme

    PubMed Central

    Bryukhovetskiy, Igor S.; Dyuizen, Inessa V.; Shevchenko, Valeriy E.; Bryukhovetskiy, Andrey S.; Mischenko, Polina V.; Milkina, Elena V.; Khotimchenko, Yuri S.

    2016-01-01

    Glioblastoma multiforme is an aggressive malignant brain tumor with terminal consequences. A primary reason for its resistance to treatment is associated with cancer stem cells (CSCs), of which there are currently no effective ways to destroy. It remains unclear what cancer cells become a target of stem cell migration, what the role of this process is in oncogenesis and what stem cell lines should be used in developing antitumor technologies. Using modern post-genome technologies, the present study investigated the migration of human stem cells to cancer cells in vitro, the comparative study of cell proteomes of certain stem cells (including CSCs) was conducted and stem cell migration in vivo was examined. Of all glioblastoma cells, CSCs have the stability to attract normal stem cells. Critical differences in cell proteomes allow the consideration of hematopoietic stem cells (HSCs) as an instrument for interaction with glioblastoma CSCs. Following injection into the bloodstream of animals with glioblastoma, the majority of HSCs migrated to the tumor-containing brain hemisphere and penetrated the tumor tissue. HSCs therefore are of potential use in the development of methods to target CSCs. PMID:27748891

  3. MicroRNA-34a targets notch1 and inhibits cell proliferation in glioblastoma multiforme.

    PubMed

    Li, Wen-Bo; Ma, Min-Wang; Dong, Li-Jie; Wang, Fei; Chen, Lu-Xia; Li, Xiao-Rong

    2011-09-15

    Aberrant expression of microRNAs (miRNAs) has been implicated in cancer initiation and progression. In this study, we found that microRNA-34a (miR-34a) is significantly downregulated in glioblastoma multiforme (GBM) specimens compared with normal brain tissues. Growth curve and colony formation assays revealed that miR-34a suppresses proliferation of U373MG and SHG44 glioblastoma cells. Overexpression of miR-34a could induce apoptosis of glioblastoma cells. Also, we identified notch1 as a direct target gene of miR-34a. Knockdown of notch1 showed similar cellular functions as overexpression of miR-34a both in vitro and in vivo. Collectively, our findings show that miR-34a is downregulated in GBM cells and inhibits GBM growth by targeting notch1.

  4. Real-time visualization of nanoparticles interacting with glioblastoma stem cells.

    PubMed

    Pohlmann, Elliot S; Patel, Kaya; Guo, Sujuan; Dukes, Madeline J; Sheng, Zhi; Kelly, Deborah F

    2015-04-08

    Nanoparticle-based therapy represents a novel and promising approach to treat glioblastoma, the most common and lethal malignant brain cancer. Although similar therapies have achieved significant cytotoxicity in cultured glioblastoma or glioblastoma stem cells (GSCs), the lack of an appropriate approach to monitor interactions between cells and nanoparticle-based therapies impedes their further clinical application in human patients. To address this critical issue, we first obtained NOTCH1 positive GSCs from patient-derived primary cultures. We then developed a new imaging approach to directly observe the dynamic nature of nanoparticles at the molecular level using in situ transmission electron microscopy (TEM). Utilizing these tools we were able to visualize real-time movements of nanoparticles interacting with GSCs for the first time. Overall, we show strong proof-of-concept results that real-time visualization of nanoparticles in single cells can be achieved at the nanoscale using TEM, thereby providing a powerful platform for the development of nanotherapeutics.

  5. Tumor treating fields therapy device for glioblastoma: physics and clinical practice considerations.

    PubMed

    Lok, Edwin; Swanson, Kenneth D; Wong, Eric T

    2015-01-01

    Alternating electric fields therapy, as delivered by the tumor treating fields device, is a new modality of cancer treatment that has been approved by the US FDA for recurrent glioblastoma. At a frequency of 200 kHz, these fields emanate from transducer arrays on the surface of the patient's scalp into the brain and perturb processes necessary for cytokinesis during tumor cell mitosis. In the registration Phase III trial for recurrent glioblastoma patients, the efficacy of the tumor treating fields as monotherapy was equivalent to chemotherapy, while scalp irritation was its major adverse event compared with systemic toxicities that were associated with cytotoxic chemotherapies. Alternating electric fields therapy is, therefore, an essential option for the treatment of recurrent glioblastoma. Here, we summarize our current knowledge of the physics, cell biology and clinical data supporting the use of the tumor treating fields therapy.

  6. MicroRNA-132 induces temozolomide resistance and promotes the formation of cancer stem cell phenotypes by targeting tumor suppressor candidate 3 in glioblastoma.

    PubMed

    Cheng, Zhen-Xiu; Yin, Wen-Bo; Wang, Zhong-Yu

    2017-09-07

    The prognosis of patients suffering from glioblastoma [also referred to as glioblastoma multiforme (GBM)] is dismal despite multimodal therapy. Chemotherapy with temozolomide may suppress tumor growth for a certain period of time (a few months); however, invariable tumor recurrence suggests that glioblastoma initiating cells (GICs) render these tumors persistant. Thus, the understanding of the molecular mechanisms of action of GICs as regards their role in the progression of GBM is important as such knowledge will be helpful in the discovery of novel drug targets, as well as in the design of novel therapeutic strategies for more effective treatment of the disease. In this study, we found that tumor suppressor candidate 3 (TUSC3) was downregulated in temozolomide-resistant U87MG cells (U87MG-res cells) and its restoration sensitized U87MG-res cells to temozolomide. TUSC3 was able to inhibit the formation of GIC phenotypes in the U87MG-res cells. The overexpression of microRNA (miR)‑132 inhibited TUSC3 protein expression in the U87MG cells. However, its overexpression did not degrade TUSC3 mRNA expression in the cells. miR‑132 was upregulated in the U87MG-res cells and its overexpression induced temozolomide resistance and the formation of cancer stem cell phenotypes in the U87MG cells. Thus, our data indicate that miR-132 induces temozolomide resistance and promotes the formation of cancer stem cell phenotypes by targeting TUSC3 in glioblastoma.

  7. Glioblastoma Circulating Cells: Reality, Trap or Illusion?

    PubMed Central

    Lombard, A.; Goffart, N.; Rogister, B.

    2015-01-01

    Metastases are the hallmark of cancer. This event is in direct relationship with the ability of cancer cells to leave the tumor mass and travel long distances within the bloodstream and/or lymphatic vessels. Glioblastoma multiforme (GBM), the most frequent primary brain neoplasm, is mainly characterized by a dismal prognosis. The usual fatal issue for GBM patients is a consequence of local recurrence that is observed most of the time without any distant metastases. However, it has recently been documented that GBM cells could be isolated from the bloodstream in several studies. This observation raises the question of the possible involvement of glioblastoma-circulating cells in GBM deadly recurrence by a “homing metastasis” process. Therefore, we think it is important to review the already known molecular mechanisms underlying circulating tumor cells (CTC) specific properties, emphasizing their epithelial to mesenchymal transition (EMT) abilities and their possible involvement in tumor initiation. The idea is here to review these mechanisms and speculate on how relevant they could be applied in the forthcoming battles against GBM. PMID:26078762

  8. Decoding brain cancer dynamics: a quantitative histogram-based approach using temporal MRI

    NASA Astrophysics Data System (ADS)

    Zhou, Mu; Hall, Lawrence O.; Goldgof, Dmitry B.; Russo, Robin; Gillies, Robert J.; Gatenby, Robert A.

    2015-03-01

    Brain tumor heterogeneity remains a challenge for probing brain cancer evolutionary dynamics. In light of evolution, it is a priority to inspect the cancer system from a time-domain perspective since it explicitly tracks the dynamics of cancer variations. In this paper, we study the problem of exploring brain tumor heterogeneity from temporal clinical magnetic resonance imaging (MRI) data. Our goal is to discover evidence-based knowledge from such temporal imaging data, where multiple clinical MRI scans from Glioblastoma multiforme (GBM) patients are generated during therapy. In particular, we propose a quantitative histogram-based approach that builds a prediction model to measure the difference in histograms obtained from pre- and post-treatment. The study could significantly assist radiologists by providing a metric to identify distinctive patterns within each tumor, which is crucial for the goal of providing patient-specific treatments. We examine the proposed approach for a practical application - clinical survival group prediction. Experimental results show that our approach achieved 90.91% accuracy.

  9. Seniors with Brain Cancer May Have Better Treatment Option

    MedlinePlus

    ... page: https://medlineplus.gov/news/fullstory_164102.html Seniors With Brain Cancer May Have Better Treatment Option ... More Health News on: Brain Tumors Cancer Chemotherapy Seniors' Health Recent Health News Related MedlinePlus Health Topics ...

  10. Study Casts Doubt on A Brain Cancer's Link to Herpes

    MedlinePlus

    ... between a common type of herpes virus and aggressive brain cancers, according to a new study that ... researchers analyzed tumor tissue from 125 patients with aggressive brain cancers called gliomas. Ninety-nine of the ...

  11. Highly penetrative, drug-loaded nanocarriers improve treatment of glioblastoma.

    PubMed

    Zhou, Jiangbing; Patel, Toral R; Sirianni, Rachael W; Strohbehn, Garth; Zheng, Ming-Qiang; Duong, Nha; Schafbauer, Thomas; Huttner, Anita J; Huang, Yiyun; Carson, Richard E; Zhang, Ying; Sullivan, David J; Piepmeier, Joseph M; Saltzman, W Mark

    2013-07-16

    Current therapy for glioblastoma multiforme is insufficient, with nearly universal recurrence. Available drug therapies are unsuccessful because they fail to penetrate through the region of the brain containing tumor cells and they fail to kill the cells most responsible for tumor development and therapy resistance, brain cancer stem cells (BCSCs). To address these challenges, we combined two major advances in technology: (i) brain-penetrating polymeric nanoparticles that can be loaded with drugs and are optimized for intracranial convection-enhanced delivery and (ii) repurposed compounds, previously used in Food and Drug Administration-approved products, which were identified through library screening to target BCSCs. Using fluorescence imaging and positron emission tomography, we demonstrate that brain-penetrating nanoparticles can be delivered to large intracranial volumes in both rats and pigs. We identified several agents (from Food and Drug Administration-approved products) that potently inhibit proliferation and self-renewal of BCSCs. When loaded into brain-penetrating nanoparticles and administered by convection-enhanced delivery, one of these agents, dithiazanine iodide, significantly increased survival in rats bearing BCSC-derived xenografts. This unique approach to controlled delivery in the brain should have a significant impact on treatment of glioblastoma multiforme and suggests previously undescribed routes for drug and gene delivery to treat other diseases of the central nervous system.

  12. Optimization of Glioblastoma Mouse Orthotopic Xenograft Models for Translational Research.

    PubMed

    Irtenkauf, Susan M; Sobiechowski, Susan; Hasselbach, Laura A; Nelson, Kevin K; Transou, Andrea D; Carlton, Enoch T; Mikkelsen, Tom; deCarvalho, Ana C

    2017-08-01

    Glioblastoma is an aggressive primary brain tumor predominantly localized to the cerebral cortex. We developed a panel of patient-derived mouse orthotopic xenografts (PDOX) for preclinical drug studies by implanting cancer stem cells (CSC) cultured from fresh surgical specimens intracranially into 8-wk-old female athymic nude mice. Here we optimize the glioblastoma PDOX model by assessing the effect of implantation location on tumor growth, survival, and histologic characteristics. To trace the distribution of intracranial injections, toluidine blue dye was injected at 4 locations with defined mediolateral, anterioposterior, and dorsoventral coordinates within the cerebral cortex. Glioblastoma CSC from 4 patients and a glioblastoma nonstem-cell line were then implanted by using the same coordinates for evaluation of tumor location, growth rate, and morphologic and histologic features. Dye injections into one of the defined locations resulted in dye dissemination throughout the ventricles, whereas tumor cell implantation at the same location resulted in a much higher percentage of small multifocal ventricular tumors than did the other 3 locations tested. Ventricular tumors were associated with a lower tumor growth rate, as measured by in vivo bioluminescence imaging, and decreased survival in 4 of 5 cell lines. In addition, tissue oxygenation, vasculature, and the expression of astrocytic markers were altered in ventricular tumors compared with nonventricular tumors. Based on this information, we identified an optimal implantation location that avoided the ventricles and favored cortical tumor growth. To assess the effects of stress from oral drug administration, mice that underwent daily gavage were compared with stress-positive and -negative control groups. Oral gavage procedures did not significantly affect the survival of the implanted mice or physiologic measurements of stress. Our findings document the importance of optimization of the implantation site for

  13. Low Incidence along with Low mRNA Levels of EGFR(vIII) in Prostate and Colorectal Cancers Compared to Glioblastoma.

    PubMed

    Peciak, Joanna; Stec, Wojciech J; Treda, Cezary; Ksiazkiewicz, Magdalena; Janik, Karolina; Popeda, Marta; Smolarz, Maciej; Rosiak, Kamila; Hulas-Bigoszewska, Krystyna; Och, Waldemar; Rieske, Piotr; Stoczynska-Fidelus, Ewelina

    2017-01-01

    Background: The presence as well as the potential role of EGFR(vIII) in tumors other than glioblastoma still remains a controversial subject with many contradictory data published. Previous analyses, however, did not consider the level of EGFR(vIII) mRNA expression in different tumor types. Methods: Appropriately designed protocol for Real-time quantitative reverse-transcription PCR (Real-time qRT-PCR) was applied to analyze EGFR(vIII) and EGFR(WT) mRNA expression in 155 tumor specimens. Additionally, Western Blot (WB) analysis was performed for selected samples. Stable cell lines showing EGFR(vIII) expression (CAS-1 and DK-MG) were analyzed by means of WB, immunocytochemistry (ICC) and fluorescence in situ hybridization (FISH). Results: Our analyses revealed EGFR(vIII) expression in 27.59% of glioblastomas (8/29), 8.11% of colorectal cancers (3/37), 6.52% of prostate cancers (3/46) and none of breast cancers (0/43). Despite the average relative expression of EGFR(vIII) varying greatly among tumors of different tissues (approximately 800-fold) or even within the same tissue group (up to 8000-fold for GB), even the marginal expression of EGFR(vIII) mRNA can be detrimental to cancer progression, as determined by the analysis of stable cell lines endogenously expressing the oncogene. Conclusion: EGFR(vIII) plays an unquestionable role in glioblastomas with high expression of this oncogene. Our data suggests that EGFR(vIII) importance should not be underestimated even in tumors with relatively low expression of this oncogene.

  14. Low Incidence along with Low mRNA Levels of EGFRvIII in Prostate and Colorectal Cancers Compared to Glioblastoma

    PubMed Central

    Peciak, Joanna; Stec, Wojciech J; Treda, Cezary; Ksiazkiewicz, Magdalena; Janik, Karolina; Popeda, Marta; Smolarz, Maciej; Rosiak, Kamila; Hulas-Bigoszewska, Krystyna; Och, Waldemar; Rieske, Piotr; Stoczynska-Fidelus, Ewelina

    2017-01-01

    Background: The presence as well as the potential role of EGFRvIII in tumors other than glioblastoma still remains a controversial subject with many contradictory data published. Previous analyses, however, did not consider the level of EGFRvIII mRNA expression in different tumor types. Methods: Appropriately designed protocol for Real-time quantitative reverse-transcription PCR (Real-time qRT-PCR) was applied to analyze EGFRvIII and EGFRWT mRNA expression in 155 tumor specimens. Additionally, Western Blot (WB) analysis was performed for selected samples. Stable cell lines showing EGFRvIII expression (CAS-1 and DK-MG) were analyzed by means of WB, immunocytochemistry (ICC) and fluorescence in situ hybridization (FISH). Results: Our analyses revealed EGFRvIII expression in 27.59% of glioblastomas (8/29), 8.11% of colorectal cancers (3/37), 6.52% of prostate cancers (3/46) and none of breast cancers (0/43). Despite the average relative expression of EGFRvIII varying greatly among tumors of different tissues (approximately 800-fold) or even within the same tissue group (up to 8000-fold for GB), even the marginal expression of EGFRvIII mRNA can be detrimental to cancer progression, as determined by the analysis of stable cell lines endogenously expressing the oncogene. Conclusion: EGFRvIII plays an unquestionable role in glioblastomas with high expression of this oncogene. Our data suggests that EGFRvIII importance should not be underestimated even in tumors with relatively low expression of this oncogene. PMID:28123609

  15. Patterns of care and predictors of adjuvant therapies in elderly patients with glioblastoma: An analysis of the National Cancer Data Base.

    PubMed

    Amsbaugh, Mark J; Yusuf, Mehran B; Gaskins, Jeremy; Burton, Eric C; Woo, Shiao Y

    2017-09-01

    The objectives of this study were to characterize patterns of care and to identify predictors for adjuvant therapy in elderly patients with glioblastoma in the modern era. The National Cancer Data Base was queried for patients aged 70 years and older with glioblastoma diagnosed from January 1, 2004 through December 31, 2012. Multinomial logistic regression was used to identify predictors for receiving adjuvant therapy. Survival outcomes were estimated using the Kaplan-Meier method and were analyzed using Cox regression models and the log-rank test. In total, 14,886 patients were identified. Of these, 8214 patients (55.2%) received combined-modality therapy with chemotherapy and radiation (CRT), 3955 (26.6%) received no adjuvant therapy, 2065 (13.9%) received radiation therapy (RT) alone, and 652 (4.4%) received chemotherapy (CT) alone after undergoing resection. The receipt of CRT increased in frequency over the study interval, from 40.3% in 2004 to 59.8% in 2012. Younger patients (ages 70-75 years) were more likely to receive CRT than no adjuvant therapy (P < .0001 for all other age groups) or adjuvant RT alone (P < .0001 for all other age groups). Combined-modality therapy with adjuvant CRT produced improved survival outcomes, and the highest median overall survival was 9.2 months. In this analysis of elderly patients who had glioblastoma diagnosed from 2004 through 2012, a significant increase in the receipt of combined-modality therapy was observed. Combined-modality treatment produces improved survival outcomes and should be considered as adjuvant treatment for carefully selected elderly patients. Cancer 2017;123:3277-84. © 2017 American Cancer Society. © 2017 American Cancer Society.

  16. Second Generation Amphiphilic Poly-Lysine Dendrons Inhibit Glioblastoma Cell Proliferation without Toxicity for Neurons or Astrocytes

    PubMed Central

    Janiszewska, Jolanta; Posadas, Inmaculada; Játiva, Pablo; Bugaj-Zarebska, Marta; Urbanczyk-Lipkowska, Zofia; Ceña, Valentín

    2016-01-01

    Glioblastomas are the most common malignant primary brain tumours in adults and one of the most aggressive and difficult-to-treat cancers. No effective treatment exits actually for this tumour and new therapeutic approaches are needed for this disease. One possible innovative approach involves the nanoparticle-mediated specific delivery of drugs and/or genetic material to glioblastoma cells where they can provide therapeutic benefits. In the present work, we have synthesised and characterised several second generation amphiphilic polylysine dendrons to be used as siRNA carriers. We have found that, in addition to their siRNA binding properties, these new compounds inhibit the proliferation of two glioblastoma cell lines while being nontoxic for non-tumoural central nervous system cells like neurons and glia, cell types that share the anatomical space with glioblastoma cells during the course of the disease. The selective toxicity of these nanoparticles to glioblastoma cells, as compared to neurons and glial cells, involves mitochondrial depolarisation and reactive oxygen species production. This selective toxicity, together with the ability to complex and release siRNA, suggests that these new polylysine dendrons might offer a scaffold in the development of future nanoparticles designed to restrict the proliferation of glioblastoma cells. PMID:27832093

  17. Enhanced expression of proapoptotic and autophagic proteins involved in the cell death of glioblastoma induced by synthetic glycans.

    PubMed

    Faried, Ahmad; Arifin, Muhammad Zafrullah; Ishiuchi, Shogo; Kuwano, Hiroyuki; Yazawa, Shin

    2014-06-01

    Glioblastoma is the most aggressive malignant brain tumor, and overall patient survival has not been prolonged even by conventional therapies. Previously, the authors found that chemically synthesized glycans could be anticancer agents against growth of a series of cancer cells. In this study, the authors examined the effects of glycans on the growth of glioblastoma cells both in vitro and in vivo. The authors investigated not only the occurrence of changes in the cell signaling molecules and expression levels of various proteins related to cell death, but also a mouse model involving the injection of glioblastoma cells following the administration of synthetic glycans. Synthetic glycans inhibited the growth of glioblastoma cells, induced the apoptosis of the cells with cleaved poly (adenosine diphosphate-ribose) polymerase (PARP) expression and DNA fragmentation, and also caused autophagy, as shown by the detection of autophagosome proteins and monodansylcadaverine staining. Furthermore, tumor growth in the in vivo mouse model was significantly inhibited. A dramatic induction of programmed cell death was found in glioblastoma cells after treatment with synthetic glycans. These results suggest that synthetic glycans could be a promising novel anticancer agent for performing chemotherapy against glioblastoma.

  18. Brain Tumor’s Radioresistance: The Neighborhood Helps | Center for Cancer Research

    Cancer.gov

    Glioblastoma (GBM) is the most common and most aggressive form of brain cancer. The primary treatment for GBM is radiation therapy. Unfortunately, while some patients initially respond, the vast majority of GBM patients fail radiotherapy, and the tumor usually grows back within two years. To gain a better understanding of the biological basis for GBM resistance to radiation, researchers initially studied GBM cell lines in vitro. In recent years, the focus has been on so-called tumor stem-like cells (TSCs), which are thought to be responsible for driving and maintaining tumor growth. To the researchers’ surprise, TSCs grown in vitro did not have the same ability to resist radiation as TSCs in the GBM tumors.

  19. Microenvironmental Modulation of Decorin and Lumican in Temozolomide-Resistant Glioblastoma and Neuroblastoma Cancer Stem-Like Cells

    PubMed Central

    Melguizo, Consolacion; Alvarez, Pablo; Bandiera, Pasquale; Rama, Ana Rosa; Malaguarnera, Giulia; Ortiz, Raul; Madeddu, Roberto; Prados, Jose

    2015-01-01

    The presence of cancer stem cells (CSCs) or tumor-initiating cells can lead to cancer recurrence in a permissive cell–microenvironment interplay, promoting invasion in glioblastoma (GBM) and neuroblastoma (NB). Extracellular matrix (ECM) small leucine-rich proteoglycans (SLRPs) play multiple roles in tissue homeostasis by remodeling the extracellular matrix (ECM) components and modulating intracellular signaling pathways. Due to their pan-inhibitory properties against receptor tyrosine kinases (RTKs), SLRPs are reported to exert anticancer effects in vitro and in vivo. However, their roles seem to be tissue-specific and they are also involved in cancer cell migration and drug resistance, paving the way to complex different scenarios. The aim of this study was to determine whether the SLRPs decorin (DCN) and lumican (LUM) are recruited in cell plasticity and microenvironmental adaptation of differentiated cancer cells induced towards stem-like phenotype. Floating neurospheres were generated by applying CSC enrichment medium (neural stem cell serum-free medium, NSC SFM) to the established SF-268 and SK-N-SH cancer cell lines, cellular models of GBM and NB, respectively. In both models, the time-dependent synergistic activation of DCN and LUM was observed. The highest DCN and LUM mRNA/protein expression was detected after cell exposure to NSC SFM for 8/12 days, considering these cells as SLRP-expressing (SLRP+) CSC-like. Ultrastructural imaging showed the cellular heterogeneity of both the GBM and NB neurospheres and identified the inner living cells. Parental cell lines of both GBM and NB grew only in soft agar + NSC SFM, whereas the secondary neurospheres (originated from SLRP+ t8 CSC-like) showed lower proliferation rates than primary neurospheres. Interestingly, the SLRP+ CSC-like from the GBM and NB neurospheres were resistant to temozolomide (TMZ) at concentrations >750 μM. Our results suggest that GBM and NB CSC-like promote the activation of huge quantities

  20. Incorporating Cancer Stem Cells in Radiation Therapy Treatment Response Modeling and the Implication in Glioblastoma Multiforme Treatment Resistance

    SciTech Connect

    Yu, Victoria Y.; Nguyen, Dan; Pajonk, Frank; Kupelian, Patrick; Kaprealian, Tania; Selch, Michael; Low, Daniel A.; Sheng, Ke

    2015-03-15

    Purpose: To perform a preliminary exploration with a simplistic mathematical cancer stem cell (CSC) interaction model to determine whether the tumor-intrinsic heterogeneity and dynamic equilibrium between CSCs and differentiated cancer cells (DCCs) can better explain radiation therapy treatment response with a dual-compartment linear-quadratic (DLQ) model. Methods and Materials: The radiosensitivity parameters of CSCs and DCCs for cancer cell lines including glioblastoma multiforme (GBM), non–small cell lung cancer, melanoma, osteosarcoma, and prostate, cervical, and breast cancer were determined by performing robust least-square fitting using the DLQ model on published clonogenic survival data. Fitting performance was compared with the single-compartment LQ (SLQ) and universal survival curve models. The fitting results were then used in an ordinary differential equation describing the kinetics of DCCs and CSCs in response to 2- to 14.3-Gy fractionated treatments. The total dose to achieve tumor control and the fraction size that achieved the least normal biological equivalent dose were calculated. Results: Smaller cell survival fitting errors were observed using DLQ, with the exception of melanoma, which had a low α/β = 0.16 in SLQ. Ordinary differential equation simulation indicated lower normal tissue biological equivalent dose to achieve the same tumor control with a hypofractionated approach for 4 cell lines for the DLQ model, in contrast to SLQ, which favored 2 Gy per fraction for all cells except melanoma. The DLQ model indicated greater tumor radioresistance than SLQ, but the radioresistance was overcome by hypofractionation, other than the GBM cells, which responded poorly to all fractionations. Conclusion: The distinct radiosensitivity and dynamics between CSCs and DCCs in radiation therapy response could perhaps be one possible explanation for the heterogeneous intertumor response to hypofractionation and in some cases superior outcome from

  1. Elimination of cancer stem-like cells and potentiation of temozolomide sensitivity by Honokiol in glioblastoma multiforme cells.

    PubMed

    Lai, I-Chun; Shih, Ping-Hsiao; Yao, Chih-Jung; Yeh, Chi-Tai; Wang-Peng, Jacqueline; Lui, Tai-Ngar; Chuang, Suang-En; Hu, Tsai-Shu; Lai, Tung-Yuan; Lai, Gi-Ming

    2015-01-01

    Glioblastoma multiforme (GBM) is the most common adult malignant glioma with poor prognosis due to the resistance to radiotherapy and chemotherapy, which might be critically involved in the repopulation of cancer stem cells (CSCs) after treatment. We had investigated the characteristics of cancer stem-like side population (SP) cells sorted from GBM cells, and studied the effect of Honokiol targeting on CSCs. GBM8401 SP cells possessed the stem cell markers, such as nestin, CD133 and Oct4, and the expressions of self-renewal related stemness genes, such as SMO, Notch3 and IHH (Indian Hedgehog). Honokiol inhibited the proliferation of both GBM8401 parental cells and SP cells in a dose-dependent manner, the IC50 were 5.3±0.72 and 11±1.1 μM, respectively. The proportions of SP in GBM8401 cells were diminished by Honokiol from 1.5±0.22% down to 0.3±0.02% and 0.2±0.01% at doses of 2.5 μM and 5 μM, respectively. The SP cells appeared to have higher expression of O6-methylguanine-DNA methyltransferase (MGMT) and be more resistant to Temozolomide (TMZ). The resistance to TMZ could be only slightly reversed by MGMT inhibitor O6-benzylguanine (O6-BG), but markedly further enhanced by Honokiol addition. Such significant enhancement was accompanied with the higher induction of apoptosis, greater down-regulation of Notch3 as well as its downstream Hes1 expressions in SP cells. Our data indicate that Honokiol might have clinical benefits for the GBM patients who are refractory to TMZ treatment.

  2. Inhibition of the Autophagy Pathway Synergistically Potentiates the Cytotoxic Activity of Givinostat (ITF2357) on Human Glioblastoma Cancer Stem Cells

    PubMed Central

    Angeletti, Francesca; Fossati, Gianluca; Pattarozzi, Alessandra; Würth, Roberto; Solari, Agnese; Daga, Antonio; Masiello, Irene; Barbieri, Federica; Florio, Tullio; Comincini, Sergio

    2016-01-01

    Increasing evidence highlighted the role of cancer stem cells (CSCs) in the development of tumor resistance to therapy, particularly in glioblastoma (GBM). Therefore, the development of new therapies, specifically directed against GBM CSCs, constitutes an important research avenue. Considering the extended range of cancer-related pathways modulated by histone acetylation/deacetylation processes, we studied the anti-proliferative and pro-apoptotic efficacy of givinostat (GVS), a pan-histone deacetylase inhibitor, on cell cultures enriched in CSCs, isolated from nine human GBMs. We report that GVS induced a significant reduction of viability and self-renewal ability in all GBM CSC cultures; conversely, GVS exposure did not cause a significant cytotoxic activity toward differentiated GBM cells and normal mesenchymal human stem cells. Analyzing the cellular and molecular mechanisms involved, we demonstrated that GVS affected CSC viability through the activation of programmed cell death pathways. In particular, a marked stimulation of macroautophagy was observed after GVS treatment. To understand the functional link between GVS treatment and autophagy activation, different genetic and pharmacological interfering strategies were used. We show that the up-regulation of the autophagy process, obtained by deprivation of growth factors, induced a reduction of CSC sensitivity to GVS, while the pharmacological inhibition of the autophagy pathway and the silencing of the key autophagy gene ATG7, increased the cell death rate induced by GVS. Altogether these findings suggest that autophagy represents a pro-survival mechanism activated by GBM CSCs to counteract the efficacy of the anti-proliferative activity of GVS. In conclusion, we demonstrate that GVS is a novel pharmacological tool able to target GBM CSC viability and its efficacy can be enhanced by autophagy inhibitory strategies. PMID:27833530

  3. Elimination of Cancer Stem-Like Cells and Potentiation of Temozolomide Sensitivity by Honokiol in Glioblastoma Multiforme Cells

    PubMed Central

    Lai, I-Chun; Shih, Ping-Hsiao; Yao, Chih-Jung; Yeh, Chi-Tai; Wang-Peng, Jacqueline; Lui, Tai-Ngar; Chuang, Suang-En; Hu, Tsai-Shu; Lai, Tung-Yuan; Lai, Gi-Ming

    2015-01-01

    Glioblastoma multiforme (GBM) is the most common adult malignant glioma with poor prognosis due to the resistance to radiotherapy and chemotherapy, which might be critically involved in the repopulation of cancer stem cells (CSCs) after treatment. We had investigated the characteristics of cancer stem-like side population (SP) cells sorted from GBM cells, and studied the effect of Honokiol targeting on CSCs. GBM8401 SP cells possessed the stem cell markers, such as nestin, CD133 and Oct4, and the expressions of self-renewal related stemness genes, such as SMO, Notch3 and IHH (Indian Hedgehog). Honokiol inhibited the proliferation of both GBM8401 parental cells and SP cells in a dose-dependent manner, the IC50 were 5.3±0.72 and 11±1.1 μM, respectively. The proportions of SP in GBM8401 cells were diminished by Honokiol from 1.5±0.22% down to 0.3±0.02% and 0.2±0.01% at doses of 2.5 μM and 5 μM, respectively. The SP cells appeared to have higher expression of O6-methylguanine-DNA methyltransferase (MGMT) and be more resistant to Temozolomide (TMZ). The resistance to TMZ could be only slightly reversed by MGMT inhibitor O6-benzylguanine (O6-BG), but markedly further enhanced by Honokiol addition. Such significant enhancement was accompanied with the higher induction of apoptosis, greater down-regulation of Notch3 as well as its downstream Hes1 expressions in SP cells. Our data indicate that Honokiol might have clinical benefits for the GBM patients who are refractory to TMZ treatment. PMID:25763821

  4. BAG3 Protein Is Overexpressed in Human Glioblastoma and Is a Potential Target for Therapy

    PubMed Central

    Festa, Michelina; Del Valle, Luis; Khalili, Kamel; Franco, Renato; Scognamiglio, Giosuè; Graziano, Vincenzo; De Laurenzi, Vincenzo; Turco, Maria Caterina; Rosati, Alessandra

    2011-01-01

    Glioblastoma multiforme, which represents 80% of malignant gliomas, is characterized by aggressiveness and high recurrence rates. Despite therapeutic advances, patients with glioblastoma multiforme show a poor survival, and identification of novel markers and molecular targets for therapy is needed. A role for BAG3, a member of the BAG family of HSC/HSP70 co-chaperones, in promoting tumor cell growth in vivo has recently been described. We analyzed BAG3 levels by IHC in specimens from patients affected by brain tumors and we found that BAG3, although negative in normal brain tissues, was highly expressed in astrocytic tumors and increasingly expressed in more aggressive types of cancer; it was particularly high in glioblastomas. Down-regulating BAG3 both in vitro and in vivo in a rat glioblastoma model resulted in increased sensitivity to apoptosis, suggesting that BAG3 is a potential target for novel therapies. Finally, we determined that the underlying molecular mechanism requires the formation of a complex of BAG3, HSP70, and BAX that prevents BAX translocation to mitochondria, thus protecting tumor cells from apoptosis. Our data identify BAG3 as a potential marker of glial brain tumor sensitivity to therapy and thus also an attractive candidate for new molecular therapies. PMID:21561597

  5. Narciclasine as well as other Amaryllidaceae isocarbostyrils are promising GTP-ase targeting agents against brain cancers.

    PubMed

    Van Goietsenoven, Gwendoline; Mathieu, Véronique; Lefranc, Florence; Kornienko, Alexander; Evidente, Antonio; Kiss, Robert

    2013-03-01

    The anticancer activity of Amaryllidaceae isocarbostyrils is well documented. At pharmacological concentrations, that is, approximately 1 μM in vitro and approximately 10 mg/kg in vivo, narciclasine displays marked proapoptotic and cytotoxic activity, as does pancratistatin, and significant in vivo anticancer effects in various experimental models, but it is also associated with severe toxic side effects. At physiological doses, that is, approximately 50 nM in vitro and approximately 1 mg/kg in vivo, narciclasine is not cytotoxic but cytostatic and displays marked anticancer activity in vivo in experimental models of brain cancer (including gliomas and brain metastases), but it is not associated with toxic side effects. The cytostatic activity of narciclasine involves the impairment of actin cytoskeleton organization by targeting GTPases, including RhoA and the elongation factor eEF1A. We have demonstrated that chronic treatments of narciclasine (1 mg/kg) significantly increased the survival of immunodeficient mice orthotopically xenografted with highly invasive human glioblastomas and apoptosis-resistant brain metastases, including melanoma- and non-small-cell-lung cancer- (NSCLC) related brain metastases. Thus, narciclasine is a potentially promising agent for the treatment of primary brain cancers and various brain metastases. To date, efforts to develop synthetic analogs with anticancer properties superior to those of narciclasine have failed; thus, research efforts are now focused on narciclasine prodrugs.

  6. Negative prognostic effect of low nuclear GLI1 expression in glioblastomas.

    PubMed

    Kim, Yuil; Do, In-Gu; Hong, Mineui; Suh, Yeon-Lim

    2017-05-01

    The hedgehog signaling plays supportive roles in various aspects of tumorigenesis. Increased expression of the key component, GLI1, has been shown to correlate with poor prognosis in many types of cancers. We aimed to investigate the effect of GLI1 expression in glioblastoma focusing on the nuclear localization. Immunohistochemistry for GLI1, GLI2, PTCH1, SMO, and SHH were done in 140 glioblastoma tissues, and the staining was graded. For GLI1, nuclear and cytoplasmic expression was separately assessed. No significant correlation was found between clinicopathologic parameters and expression grades of the five proteins. Low nuclear GLI1 expression was associated with a worse progression-free survival while overall survival was not significantly affected. In contrast, cytoplasmic GLI1 expression did not have a prognostic effect. PTCH1 expression correlated with nuclear GLI1 expression without exerting a significant prognostic effect. Analysis of the TCGA-glioblastoma dataset revealed that low GLI1 mRNA level also correlated with a poor prognosis for both overall and progression-free survival. The adverse effect of low nuclear GLI1 expression in glioblastomas is in contrast with the negative prognostic effect of high GLI1 expression reported in non-cranial malignancies. The relative impact of hedgehog signaling among other oncogenic pathways in the brain may be responsible for the difference. The different implication of GLI1 expression in glioblastomas needs to be considered in studies of hedgehog signaling-targeted therapy.

  7. End of life care for glioblastoma patients at a large academic cancer center.

    PubMed

    Kuchinad, Kamini E; Strowd, Roy; Evans, Anne; Riley, W Anthony; Smith, Thomas J

    2017-08-01

    Glioblastoma (GBM) is a universally fatal disease, complicated by significant cognitive and physical disabilities, inherent to the disease course. The purpose of this study was to retrospectively analyze end-of-life care for GBM patients at an academic center and compare utilization of these services to national quality of care guidelines, with the goal of identifying opportunities to improve end-of-life care. Single center retrospective cohort study of GBM patients at Johns Hopkins Hospital (JHH) between 2009 and 2014, using electronic medical records and hospice records. Comprehensive medical record review of 100 randomly selected patients with GBM, who were actively treated at JHH. Secondary analysis of all JHH GBM patients (n = 45) who received hospice care at Gilchrist Services, our largest provider, during this time period. Of 100 patients, 76 were referred to hospice. Despite the poor survival and changes in mental capacity associated with this disease, only 40% of individuals had documentation of code status and only 17% had any documentation of advance directives (ADs). None had documentation by a health care provider of a formal symptom, psychosocial, or spiritual assessment at greater than 50% of clinic visits. Only 17% used chemotherapy in their last month of life. 37% were hospitalized in the last month of life for an average of 9 days. Of the Gilchrist Services patients, the median length of stay in hospice was 21 days and 64% of these patients died in their residence with hospice services. Documentation of palliative care and end-of-life measures could improve quality of care for GBM patients, especially in the use of ADs, symptom, spiritual, and psychosocial assessments, with earlier use of hospice to prevent end-of-life hospitalizations.

  8. The evolution of the EGFRvIII (rindopepimut) immunotherapy for glioblastoma multiforme patients

    PubMed Central

    Paff, Michelle; Alexandru-Abrams, Daniela; Hsu, Frank P K; Bota, Daniela A

    2015-01-01

    Glioblastoma Multiforme (GBM) is the most common type of brain tumor and it is uniformly fatal. The community standard of treatment for this disease is gross or subtotal resection of the tumor, followed by radiation and temozolomide. At recurrence bevacizumab can be added for increased progression free survival. Many challenges are encountered while trying to devise new drugs to treat GBM, such as the presence of the blood brain barrier which is impermeable to most drugs. Therefore in the past few years attention was turned to immunological means for the treatment of this devastating disease. EGFRvIII targeting has proven a good way to attack glioblastoma cells by using the immune system. Although in still in development, this approach holds the promise as a great first step toward immune-tailored drugs for the treatment of brain cancers. PMID:25625931

  9. Characteristic features of stem cells in glioblastomas: from cellular biology to genetics.

    PubMed

    Knights, Mark J; Kyle, Stuart; Ismail, Azzam

    2012-09-01

    Glioblastoma is the most common type of primary brain tumor in adults and is among the most lethal and least successfully treated solid tumors. Recently, research into the area of stem cells in brain tumors has gained momentum. However, due to the relatively new and novel hypothesis that a subpopulation of cancer cells in each malignancy has the potential for tumor initiation and repopulation, the data in this area of research are still in its infancy. This review article is aimed at attempting to bring together research carried out so far in order to build an understanding of glioblastoma stem cells (GSCs). Initially, we consider GSCs at a morphological and cellular level, and then discuss important cell markers, signaling pathways and genetics. Furthermore, we highlight the difficulties associated with what some of the evidence indicates and what collectively the studies contribute to further defining the interpretation of GSCs. © 2012 The Authors; Brain Pathology © 2012 International Society of Neuropathology.

  10. Treatment of breast cancer brain metastases.

    PubMed

    Hofer, Silvia; Pestalozzi, Bernhard C

    2013-10-05

    Breast cancer represents the second most frequent cause of brain metastases. Treatment planning should consider several tumor and patient factors to estimate prognosis based on the Karnofsky Performance Status (KPS), age, extent of extra-cerebral disease as well as genetic subtype. When systemic disease is under control patients with up to three metastases qualify for local therapy, such as surgical excision or stereotactic radiotherapy. After the local treatment the addition of whole brain radiation therapy may be postponed until disease progression in the brain is observed and overall survival will not be compromised. Asymptomatic brain metastases may be first approached with a systemic treatment to which the primary tumor is considered to be sensitive.

  11. Drug delivery approaches for the treatment of glioblastoma multiforme.

    PubMed

    Fakhoury, Marc

    2016-09-01

    Glioblastoma multiforme (GBM) is by far the most common and aggressive form of glial tumor. It is characterized by a highly proliferative population of cells that invade surrounding tissue and that frequently recur after surgical resection and chemotherapy. Over the last decades, a number of promising novel pharmacological approaches have been investigated, but most of them have failed clinical trials due to some side-effects such as toxicity and poor drug delivery to the brain. The major obstacle in the treatment of GBM is the presence of the blood-brain barrier (BBB). Due to their relatively high molecular weight, most therapeutic drugs fail to cross the BBB from the blood circulation. This paper sheds light on the characteristics of GBM and the challenges of current pharmacological treatments. A closer look is given to the role of nanotechnology in the field of drug delivery, and its application in the treatment of brain tumors such as GBM. For this purpose, effort was made to select the most recent studies using predefined search criteria that included at least one of the following keywords in the PubMed and Medline databases: glioblastoma, drug delivery, blood-brain barrier, nanotechnology, and nanoparticle. Breakthrough in nanotechnology offers promising applications in cancer therapy and targeted drug delivery. However, more efforts need to be devoted to the development of novel therapeutic strategies that enable the delivery of drugs to desired areas of the brain with limited side-effects and higher therapeutic efficiency.

  12. Functional analysis of [methyl-(3)H]choline uptake in glioblastoma cells: Influence of anti-cancer and central nervous system drugs.

    PubMed

    Taguchi, Chiaki; Inazu, Masato; Saiki, Iwao; Yara, Miki; Hara, Naomi; Yamanaka, Tsuyoshi; Uchino, Hiroyuki

    2014-04-01

    Positron emission tomography (PET) and PET/computed tomography (PET-CT) studies with (11)C- or (18)F-labeled choline derivatives are used for PET imaging in glioblastoma patients. However, the nature of the choline transport system in glioblastoma is poorly understood. In this study, we performed a functional characterization of [methyl-(3)H]choline uptake and sought to identify the transporters that mediate choline uptake in the human glioblastoma cell lines A-172 and U-251MG. In addition, we examined the influence of anti-cancer drugs and central nervous system drugs on the transport of [methyl-(3)H]choline. High- and low-affinity choline transport systems were present in A-172 cells, U-251MG cells and astrocytes, and these were Na(+)-independent and pH-dependent. Cell viability in A-172 cells was not affected by choline deficiency. However, cell viability in U-251MG cells was significantly inhibited by choline deficiency. Both A-172 and U-251MG cells have two different choline transporters, choline transporter-like protein 1 (CTL1) and CTL2. In A-172 cells, CTL1 is predominantly expressed, whereas in U-251MG cells, CTL2 is predominantly expressed. Treatment with anti-cancer drugs such as cisplatin, etoposide and vincristine influenced [methyl-(3)H]choline uptake in U-251MG cells, but not A-172 cells. Central nervous system drugs such as imipramine, fluvoxamine, paroxetine, reboxetine, citalopram and donepezil did not affect cell viability or [methyl-(3)H]choline uptake. The data presented here suggest that CTL1 and CTL2 are functionally expressed in A-172 and U-251MG cells and are responsible for [methyl-(3)H]choline uptake that relies on a directed H(+) gradient as a driving force. Furthermore, while anti-cancer drugs altered [methyl-(3)H]choline uptake, central nervous system drugs did not affect [methyl-(3)H]choline uptake.

  13. Integrating the glioblastoma microenvironment into engineered experimental models

    PubMed Central

    Xiao, Weikun; Sohrabi, Alireza; Seidlits, Stephanie K

    2017-01-01

    Glioblastoma (GBM) is the most lethal cancer originating in the brain. Its high mortality rate has been attributed to therapeutic resistance and rapid, diffuse invasion – both of which are strongly influenced by the unique microenvironment. Thus, there is a need to develop new models that mimic individual microenvironmental features and are able to provide clinically relevant data. Current understanding of the effects of the microenvironment on GBM progression, established experimental models of GBM and recent developments using bioengineered microenvironments as ex vivo experimental platforms that mimic the biochemical and physical properties of GBM tumors are discussed. PMID:28883992

  14. Suppression of p53-inducible gene 3 is significant for glioblastoma progression and predicts poor patient prognosis.

    PubMed

    Quan, Jishu; Li, Yong; Jin, Meihua; Chen, Dunfu; Yin, Xuezhe; Jin, Ming

    2017-03-01

    Glioblastoma is the most malignant and invasive brain tumor with extremely poor prognosis. p53-inducible gene 3, a downstream molecule of the tumor suppressor p53, has been found involved in apoptosis and oxidative stress response. However, the functions of p53-inducible gene 3(PIG3) in cancer are far from clear including glioblastoma. In this study, we found that p53-inducible gene 3 expression was suppressed in glioblastoma tissues compared with normal tissues. And the expression of p53-inducible gene 3 was significantly associated with the World Health Organization grade. Patients with high p53-inducible gene 3 expression have a significantly longer median survival time (15 months) than those with low p53-inducible gene 3 expression (8 months). According to Cox regression analysis, p53-inducible gene 3 was an independent prognostic factor with multivariate hazard ratio of 0.578 (95% confidence interval, 0.352-0.947; p = 0.030) for overall survival. Additionally, gain and loss of function experiments showed that knockdown of p53-inducible gene 3 significantly increased the proliferation and invasion ability of glioblastoma cells while overexpression of p53-inducible gene 3 inhibited the proliferation and invasion ability. The results of in vivo glioblastoma models further confirmed that p53-inducible gene 3 suppression promoted glioblastoma progression. Altogether, our data suggest that high expression of p53-inducible gene 3 is significant for glioblastoma inhibition and p53-inducible gene 3 independently indicates good prognosis in patients, which might be a novel prognostic biomarker or potential therapeutic target in glioblastoma.

  15. Brain metastases from breast cancer during pregnancy

    PubMed Central

    Sharma, Ashish; Nguyen, Ha Son; Lozen, Andrew; Sharma, Abhishiek; Mueller, Wade

    2016-01-01

    Background: Brain metastasis during pregnancy is a rare occurrence. In particular, there have only been three prior cases regarding breast cancer metastasis. We report a patient with breast cancer metastasis to the brain during pregnancy and review the literature. Case Description: The patient was a 35-year-old female with a history of breast cancer (estrogen receptor/progesterone receptor negative, human epidermal growth factor receptor 2/neu positive, status post-neoadjuvant docetaxel/carboplatin/trastuzumab/pertuzumab therapy, status post-bilateral mastectomies), and prior right frontal brain metastases (status post-resection, capecitabine/lapatinib/temozolomide therapy, and cyberknife treatment). Patient was found to be pregnant at 9 weeks’ gestation while on chemotherapy; the patient elected to continue with the pregnancy and chemotherapy was discontinued. At 14 weeks’ gestation, she returned with recurrent right frontal disease. She was taken for a craniotomy at 16 weeks’ gestation, which confirmed metastases. Six weeks later, patient returned with worsening headaches and fatigue, with more recurrent right frontal disease. She was started on decadron and chemotherapy (5-fluorouracil, adriamycin, and cyclophosphamide). Serial magnetic resonance imaging (MRI) demonstrated enlarging right frontal lesions. She underwent a craniotomy at 27 weeks’ gestation, and chemotherapy was discontinued promptly. Starting at 30 weeks’ gestation, she received whole brain radiation for 2 weeks. Subsequently, she delivered a baby girl via cesarean section at 32 weeks’ gestation. At 6 weeks follow-up, an MRI brain demonstrated no new intracranial disease, with stable postoperative findings. Conclusion: There is a lack of guidelines and clinical consensus on medical and surgical treatment for breast cancer metastases in pregnant patients. Treatment usually varies based upon underlying tumor burden, location, gestational age of the fetus, and patient's preference and

  16. Targeted Nanotechnology in Glioblastoma Multiforme.

    PubMed

    Glaser, Talita; Han, Inbo; Wu, Liquan; Zeng, Xiang

    2017-01-01

    Gliomas, and in particular glioblastoma multiforme, are aggressive brain tumors characterized by a poor prognosis and high rates of recurrence. Current treatment strategies are based on open surgery, chemotherapy (temozolomide) and radiotherapy. However, none of these treatments, alone or in combination, are considered effective in managing this devastating disease, resulting in a median survival time of less than 15 months. The efficiency of chemotherapy is mainly compromised by the blood-brain barrier (BBB) that selectively inhibits drugs from infiltrating into the tumor mass. Cancer stem cells (CSCs), with their unique biology and their resistance to both radio- and chemotherapy, compound tumor aggressiveness and increase the chances of treatment failure. Therefore, more effective targeted therapeutic regimens are urgently required. In this article, some well-recognized biological features and biomarkers of this specific subgroup of tumor cells are profiled and new strategies and technologies in nanomedicine that explicitly target CSCs, after circumventing the BBB, are detailed. Major achievements in the development of nanotherapies, such as organic poly(propylene glycol) and poly(ethylene glycol) or inorganic (iron and gold) nanoparticles that can be conjugated to metal ions, liposomes, dendrimers and polymeric micelles, form the main scope of this summary. Moreover, novel biological strategies focused on manipulating gene expression (small interfering RNA and clustered regularly interspaced short palindromic repeats [CRISPR]/CRISPR associated protein 9 [Cas 9] technologies) for cancer therapy are also analyzed. The aim of this review is to analyze the gap between CSC biology and the development of targeted therapies. A better understanding of CSC properties could result in the development of precise nanotherapies to fulfill unmet clinical needs.

  17. Targeted Nanotechnology in Glioblastoma Multiforme

    PubMed Central

    Glaser, Talita; Han, Inbo; Wu, Liquan; Zeng, Xiang

    2017-01-01

    Gliomas, and in particular glioblastoma multiforme, are aggressive brain tumors characterized by a poor prognosis and high rates of recurrence. Current treatment strategies are based on open surgery, chemotherapy (temozolomide) and radiotherapy. However, none of these treatments, alone or in combination, are considered effective in managing this devastating disease, resulting in a median survival time of less than 15 months. The efficiency of chemotherapy is mainly compromised by the blood-brain barrier (BBB) that selectively inhibits drugs from infiltrating into the tumor mass. Cancer stem cells (CSCs), with their unique biology and their resistance to both radio- and chemotherapy, compound tumor aggressiveness and increase the chances of treatment failure. Therefore, more effective targeted therapeutic regimens are urgently required. In this article, some well-recognized biological features and biomarkers of this specific subgroup of tumor cells are profiled and new strategies and technologies in nanomedicine that explicitly target CSCs, after circumventing the BBB, are detailed. Major achievements in the development of nanotherapies, such as organic poly(propylene glycol) and poly(ethylene glycol) or inorganic (iron and gold) nanoparticles that can be conjugated to metal ions, liposomes, dendrimers and polymeric micelles, form the main scope of this summary. Moreover, novel biological strategies focused on manipulating gene expression (small interfering RNA and clustered regularly interspaced short palindromic repeats [CRISPR]/CRISPR associated protein 9 [Cas 9] technologies) for cancer therapy are also analyzed. The aim of this review is to analyze the gap between CSC biology and the development of targeted therapies. A better understanding of CSC properties could result in the development of precise nanotherapies to fulfill unmet clinical needs. PMID:28408882

  18. Targeting metabolic remodeling in glioblastoma multiforme.

    PubMed

    Wolf, Amparo; Agnihotri, Sameer; Guha, Abhijit

    2010-11-01

    A key aberrant biological difference between tumor cells and normal differentiated cells is altered metabolism, whereby cancer cells acquire a number of stable genetic and epigenetic alterations to retain proliferation, survive under unfavorable microenvironments and invade into surrounding tissues. A classic biochemical adaptation is the metabolic shift to aerobic glycolysis rather than mitochondrial oxidative phosphorylation, regardless of oxygen availability, a phenomenon termed the "Warburg Effect". Aerobic glycolysis, characterized by high glucose uptake, low oxygen consumption and elevated production of lactate, is associated with a survival advantage as well as the generation of substrates such as fatty acids, amino acids and nucleotides necessary in rapidly proliferating cells. This review discusses the role of key metabolic enzymes and their association with aerobic glycolysis in Glioblastoma Multiforme (GBM), an aggressive, highly glycolytic and deadly brain tumor. Targeting key metabolic enzymes involved in modulating the "Warburg Effect" may provide a novel therapeutic approach either singularly or in combination with existing therapies in GBMs.

  19. Outcome and prognostic factors in cerebellar glioblastoma multiforme in adults: A retrospective study from the Rare Cancer Network

    SciTech Connect

    Weber, Damien C. . E-mail: damien.weber@hcuge.ch; Miller, Robert C.; Villa, Salvador; Hanssens, Patrick; Baumert, Brigitta G.; Castadot, Pierre; Varlet, Pascale; Abacioglu, Ufuk; Igdem, Sefik; Szutowicz, Ewa; Nishioka, Hiroshi; Hofer, Silvia; Rutz, Hans Peter; Ozsahin, Mahmut; Taghian, Alphonse; Mirimanoff, Rene O.

    2006-09-01

    Purpose: The aim of this study was to assess the outcome in patients with cerebellar glioblastoma (GBM) treated in 15 institutions of the Rare Cancer Network. Methods and Materials: Data from a series of 45 adult patients with cerebellar GBM were collected in a retrospective multicenter study. Median age was 50.3 years. Brainstem invasion was observed in 9 (20%) patients. Radiotherapy (RT) was administered to 36 patients (with concomitant chemotherapy, 7 patients). Adjuvant chemotherapy after RT was administered in 8 patients. Median RT dose was 59.4 Gy. Median follow-up was 7.2 months (range, 3.4-39.0). Results: The 1-year and 2-year actuarial overall survival rate was 37.8% and 14.7%, respectively, and was significantly influenced by salvage treatment (p = 0.048), tumor volume (p = 0.044), extent of neurosurgical resection (p = 0.019), brainstem invasion (p = 0.0013), additional treatment after surgery (p < 0.001), and completion of the initial treatment (p < 0.001) on univariate analysis. All patients experienced local progression: 8 and 22 had progression with and without a distant failure, respectively. The 1- and 2-year actuarial progression free survival was 25% and 10.7%, respectively, and was significantly influenced by brainstem invasion (p = 0.002), additional treatment after surgery (p = 0.0016), and completion of the initial treatment (p < 0.001). On multivariate analysis, survival was negatively influenced by the extent of surgery (p = 0.03) and brainstem invasion (p = 0.02). Conclusions: In this multicenter retrospective study, the observed pattern of failure was local in all cases, but approximately 1 patient of 4 presented with an extracerebellar component. Brainstem invasion was observed in a substantial number of patients and was an adverse prognostic factor.

  20. Agomelatine or ramelteon as treatment adjuncts in glioblastoma and other M1- or M2-expressing cancers

    PubMed Central

    2015-01-01

    The impressive but sad list of over forty clinical studies using various cytotoxic chemotherapies published in the last few years has failed to increase median survival of glioblastoma beyond two years after diagnosis. In view of this apparent brick wall, adjunctive non-cytotoxic growth factor blocking drugs are being tried, as in the CUSP9* protocol. A related theme is searching for agonists at growth inhibiting receptors. One such dataset is that of melatonin agonism at M1 or M2 receptors found on glioblastoma cells, being a negative regulator of these cells’ growth. Melatonin itself is an endogenous hormone, but when used as an exogenously administered drug it has many disadvantages. Agomelatine, marketed as an antidepressant, and ramelteon, marketed as a treatment for insomnia, are currently-available melatonin receptor agonists. These melatonin receptor agonists have significant advantages over the natural ligand: longer half-life, better oral absorption, and higher affinity to melatonin receptors. They have an eminently benign side effect profile. As full agonists they should function to inhibit glioblastoma growth, as demonstrated for melatonin. A potentially helpful ancillary attribute of melatonergic agonists in glioblastoma treatment is an increase in interleukin-2 synthesis, expected, at least partially, to reverse some of the immunosuppression associated with glioblastoma. PMID:26034396

  1. EGFRvIII-Specific Chimeric Antigen Receptor T Cells Migrate to and Kill Tumor Deposits Infiltrating the Brain Parenchyma in an Invasive Xenograft Model of Glioblastoma

    PubMed Central

    Miao, Hongsheng; Choi, Bryan D.; Suryadevara, Carter M.; Sanchez-Perez, Luis; Yang, Shicheng; De Leon, Gabriel; Sayour, Elias J.; McLendon, Roger; Herndon, James E.; Healy, Patrick; Archer, Gary E.; Bigner, Darell D.; Johnson, Laura A.; Sampson, John H.

    2014-01-01

    Glioblastoma (GBM) is the most common primary malignant brain tumor in adults and is uniformly lethal. T-cell-based immunotherapy offers a promising platform for treatment given its potential to specifically target tumor tissue while sparing the normal brain. However, the diffuse and infiltrative nature of these tumors in the brain parenchyma may pose an exceptional hurdle to successful immunotherapy in patients. Areas of invasive tumor are thought to reside behind an intact blood brain barrier, isolating them from effective immunosurveillance and thereby predisposing the development of "immunologically silent" tumor peninsulas. Therefore, it remains unclear if adoptively transferred T cells can migrate to and mediate regression in areas of invasive GBM. One barrier has been the lack of a preclinical mouse model that accurately recapitulates the growth patterns of human GBM in vivo. Here, we demonstrate that D-270 MG xenografts exhibit the classical features of GBM and produce the diffuse and invasive tumors seen in patients. Using this model, we designed experiments to assess whether T cells expressing third-generation chimeric antigen receptors (CARs) targeting the tumor-specific mutation of the epidermal growth factor receptor, EGFRvIII, would localize to and treat invasive intracerebral GBM. EGFRvIII-targeted CAR (EGFRvIII+ CAR) T cells demonstrated in vitro EGFRvIII antigen-specific recognition and reactivity to the D-270 MG cell line, which naturally expresses EGFRvIII. Moreover, when administered systemically, EGFRvIII+ CAR T cells localized to areas of invasive tumor, suppressed tumor growth, and enhanced survival of mice with established intracranial D-270 MG tumors. Together, these data demonstrate that systemically administered T cells are capable of migrating to the invasive edges of GBM to mediate antitumor efficacy and tumor regression. PMID:24722266

  2. Pentavalent technetium-99m-dimercaptosuccinic acid [Tc-99m (V) DMSA] brain SPECT: does it have a place in predicting survival in patients with glioblastoma multiforme?

    PubMed

    Amin, Amr; Mustafa, M; Abd El-Hadi, E; Monier, A; Badwey, A; Saad, E

    2015-01-01

    Pentavalent technetium-99m dimercaptosuccinic acid (Tc-99m (V) DMSA) is reported as a useful tool for detection of residual or recurrent gliomas. We aimed to investigate the prognostic value of Tc-99m (V) DMSA brain SPECT in patients with glioblastoma multiforme (GBM). 40 patients [21 males and 19 females; mean age 48.6 ± 12.2 years] with GBM were included. Tc-99m (V) DMSA brain SPECT was done after surgery and before onset of radiation therapy or chemotherapy (Baseline study), at 4-6 weeks and at 6 months as a follow-up after therapy. The end point of the study was clinical follow-up for 2 years and/or death. 4-6 weeks after therapy, 40 and 60 % had negative and positive Tc-99m (V) DMSA for viable tumor tissues respectively (P = 0.09). At 6 months follow-up, 62.5 % of (V) DMSA negative patients and 12.5 % of the positive subjects were responders (P = 0.001). The median over-all survival (OS) of all patients was 12.3 month [range 5-24 month]. Patients with positive (V) DMSA had worse survival (8.87 month) compared to the negative ones (16.67 month) (P = 0.0001). Multivariate Cox regression analysis showed that Tc-99m (V) DMSA brain SPECT studies at 4-6 weeks and 6-months follow-up were independent prognostic factors for survival [OR 1.069; 95 % CI 1.417-2.174; P = 0.03 and OR 1.055; 95 % CI 0.821-1.186; P = 0.01 respectively]. Stratification of tumors into risk groups based on prognostic parameters may improve outcome by altering or intensifying treatment methods. Technetium-99m dimercaptosuccinic acid brain SPECT may have an additional prognostic role in patients with GBM which needs further evaluation in larger future series.

  3. Major vault protein supports glioblastoma survival and migration by upregulating the EGFR/PI3K signalling axis

    PubMed Central

    Lötsch, Daniela; Steiner, Elisabeth; Holzmann, Klaus; Spiegl-Kreinecker, Sabine; Pirker, Christine; Hlavaty, Juraj; Petznek, Helga; Hegedus, Balazs; Garay, Tamas; Mohr, Thomas; Sommergruber, Wolfgang; Grusch, Michael; Berger, Walter

    2013-01-01

    Despite their ubiquitous expression and high conservation during evolution, precise cellular functions of vault ribonucleoparticles, mainly built of multiple major vault protein (MVP) copies, are still enigmatic. With regard to cancer, vaults were shown to be upregulated during drug resistance development as well as malignant transformation and progression. Such in a previous study we demonstrated that human astrocytic brain tumours including glioblastoma are generally high in vault levels while MVP expression in normal brain is comparably low. However a direct contribution to the malignant phenotype in general and that of glioblastoma in particular has not been established so far. Thus we address the questions whether MVP itself has a pro-tumorigenic function in glioblastoma. Based on a large tissue collection, we re-confirm strong MVP expression in gliomas as compared to healthy brain. Further, the impact of MVP on human glioblastoma aggressiveness was analysed by using gene transfection, siRNA knock-down and dominant-negative genetic approaches. Our results demonstrate that MVP/vaults significantly support migratory and invasive competence as well as starvation resistance of glioma cells in vitro and in vivo. The enhanced aggressiveness was based on MVP-mediated stabilization of the epidermal growth factor receptor (EGFR)/phosphatidyl-inositol-3-kinase (PI3K) signalling axis. Consequently, MVP overexpression resulted in enhanced growth and brain invasion in human glioblastoma xenograft models. Our study demonstrates, for the first time, that vaults have a tumour-promoting potential by stabilizing EGFR/PI3K-mediated migration and survival pathways in human glioblastoma. PMID:24243798

  4. Major vault protein supports glioblastoma survival and migration by upregulating the EGFR/PI3K signalling axis.

    PubMed

    Lötsch, Daniela; Steiner, Elisabeth; Holzmann, Klaus; Spiegl-Kreinecker, Sabine; Pirker, Christine; Hlavaty, Juraj; Petznek, Helga; Hegedus, Balazs; Garay, Tamas; Mohr, Thomas; Sommergruber, Wolfgang; Grusch, Michael; Berger, Walter

    2013-11-01

    Despite their ubiquitous expression and high conservation during evolution, precise cellular functions of vault ribonucleoparticles, mainly built of multiple major vault protein (MVP) copies, are still enigmatic. With regard to cancer, vaults were shown to be upregulated during drug resistance development as well as malignant transformation and progression. Such in a previous study we demonstrated that human astrocytic brain tumours including glioblastoma are generally high in vault levels while MVP expression in normal brain is comparably low. However a direct contribution to the malignant phenotype in general and that of glioblastoma in particular has not been established so far. Thus we address the questions whether MVP itself has a pro-tumorigenic function in glioblastoma. Based on a large tissue collection, we re-confirm strong MVP expression in gliomas as compared to healthy brain. Further, the impact of MVP on human glioblastoma aggressiveness was analysed by using gene transfection, siRNA knock-down and dominant-negative genetic approaches. Our results demonstrate that MVP/vaults significantly support migratory and invasive competence as well as starvation resistance of glioma cells in vitro and in vivo. The enhanced aggressiveness was based on MVP-mediated stabilization of the epidermal growth factor receptor (EGFR)/phosphatidyl-inositol-3-kinase (PI3K) signalling axis. Consequently, MVP overexpression resulted in enhanced growth and brain invasion in human glioblastoma xenograft models. Our study demonstrates, for the first time, that vaults have a tumour-promoting potential by stabilizing EGFR/PI3K-mediated migration and survival pathways in human glioblastoma.

  5. Comprehensive genomic characterization defines human glioblastoma genes and core pathways

    PubMed Central

    2008-01-01

    Human cancer cells typically harbor multiple chromosomal aberrations, nucleotide substitutions and epigenetic modifications that drive malignant transformation. The Cancer Genome Atlas (TCGA) pilot project aims to assess the value of large-scale multidimensional analysis of these molecular characteristics in human cancer and to provide the data rapidly to the research community. Here, we report the interim integrative analysis of DNA copy number, gene expression and DNA methylation aberrations in 206 glioblastomas (GBM), the most common type of adult brain cancer, and nucleotide sequence aberrations in 91 of the 206 GBMs. This analysis provides new insights into the roles of ERBB2, NF1 and TP53, uncovers frequent mutations of the PI3 kinase regulatory subunit gene PIK3R1, and provides a network view of the pathways altered in the development of GBM. Furthermore, integration of mutation, DNA methylation and clinical treatment data reveals a link between MGMT promoter methylation and a hypermutator phenotype consequent to mismatch repair deficiency in treated glioblastomas, an observation with potential clinical implications. Together, these findings establish the feasibility and power of TCGA, demonstrating that it can rapidly expand knowledge of the molecular basis of cancer. PMID:18772890

  6. A Cancer Research UK First Time in Human Phase I Trial of IMA950 (Novel Multipeptide Therapeutic Vaccine) in Patients with Newly Diagnosed Glioblastoma.

    PubMed

    Rampling, Roy; Peoples, Sharon; Mulholland, Paul J; James, Allan; Al-Salihi, Omar; Twelves, Christopher J; McBain, Catherine; Jefferies, Sarah; Jackson, Alan; Stewart, Willie; Lindner, Juha; Kutscher, Sarah; Hilf, Norbert; McGuigan, Lesley; Peters, Jane; Hill, Karen; Schoor, Oliver; Singh-Jasuja, Harpreet; Halford, Sarah E; Ritchie, James W A

    2016-10-01

    To perform a two-cohort, phase I safety and immunogenicity study of IMA950 in addition to standard chemoradiotherapy and adjuvant temozolomide in patients with newly diagnosed glioblastoma. IMA950 is a novel glioblastoma-specific therapeutic vaccine containing 11 tumor-associated peptides (TUMAP), identified on human leukocyte antigen (HLA) surface receptors in primary human glioblastoma tissue. Patients were HLA-A*02-positive and had undergone tumor resection. Vaccination comprised 11 intradermal injections with IMA950 plus granulocyte macrophage colony-stimulating factor (GM-CSF) over a 24-week period, beginning 7 to 14 days prior to initiation of chemoradiotherapy (Cohort 1) or 7 days after chemoradiotherapy (Cohort 2). Safety was assessed according to NCI CTCAE Version 4.0 and TUMAP-specific T-cell immune responses determined. Secondary observations included progression-free survival (PFS), pretreatment regulatory T cell (Treg) levels, and the effect of steroids on T-cell responses. Forty-five patients were recruited. Related adverse events included minor injection site reactions, rash, pruritus, fatigue, neutropenia and single cases of allergic reaction, anemia and anaphylaxis. Two patients experienced grade 3 dose-limiting toxicity of fatigue and anaphylaxis. Of 40 evaluable patients, 36 were TUMAP responders and 20 were multi-TUMAP responders, with no important differences between cohorts. No effect of pretreatment Treg levels on IMA950 immunogenicity was observed, and steroids did not affect TUMAP responses. PFS rates were 74% at 6 months and 31% at 9 months. IMA950 plus GM-CSF was well-tolerated with the primary immunogenicity endpoint of observing multi-TUMAP responses in at least 30% of patients exceeded. Further development of IMA950 is encouraged. Clin Cancer Res; 22(19); 4776-85. ©2016 AACRSee related commentary by Lowenstein and Castro, p. 4760. ©2016 American Association for Cancer Research.

  7. Computational systems biology in cancer brain metastasis.

    PubMed

    Peng, Huiming; Tan, Hua; Zhao, Weiling; Jin, Guangxu; Sharma, Sambad; Xing, Fei; Watabe, Kounosuke; Zhou, Xiaobo

    2016-01-01

    Brain metastases occur in 20-40% of patients with advanced malignancies. A better understanding of the mechanism of this disease will help us to identify novel therapeutic strategies. In this review, we will discuss the systems biology approaches used in this area, including bioinformatics and mathematical modeling. Bioinformatics has been used for identifying the molecular mechanisms driving brain metastasis and mathematical modeling methods for analyzing dynamics of a system and predicting optimal therapeutic strategies. We will illustrate the strategies, procedures, and computational techniques used for studying systems biology in cancer brain metastases. We will give examples on how to use a systems biology approach to analyze a complex disease. Some of the approaches used to identify relevant networks, pathways, and possibly biomarkers in metastasis will be reviewed into details. Finally, certain challenges and possible future directions in this area will also be discussed.

  8. Glioblastoma Multiforme: Novel Therapeutic Approaches

    PubMed Central

    Fialho, Arsenio M.; Salunkhe, Prabhakar; Manna, Sunil; Mahali, Sidharth; Chakrabarty, Ananda M.

    2012-01-01

    The current therapy for glioblastoma multiforme involves total surgical resection followed by combination of radiation therapy and temozolomide. Unfortunately, the efficacy for such current therapy is limited, and newer approaches are sorely needed to treat this deadly disease. We have recently described the isolation of bacterial proteins and peptides with anticancer activity. In phase I human clinical trials, one such peptide, p28, derived from a bacterial protein azurin, showed partial and complete regression of tumors in several patients among 15 advanced-stage cancer patients with refractory metastatic tumors where the tumors were no longer responsive to current conventional drugs. An azurin-like protein called Laz derived from Neisseria meningitides demonstrates efficient entry and high cytotoxicity towards glioblastoma cells. Laz differs from azurin in having an additional 39-amino-acid peptide called an H.8 epitope, which allows entry and high cytotoxicity towards glioblastoma cells. Since p28 has been shown to have very little toxicity and high anti-tumor activity in advanced-stage cancer patients, it will be worthwhile to explore the use of H.8-p28, H.8-azurin, and Laz in toxicity studies and glioblastoma therapy in preclinical and human clinical trials. PMID:22462021

  9. Targeting Phosphatidylserine for Radioimmunotherapy of Breast Cancer Brain Metastasis

    DTIC Science & Technology

    2014-10-01

    signal intensity lesions (arrowheads) on four consecutive coronal sections of a representative mouse brain . Only a few of the lesions (arrowheads...To radiolabel the PS-targeting antibody, mch635, with β- emitters and evaluate its biodistribution and pharmacokinetics in breast cancer brain ...Award Number: W81XWH-12-1-0317 TITLE: Targeting Phosphatidylserine for Radioimmunotherapy of Breast Cancer Brain Metastasis PRINCIPAL

  10. Bioengineered 3D brain tumor model to elucidate the effects of matrix stiffness on glioblastoma cell behavior using PEG-based hydrogels.

    PubMed

    Wang, Christine; Tong, Xinming; Yang, Fan

    2014-07-07

    Glioblastoma (GBM) is the most common and aggressive form of primary brain tumor with a median survival of 12-15 months, and the mechanisms underlying GBM tumor progression remain largely elusive. Given the importance of tumor niche signaling in driving GBM progression, there is a strong need to develop in vitro models to facilitate analysis of brain tumor cell-niche interactions in a physiologically relevant and controllable manner. Here we report the development of a bioengineered 3D brain tumor model to help elucidate the effects of matrix stiffness on GBM cell fate using poly(ethylene-glycol) (PEG)-based hydrogels with brain-mimicking biochemical and mechanical properties. We have chosen PEG given its bioinert nature and tunable physical property, and the resulting hydrogels allow tunable matrix stiffness without changing the biochemical contents. To facilitate cell proliferation and migration, CRGDS and a MMP-cleavable peptide were chemically incorporated. Hyaluronic acid (HA) was also incorporated to mimic the concentration in the brain extracellular matrix. Using U87 cells as a model GBM cell line, we demonstrate that such biomimetic hydrogels support U87 cell growth, spreading, and migration in 3D over the course of 3 weeks in culture. Gene expression analyses showed U87 cells actively deposited extracellular matrix and continued to upregulate matrix remodeling genes. To examine the effects of matrix stiffness on GBM cell fate in 3D, we encapsulated U87 cells in soft (1 kPa) or stiff (26 kPa) hydrogels, which respectively mimics the matrix stiffness of normal brain or GBM tumor tissues. Our results suggest that changes in matrix stiffness induce differential GBM cell proliferation, morphology, and migration modes in 3D. Increasing matrix stiffness led to delayed U87 cell proliferation inside hydrogels, but cells formed denser spheroids with extended cell protrusions. Cells cultured in stiff hydrogels also showed upregulation of HA synthase 1 and matrix

  11. RNA nanoparticle as a vector for targeted siRNA delivery into glioblastoma mouse model

    PubMed Central

    Lee, Tae Jin; Haque, Farzin; Shu, Dan; Yoo, Ji Young; Li, Hui; Yokel, Robert A.; Horbinski, Craig; Kim, Tae Hyong; Kim, Sung-Hak; Kwon, Chang-Hyuk; Nakano, Ichiro; Kaur, Balveen; Guo, Peixuan; Croce, Carlo M.

    2015-01-01

    Systemic siRNA administration to target and treat glioblastoma, one of the most deadly cancers, requires robust and efficient delivery platform without immunogenicity. Here we report newly emerged multivalent naked RNA nanoparticle (RNP) based on pRNA 3-way-junction (3WJ) from bacteriophage phi29 to target glioblastoma cells with folate (FA) ligand and deliver siRNA for gene silencing. Systemically injected FA-pRNA-3WJ RNPs successfully targeted and delivered siRNA into brain tumor cells in mice, and efficiently reduced luciferase reporter gene expression (4-fold lower than control). The FA-pRNA-3WJ RNP also can target human patient-derived glioblastoma stem cells, thought to be responsible for tumor initiation and deadly recurrence, without accumulation in adjacent normal brain cells, nor other major internal organs. This study provides possible application of pRNA-3WJ RNP for specific delivery of therapeutics such as siRNA, microRNA and/or chemotherapeutic drugs into glioblastoma cells without inflicting collateral damage to healthy tissues. PMID:25885522

  12. RNA nanoparticle as a vector for targeted siRNA delivery into glioblastoma mouse model.

    PubMed

    Lee, Tae Jin; Haque, Farzin; Shu, Dan; Yoo, Ji Young; Li, Hui; Yokel, Robert A; Horbinski, Craig; Kim, Tae Hyong; Kim, Sung-Hak; Kwon, Chang-Hyuk; Nakano, Ichiro; Kaur, Balveen; Guo, Peixuan; Croce, Carlo M

    2015-06-20

    Systemic siRNA administration to target and treat glioblastoma, one of the most deadly cancers, requires robust and efficient delivery platform without immunogenicity. Here we report newly emerged multivalent naked RNA nanoparticle (RNP) based on pRNA 3-way-junction (3WJ) from bacteriophage phi29 to target glioblastoma cells with folate (FA) ligand and deliver siRNA for gene silencing. Systemically injected FA-pRNA-3WJ RNPs successfully targeted and delivered siRNA into brain tumor cells in mice, and efficiently reduced luciferase reporter gene expression (4-fold lower than control). The FA-pRNA-3WJ RNP also can target human patient-derived glioblastoma stem cells, thought to be responsible for tumor initiation and deadly recurrence, without accumulation in adjacent normal brain cells, nor other major internal organs. This study provides possible application of pRNA-3WJ RNP for specific delivery of therapeutics such as siRNA, microRNA and/or chemotherapeutic drugs into glioblastoma cells without inflicting collateral damage to healthy tissues.

  13. Salinomycin induced ROS results in abortive autophagy and leads to regulated necrosis in glioblastoma

    PubMed Central

    Xipell, Enric; Gonzalez-Huarriz, Marisol; de Irujo, Juan Jose Martinez; García-Garzón, Antonia; Lang, Fred F.; Jiang, Hong; Fueyo, Juan; Gomez-Manzano, Candelaria; Alonso, Marta M.

    2016-01-01

    Glioblastoma is the most frequent malignant brain tumor. Even with aggressive treatment, prognosis for patients is poor. One characteristic of glioblastoma cells is its intrinsic resistance to apoptosis. Therefore, drugs that induce alternative cell deaths could be interesting to evaluate as alternative therapeutic candidates for glioblastoma. Salinomycin (SLM) was identified through a chemical screening as a promising anticancer drug, but its mechanism of cell death remains unclear. In the present work we set out to elucidate how SLM causes cell death in glioblastoma cell lines (both established cell lines and brain tumor stem cell lines), aiming to find a potential antitumor candidate. In addition, we sought to determine the mechanism of action of SLM so that this mechanism can be can be exploited in the fight against cancer. Our data showed that SLM induces a potent endoplasmic reticulum (ER) stress followed by the trigger of the unfolded protein response (UPR) and an aberrant autophagic flux that culminated in necrosis due to mitochondria and lysosomal alterations. Of importance, the aberrant autophagic flux was orchestrated by the production of Reactive Oxygen Species (ROS). Alleviation of ROS production restored the autophagic flux. Altogether our data suggest that in our system the oxidative stress blocks the autophagic flux through lipid oxidation. Importantly, oxidative stress could be instructing the type of cell death in SLM-treated cells, suggesting that cell death modality is a dynamic concept which depends on the cellular stresses and the cellular mechanism activated. PMID:27121320

  14. 4G/5G and A-844G Polymorphisms of Plasminogen Activator Inhibitor-1 Associated with Glioblastoma in Iran--a Case-Control Study.

    PubMed

    Pooyan, Honari; Ahmad, Ebrahimi; Azadeh, Rakhshan

    2015-01-01

    Glioblastoma is a highly aggressive and malignant brain tumor. Risk factors are largely unknown however, although several biomarkers have been identified which may support development, angiogenesis and invasion of tumor cells. One of these biomarkers is PAI-1. 4G/5G and A-844G are two common polymorphisms in the gene promotor of PAI 1 that may be related to high transcription and expression of this gene. Studies have shown that the prevalence of the 4G and 844G allele is significantly higher in patients with some cancers and genetic disorders. We here assessed the association of 4G/5G and A-844G polymorphisms with glioblastoma cancer risk in Iranians in a case-control study. All 71 patients with clinically confirmed and 140 volunteers with no history and symptoms of glioblastoma as control group were screened for 4G/5G and A-844G polymorphisms of PAI-1, using ARMS-PCR. Genotype and allele frequencies of case and control groups were analyzed using the DeFinetti program. Our results showed significant associations between 4G/5G (p=0.01824) and A-844G (p=0.02012) polymorphisms of the PAI-1 gene with glioblastoma cancer risk in our Iranian population. The results of this study supporting an association of the PAI-1 4G/5G (p=0.01824) and A-844G (p=0.02012) polymorphisms with increasing glioblastoma cancer risk in Iranian patients.

  15. Bisacodyl and its cytotoxic activity on human glioblastoma stem-like cells. Implication of inositol 1,4,5-triphosphate receptor dependent calcium signaling.

    PubMed

    Dong, Jihu; Aulestia, Francisco J; Assad Kahn, Suzana; Zeniou, Maria; Dubois, Luiz Gustavo; El-Habr, Elias A; Daubeuf, François; Tounsi, Nassera; Cheshier, Samuel H; Frossard, Nelly; Junier, Marie-Pierre; Chneiweiss, Hervé; Néant, Isabelle; Moreau, Marc; Leclerc, Catherine; Haiech, Jacques; Kilhoffer, Marie-Claude

    2017-06-01

    Glioblastoma is the most common malignant brain tumor. The heterogeneity at the cellular level, metabolic specificities and plasticity of the cancer cells are a challenge for glioblastoma treatment. Identification of cancer cells endowed with stem properties and able to propagate the tumor in animal xenografts has opened a new paradigm in cancer therapy. Thus, to increase efficacy and avoid tumor recurrence, therapies need to target not only the differentiated cells of the tumor mass, but also the cancer stem-like cells. These therapies need to be effective on cells present in the hypoxic, slightly acidic microenvironment found within tumors. Such a microenvironment is known to favor more aggressive undifferentiated phenotypes and a slow-growing "quiescent state" that preserves the cells from chemotherapeutic agents, which mostly target proliferating cells. Based on these considerations, we performed a differential screening of the Prestwick Chemical Library of approved drugs on both proliferating and quiescent glioblastoma stem-like cells and identified bisacodyl as a cytotoxic agent with selectivity for quiescent glioblastoma stem-like cells. In the present study we further characterize bisacodyl activity and show its efficacy in vitro on clonal macro-tumorospheres, as well as in vivo in glioblastoma mouse models. Our work further suggests that bisacodyl acts through inhibition of Ca(2+) release from the InsP3 receptors. Copyright © 2017. Published by Elsevier B.V.

  16. Making a tumour's bed: glioblastoma stem cells and the vascular niche.

    PubMed

    Gilbertson, Richard J; Rich, Jeremy N

    2007-10-01

    Parallel to the role that normal stem cells play in organogenesis, cancer stem cells are thought to be crucial for tumorigenesis. Understanding normal development might therefore lead to better treatments of cancer. We review recent data that stem cells of glioblastoma, a highly malignant brain tumour, seem to be dependent on cues from aberrant vascular niches that mimic the normal neural stem cell niche. These data have direct implications for cancer, highlighting the similarity between normal and malignant stem cells and identifying the tumour microenvironment as a target for new therapies.

  17. Bortezomib sensitizes human glioblastoma cells to induction of apoptosis by type I interferons through NOXA expression and Mcl-1 cleavage.

    PubMed

    Wang, Ruishan; Davidoff, Andrew M; Pfeffer, Lawrence M

    2016-09-09

    Glioblastomas are highly invasive and aggressive primary brain tumors. Type I interferons have significant, pleiotropic anticancer activity. However, through various pathways many cancers become interferon-resistant, limiting interferon's clinical utility. In this study, we demonstrated that the proteasomal inhibitor bortezomib sensitized human glioblastoma cells to the antiproliferative action of interferons, which involved the induction of caspase-dependent apoptosis but not necroptosis. We found that death ligands such as TRAIL (TNF-related apoptosis-inducing ligand) were not involved in interferon/bortezomib-induced apoptosis, although interferon induced TRAIL expression. However, apoptosis was induced through an intrinsic pathway involving increased NOXA expression and Mcl-1 cleavage. Our findings may provide an important rationale for combining type I interferons with bortezomib for glioblastoma therapy. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. 140 Genome-wide CRISPR/cas9 Knockout Screens in Human Glioblastoma Identify Genetic Vulnerabilities.

    PubMed

    Noorani, Imran

    2016-08-01

    Glioblastoma is the most common primary brain tumor with a poor prognosis. Identifying the genetic vulnerabilities of cancer is a novel method for discovering new cancer therapeutic targets. The genetic vulnerabilities of glioblastoma are poorly understood, however. The recent CRISPR/cas9 genetic knockout approach has been proposed as a useful method for high-throughput screening of such genetic liabilities. We established human glioblastoma stem cell lines from 5 patients with primary glioblastoma. The validity of these cell lines was confirmed by demonstrating expression of nestin and SOX2 with RT-PCR, and of CD133 with flow cytometry. Cell lines were subcutaneously injected into mice to track tumor growth in vivo. Lentiviral transfection of a cas9 vector followed by antibiotic selection led to generation of stable cas9-expressing cell lines. A genome-wide library containing 123 411 CRISPR guide RNAs (6 guide RNAs per gene, targeting 19 050 genes) was lentivirally transfected into these cell lines. DNA was extracted from cells and sequenced with Illumina Hi-Seq at day 1 and day 25 after transfection. These patient-derived stem cell lines displayed clonal sphere growth of between 42% and 61%, with a median time survival time of 40 days when transplanted into immunocompromised mice. High-throughput sequencing revealed significant depletion of CRISPR guide RNAs for 1190 genes, with a high degree of overlap between independent replicates for a given cell line. Analysis of gene function using ontology databases demonstrated that DNA repair pathways, RNA and protein synthesis, and regulators of cell proliferation were significantly depleted genes. Moreover, a number of genes specific for neuronal proliferation and differentiation were identified. Comparison with known genetic vulnerabilities of other cancer types revealed a specific profile of genetic liabilities unique to glioblastoma. We have identified a unique genetic vulnerability profile for glioblastoma

  19. MicroRNAs/TP53 feedback circuitry in glioblastoma multiforme

    PubMed Central

    Suh, Sung-Suk; Yoo, Ji Young; Nuovo, Gerard J.; Jeon, Young-Jun; Kim, Seokho; Lee, Tae Jin; Kim, Taewan; Bakàcs, Arianna; Alder, Hansjuerg; Kaur, Balveen; Aqeilan, Rami I.; Pichiorri, Flavia; Croce, Carlo M.

    2012-01-01

    MicroRNAs (miRNAs) are increasingly implicated in regulating cancer initiation and progression. In this study, two miRNAs, miR-25 and -32, are identified as p53-repressed miRNAs by p53-dependent negative regulation of their transcriptional regulators, E2F1 and MYC. However, miR-25 and -32 result in p53 accumulation by directly targeting Mdm2 and TSC1, which are negative regulators of p53 and the mTOR (mammalian target of rapamycin) pathway, respectively, leading to inhibition of cellular proliferation through cell cycle arrest. Thus, there is a recurrent autoregulatory circuit involving expression of p53, E2F1, and MYC to regulate the expression of miR-25 and -32, which are miRNAs that, in turn, control p53 accumulation. Significantly, overexpression of transfected miR-25 and -32 in glioblastoma multiforme cells inhibited growth of the glioblastoma multiforme cells in mouse brain in vivo. The results define miR-25 and -32 as positive regulators of p53, underscoring their role in tumorigenesis in glioblastoma. PMID:22431589

  20. MicroRNAs/TP53 feedback circuitry in glioblastoma multiforme.

    PubMed

    Suh, Sung-Suk; Yoo, Ji Young; Nuovo, Gerard J; Jeon, Young-Jun; Kim, Seokho; Lee, Tae Jin; Kim, Taewan; Bakàcs, Arianna; Alder, Hansjuerg; Kaur, Balveen; Aqeilan, Rami I; Pichiorri, Flavia; Croce, Carlo M

    2012-04-03

    MicroRNAs (miRNAs) are increasingly implicated in regulating cancer initiation and progression. In this study, two miRNAs, miR-25 and -32, are identified as p53-repressed miRNAs by p53-dependent negative regulation of their transcriptional regulators, E2F1 and MYC. However, miR-25 and -32 result in p53 accumulation by directly targeting Mdm2 and TSC1, which are negative regulators of p53 and the mTOR (mammalian target of rapamycin) pathway, respectively, leading to inhibition of cellular proliferation through cell cycle arrest. Thus, there is a recurrent autoregulatory circuit involving expression of p53, E2F1, and MYC to regulate the expression of miR-25 and -32, which are miRNAs that, in turn, control p53 accumulation. Significantly, overexpression of transfected miR-25 and -32 in glioblastoma multiforme cells inhibited growth of the glioblastoma multiforme cells in mouse brain in vivo. The results define miR-25 and -32 as positive regulators of p53, underscoring their role in tumorigenesis in glioblastoma.

  1. DNA repair mechanisms and their clinical impact in glioblastoma.

    PubMed

    Erasimus, Hélène; Gobin, Matthieu; Niclou, Simone; Van Dyck, Eric

    2016-01-01

    Despite surgical resection and genotoxic treatment with ionizing radiation and the DNA alkylating agent temozolomide, glioblastoma remains one of the most lethal cancers, due in great part to the action of DNA repair mechanisms that drive resistance and tumor relapse. Understanding the molecular details of these mechanisms and identifying potential pharmacological targets have emerged as vital tasks to improve treatment. In this review, we introduce the various cellular systems and animal models that are used in studies of DNA repair in glioblastoma. We summarize recent progress in our knowledge of the pathways and factors involved in the removal of DNA lesions induced by ionizing radiation and temozolomide. We introduce the therapeutic strategies relying on DNA repair inhibitors that are currently being tested in vitro or in clinical trials, and present the challenges raised by drug delivery across the blood brain barrier as well as new opportunities in this field. Finally, we review the genetic and epigenetic alterations that help shape the DNA repair makeup of glioblastoma cells, and discuss their potential therapeutic impact and implications for personalized therapy. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  2. EGFRvIII antibody-conjugated iron oxide nanoparticles for magnetic resonance imaging-guided convection-enhanced delivery and targeted therapy of glioblastoma.

    PubMed

    Hadjipanayis, Costas G; Machaidze, Revaz; Kaluzova, Milota; Wang, Liya; Schuette, Albert J; Chen, Hongwei; Wu, Xinying; Mao, Hui

    2010-08-01

    The magnetic nanoparticle has emerged as a potential multifunctional clinical tool that can provide cancer cell detection by magnetic resonance imaging (MRI) contrast enhancement as well as targeted cancer cell therapy. A major barrier in the use of nanotechnology for brain tumor applications is the difficulty in delivering nanoparticles to intracranial tumors. Iron oxide nanoparticles (IONP; 10 nm in core size) conjugated to a purified antibody that selectively binds to the epidermal growth factor receptor (EGFR) deletion mutant (EGFRvIII) present on human glioblastoma multiforme (GBM) cells were used for therapeutic targeting and MRI contrast enhancement of experimental glioblastoma, both in vitro and in vivo, after convection-enhanced delivery (CED). A significant decrease in glioblastoma cell survival was observed after nanoparticle treatment and no toxicity was observed with treatment of human astrocytes (P < 0.001). Lower EGFR phosphorylation was found in glioblastoma cells after EGFRvIIIAb-IONP treatment. Apoptosis was determined to be the mode of cell death after treatment of GBM cells and glioblastoma stem cell-containing neurospheres with EGFRvIIIAb-IONPs. MRI-guided CED of EGFRvIIIAb-IONPs allowed for the initial distribution of magnetic nanoparticles within or adjacent to intracranial human xenograft tumors and continued dispersion days later. A significant increase in animal survival was found after CED of magnetic nanoparticles (P < 0.01) in mice implanted with highly tumorigenic glioblastoma xenografts (U87DeltaEGFRvIII). IONPs conjugated to an antibody specific to the EGFRvIII deletion mutant constitutively expressed by human glioblastoma tumors can provide selective MRI contrast enhancement of tumor cells and targeted therapy of infiltrative glioblastoma cells after CED.

  3. Leptin Promotes Glioblastoma

    PubMed Central

    Lawrence, Johnathan E.; Cook, Nicholas J.; Rovin, Richard A.; Winn, Robert J.

    2012-01-01

    The hormone leptin has a variety of functions. Originally known for its role in satiety and weight loss, leptin more recently has been shown to augment tumor growth in a variety of cancers. Within gliomas, there is a correlation between tumor grade and tumor expression of leptin and its receptor. This suggests that autocrine signaling within the tumor microenvironment may promote the growth of high-grade gliomas. Leptin does this through stimulation of cellular pathways that are also advantageous for tumor growth and recurrence: antiapoptosis, proliferation, angiogenesis, and migration. Conversely, a loss of leptin expression attenuates tumor growth. In animal models of colon cancer and melanoma, a decline in the expression and secretion of leptin resulted in a reduction of tumor growth. In these models, positive mental stimulation through environmental enrichment decreased leptin secretion and improved tumor outcome. This review explores the link between leptin and glioblastoma. PMID:22263109

  4. Gene Therapy for Brain Cancer: Combination Therapies Provide Enhanced Efficacy and Safety

    PubMed Central

    Candolfi, Marianela; Kroeger, Kurt M.; Muhammad, A.K.M.G.; Yagiz, Kader; Farrokhi, Catherine; Pechnick, Robert N.; Lowenstein, Pedro R.; Castro, Maria G.

    2009-01-01

    Glioblastoma multiforme (GBM) is the most common primary brain cancer in adults. Despite significant advances in treatment and intensive research, the prognosis for patients with GBM remains poor. Therapeutic challenges for GBM include its invasive nature, the proximity of the tumor to vital brain structures often preventing total resection, and the resistance of recurrent GBM to conventional radiotherapy and chemotherapy. Gene therapy has been proposed as a useful adjuvant for GBM, to be used in conjunction with current treatment. Work from our laboratory has shown that combination of conditional cytotoxic with immunotherapeutic approaches for the treatment of GBM elicits regression of large intracranial tumor masses and anti-tumor immunological memory in syngeneic rodent models of GBM. In this review we examined the currently available animal models for GBM, including rodent transplantable models, endogenous rodent tumor models and spontaneous GBM in dogs. We discuss non-invasive surrogate end points to assess tumor progression and therapeutic efficacy, such as behavioral tests and circulating biomarkers. Growing preclinical and clinical data contradict the old dogma that cytotoxic anti-cancer therapy would lead to an immune-suppression that would impair the ability of the immune system to mount an anti-tumor response. The implications of the findings reviewed indicate that combination of cytotoxic therapy with immunotherapy will lead to synergistic antitumor efficacy with reduced neurotoxicity and supports the clinical implementation of combined cytotoxic-immunotherapeutic strategies for the treatment of patients with GBM. PMID:19860655

  5. Gene therapy for brain cancer: combination therapies provide enhanced efficacy and safety.

    PubMed

    Candolfi, Marianela; Kroeger, Kurt M; Muhammad, A K M G; Yagiz, Kader; Farrokhi, Catherine; Pechnick, Robert N; Lowenstein, Pedro R; Castro, Maria G

    2009-10-01

    Glioblastoma multiforme (GBM) is the most common primary brain cancer in adults. Despite significant advances in treatment and intensive research, the prognosis for patients with GBM remains poor. Therapeutic challenges for GBM include its invasive nature, the proximity of the tumor to vital brain structures often preventing total resection, and the resistance of recurrent GBM to conventional radiotherapy and chemotherapy. Gene therapy has been proposed as a useful adjuvant for GBM, to be used in conjunction with current treatment. Work from our laboratory has shown that combination of conditional cytotoxic with immunotherapeutic approaches for the treatment of GBM elicits regression of large intracranial tumor masses and anti-tumor immunological memory in syngeneic rodent models of GBM. In this review we examined the currently available animal models for GBM, including rodent transplantable models, endogenous rodent tumor models and spontaneous GBM in dogs. We discuss non-invasive surrogate end points to assess tumor progression and therapeutic efficacy, such as behavioral tests and circulating biomarkers. Growing preclinical and clinical data contradict the old dogma that cytotoxic anti-cancer therapy would lead to an immune-suppression that would impair the ability of the immune system to mount an anti-tumor response. The implications of the findings reviewed indicate that combination of cytotoxic therapy with immunotherapy will lead to synergistic antitumor efficacy with reduced neurotoxicity and supports the clinical implementation of combined cytotoxic-immunotherapeutic strategies for the treatment of patients with GBM.

  6. Trifluoperazine, a Well-Known Antipsychotic, Inhibits Glioblastoma Invasion by Binding to Calmodulin and Disinhibiting Calcium Release Channel IP3R.

    PubMed

    Kang, Seokmin; Hong, Jinpyo; Lee, Jung Moo; Moon, Hyo Eun; Jeon, Borami; Choi, Jungil; Yoon, Nal Ae; Paek, Sun Ha; Roh, Eun Joo; Lee, C Justin; Kang, Sang Soo

    2017-01-01

    Calcium (Ca(2+)) signaling is an important signaling process, implicated in cancer cell proliferation and motility of the deadly glioblastomas that aggressively invade neighboring brain tissue. We have previously demonstrated that caffeine blocks glioblastoma invasion and extends survival by inhibiting Ca(2+) release channel inositol 1,4,5-trisphosphate receptor (IP3R) subtype 3. Trifluoperazine (TFP) is an FDA-approved antipsychotic drug for schizophrenia. Interestingly, TFP has been recently reported to show a strong anticancer effect on lung cancer, hepatocellular carcinoma, and T-cell lymphoma. However, the possible anticancer effect of TFP on glioblastoma has not been tested. Here, we report that TFP potently suppresses proliferation, motility, and invasion of glioblastoma cells in vitro, and tumor growth in in vivo xenograft mouse model. Unlike caffeine, TFP triggers massive and irreversible release of Ca(2+) from intracellular stores by IP3R subtype 1 and 2 by directly interacting at the TFP-binding site of a Ca(2+)-binding protein, calmodulin subtype 2 (CaM2). TFP binding to CaM2 causes a dissociation of CaM2 from IP3R and subsequent opening of IP3R. Compared with the control neural stem cells, various glioblastoma cell lines showed enhanced expression of CaM2 and thus enhanced sensitivity to TFP. On the basis of these findings, we propose TFP as a potential therapeutic drug for glioblastoma by aberrantly and irreversibly increasing Ca(2+) in glioblastoma cells. Mol Cancer Ther; 16(1); 217-27. ©2016 AACR. ©2016 American Association for Cancer Research.

  7. What next for newly diagnosed glioblastoma?

    PubMed Central

    Domingo-Musibay, Evidio; Galanis, Evanthia

    2015-01-01

    Glioblastoma is the most common primary brain tumor in adults. Despite current multimodality treatment including surgical resection and temozolomide-based chemoradiotherapy, median survival is only 14–16 months. Characterization of molecular alterations in glioblastoma has identified prognostic subgroups and therapeutic opportunities for clinical trials across glioblastoma subsets. Following a number of negative Phase III trials testing temozolomide dose intensification and angiogenesis inhibition, recent interim analysis data indicate survival prolongation with use of a device (Optune™) delivering alternating electrical field therapy in newly diagnosed glioblastoma patients. In this review, we present an overview of the data supporting the current standard of care and discuss novel experimental therapies in early and late phase clinical testing including devices, small molecule drugs, angiogenesis inhibitors, oncolytic virotherapy and immunotherapy. PMID:26558493

  8. Down-regulation of MicroRNA-126 in Glioblastoma and its Correlation with Patient Prognosis: A Pilot Study.

    PubMed

    Han, In Bo; Kim, Minsoo; Lee, Soo Hong; Kim, Jin Kwon; Kim, Se Hoon; Chang, Jong Hee; Teng, Yang D

    2016-12-01

    Glioblastoma is the most common primary malignant tumor of the adult human brain. Although microRNA-126 (miR-126) has been reported to exhibit expression abnormalities in various types of cancer, to date very few studies have examined changes in miR-126 level in glioblastoma. In this pilot study, we investigated the changes in miR-126 expression in newly-dissected primary glioblastoma to explore possible roles of miR-126 in patient prognosis. Total RNA was extracted from tumoral and adjacent non-cancerous tissues from 14 patients' paired frozen specimens. Using an established quantitative reverse transcriptase-PCR protocol, the levels of miR-126 in glioblastoma and adjacent non-tumor brain tissues were compared against small nucleolar RNA U48 (RNU48) as a reference gene. The expression of miR-126 in glioblastoma samples was significantly lower than in paired non-tumoral controls (p<0.05). Importantly, age-adjusted analyses suggest that glioblastoma patients with higher relative intratumoral miR-126 expression (i.e. 53-79% relative to that of the control tissue; n=7) had significantly improved survival duration than patients whose miR-126 levels were lower (i.e. 12-48%, n=7; stratified log-rank analysis p=0.011 when the dividing threshold was set at ≥51%; total: n=14, male: 8; female: 6). Thus, intraglioblastoma miR-126 may be down-regulated relative to normal tissue and patients with less down-regulation of intratumoral miR-126 expression could have improved postsurgical prognosis. Future clinical studies with larger sample sizes should be performed to validate this observation.

  9. Sequence survey of receptor tyrosine kinases reveals mutations in glioblastomas

    PubMed Central

    Rand, Vikki; Huang, Jiaqi; Stockwell, Tim; Ferriera, Steve; Buzko, Oleksandr; Levy, Samuel; Busam, Dana; Li, Kelvin; Edwards, Jennifer B.; Eberhart, Charles; Murphy, Kathleen M.; Tsiamouri, Alexia; Beeson, Karen; Simpson, Andrew J. G.; Venter, J. Craig; Riggins, Gregory J.; Strausberg, Robert L.

    2005-01-01

    It is now clear that tyrosine kinases represent attractive targets for therapeutic intervention in cancer. Recent advances in DNA sequencing technology now provide the opportunity to survey mutational changes in cancer in a high-throughput and comprehensive manner. Here we report on the sequence analysis of members of the receptor tyrosine kinase (RTK) gene family in the genomes of glioblastoma brain tumors. Previous studies have identified a number of molecular alterations in glioblastoma, including amplification of the RTK epidermal growth factor receptor. We have identified mutations in two other RTKs: (i) fibroblast growth receptor 1, including the first mutations in the kinase domain in this gene observed in any cancer, and (ii) a frameshift mutation in the platelet-derived growth factor receptor-α gene. Fibroblast growth receptor 1, platelet-derived growth factor receptor-α, and epidermal growth factor receptor are all potential entry points to the phosphatidylinositol 3-kinase and mitogen-activated protein kinase intracellular signaling pathways already known to be important for neoplasia. Our results demonstrate the utility of applying DNA sequencing technology to systematically assess the coding sequence of genes within cancer genomes. PMID:16186508

  10. Comprehensive portrait of recurrent glioblastoma multiforme in molecular and clinical characteristics.

    PubMed

    Li, Rui; Chen, Xincheng; You, Yongping; Wang, Xiefeng; Liu, Yanwei; Hu, Qi; Yan, Wei

    2015-10-13

    Glioblastoma multiforme is the most common primary malignant brain tumor in adults. In addition to poor response to treatment, a high recurrence rate contributes to the poor prognosis. The purpose of this study was to investigate the genetical and clinical characteristics of recurrent glioblastoma. We used whole transcriptome sequencing data to examine the distribution of molecular subtypes and gene signatures in 22 recurrent glioblastoma taken from the Chinese population, and further analyzed biological progression of the tumors, when compared with primary glioblastoma. The proportion of the classical subtype in recurrent ones (22%) was lower than that in primary glioblastoma (36%). The frequency of IDH1 mutations in recurrent glioblastomas was nearly twice that in primary glioblastomas. TP53 mutations were fewer in proneural recurrent glioblastomas (20%) but frequent in classical recurrent glioblastomas (80%). The most common sites of recurrent glioblastomas were the temporal lobe (41%). In patients diagnosed with recurrent glioblastoma multiforme, 64% were younger than 50 years. Gene set enrichment analysis revealed that chromatin fracture, repair, and remodeling genes were enriched in recurrent glioblastoma. Our results highlight the differences in clinical features, molecular subtypes and gene alterations between primary and recurrent glioblastoma and may be helpful for targeted therapy for recurrent glioblastoma.

  11. Mechanisms of CTC Biomarkers in Breast Cancer Brain Metastasis

    DTIC Science & Technology

    2015-10-01

    AWARD NUMBER: W81XWH-14-1-0214 TITLE: Mechanisms of CTC Biomarkers in Breast Cancer Brain Metastasis PRINCIPAL INVESTIGATOR: Dario...5a. CONTRACT NUMBER Mechanisms of CTC Biomarkers in Breast Cancer Brain Metastasis 5b. GRANT NUMBER W81XWH-14-1-0214 5c. PROGRAM ELEMENT NUMBER 6...SUPPLEMENTARY NOTES None 14. ABSTRACT Breast cancer brain metastasis (BCBM) is devastating and increasing in frequency, however, BCBM mechanisms are

  12. Solitary brain metastasis from prostate cancer: a case report.

    PubMed

    Barakat, Tasneem; Agarwal, Arnav; McDonald, Rachel; Ganesh, Vithusha; Vuong, Sherlyn; Borean, Michael; Chow, Edward; Soliman, Hany

    2016-07-01

    Brain metastases arising from prostate cancer are exceedingly rare and typically occur late in the course of the disease. Most patients have widespread metastatic disease before developing brain metastases from prostate cancer. We report the case of a 67-year-old male with prostate cancer presenting with an isolated symptomatic brain metastasis. Aggressive treatment of the metastatic site included tumor resection and adjuvant stereotactic radiation treatment (RT) to the surgical bed, resulting in a favorable outcome.

  13. SC-02CONVERSION OF DIFFERENTIATED CANCER CELLS INTO CANCER STEM-LIKE CELLS IN A GLIOBLASTOMA MODEL AFTER PRIMARY CHEMOTHERAPY

    PubMed Central

    Auffinger, Brenda; Tobias, Alex; Han, Yu; Lee, Gina; Guo, Donna; Dey, Mahua; Lesniak, Maciej; Ahmed, Atique

    2014-01-01

    Glioblastoma multiforme patients have a poor prognosis due to therapeutic resistance and tumor relapse. It has been suggested that gliomas are driven by a rare subset of tumor cells known as glioma stem cells (GSCs). This hypothesis states that only a few GSCs are able to divide, differentiate and initiate a new tumor. It has also been shown that this subpopulation is more resistant to conventional therapies than its differentiated counterpart. In order to understand glioma recurrence post therapy, we investigated the behavior of GSCs after primary chemotherapy. We first show that exposure of patient-derived as well as established glioma cell lines to therapeutic doses of temozolomide (TMZ), the most commonly used anti-glioma chemotherapy, consistently increases the GSC pool over time both in vitro and in vivo. Secondly, lineage-tracing analysis of the expanded GSC pool suggests that such amplification is a result of a phenotypic shift in the non-GSC population to GSC-like state in the presence of TMZ. The newly converted GSC population expresses markers associated with pluripotency and stemness, such as CD133, SOX2, Oct4 and Nestin. Furthermore, we show that intracranial implantation of the newly converted GSCs in nude mice results in a more efficient grafting and invasive phenotype. Taken together, these findings provide the first evidence that glioma cells exposed to chemotherapeutic agents are able to interconvert between non-GSCs and GSCs, thereby replenishing the original tumor population, leading to a more infiltrative phenotype and enhanced chemoresistance. This may represent a potential mechanism for therapeutic relapse.

  14. CS-20TRANSCRIPTIONAL CONTROL OF THE OSMOTIC ENGINE BY TEAD4 POTENTIATES INVASION AND CONFERS POOR PROGNOSIS IN GLIOBLASTOMA

    PubMed Central

    Martinez-Gutierrez, Juan Carlos; Shah, Sagar R.; Ruiz-Valls, Alejandro; Tippens, Nathaniel D.; Quinones-Hinojosa, Alfredo

    2014-01-01

    Glioblastomas are characterized by their ability to disseminate into the local brain parenchyma; thus, confounding surgical excision and radiotherapy. Hence, it is imperative to identify and decipher the signaling networks that drive invasion. Glioblastoma cells utilize molecular transporters at both their leading (inward facing) and lagging (outward facing) edge to modulate cell volume and invade the confined microenvironment of the brain. These transporters include solute transporters as well as the aquaporins, and collectively behave as an osmotic engine for cellular invasion. However, the transcriptional regulators of these transporters have not been fully identified. Here, we report that TEAD4, a transcription factor implicated in neural development, is a potent regulator of the osmotic engine through transcriptional control of solute and water transporters. In particular, our data demonstrates that loss of TEAD4 decreases glioblastoma cells ability to migrate and invade through small pores (Boyden chamber and Matrigel transwell, respectively) mimicking the confined microenvironment of the brain (p < 0.05). Additionally, we uncover the role of TEAD4 in regulating members of the Na + /H+ exchanger, chloride co-transporter and aquaporin families, as well as the volume regulated anion channel to enable water permeation (p < 0.05). Apart from regulating cell dispersal, our data also shows that TEAD4 regulates glioblastoma proliferation (p < 0.05). Using the TCGA and REMBRANDT datasets, we observed TEAD4 is selectively overexpressed and hyperactive in glioblastomas compared to non-cancer cortex and lower grade gliomas (p < 0.05). Furthermore, we found that patients with elevated TEAD4 expression have a significantly shorter progression free survival and overall survival (p < 0.05). Taken together, our results show that TEAD4 is a potent regulator of cell dispersal through transcriptional control of the osmotic engine and has relevance to clinical outcomes of

  15. Human brain glioblastoma cells do not induce but do respond to the bleomycin-induced bystander response from lung adenocarcinoma cells.

    PubMed

    Basheerudeen, Safa Abdul Syed; Mani, Chinnadurai; Kulkarni, Megha Anil Kumar; Pillai, Karthika; Rajan, Anila; Venkatachalam, Perumal

    2013-10-09

    To determine whether the bleomycin (BLM)-induced bystander response occurs in human brain glioblastoma (BMG-1) cells, the BMG-1 cells were exposed to two different concentrations of BLM. The co-culture methodology was adopted to study the in vitro bystander effects. DNA damage was measured using the micronucleus (MN) and γ-H2AX assays. Cytotoxicity was measured using the trypan blue assay. Cell cycle kinetics was analyzed using flow cytometry. The overall results did not show any significant increase in either genotoxicity or cytotoxicity or a delay in the cell cycle kinetics in BMG-1 bystander cells co-cultured with BLM-exposed cells, suggesting that BLM did not induce a bystander response in the BMG-1 cells. Furthermore, the MN results of the BLM-exposed BMG-1 cells co-cultured with unexposed bystander human lung adenocarcinoma (A549 and NCI-H460) cells and vice versa suggested that the BMG-1 cells do not secrete bystander signals but do respond to those signals. Analyzing the underlying mechanism and pathways involved in preventing the cells from secreting bystander signals will provide new insights that can be applied to inhibit these mechanisms in other cell types, thereby preventing and controlling the bystander response and genomic instability and increasing the therapeutic gain in chemotherapy. Copyright © 2013 Elsevier B.V. All rights reserved.

  16. Na⁺/K⁺-ATPase β2-subunit (AMOG) expression abrogates invasion of glioblastoma-derived brain tumor-initiating cells.

    PubMed

    Sun, Matthew Z; Kim, Joseph M; Oh, Michael C; Safaee, Michael; Kaur, Gurvinder; Clark, Aaron J; Bloch, Orin; Ivan, Michael E; Kaur, Rajwant; Oh, Taemin; Fouse, Shaun D; Phillips, Joanna J; Berger, Mitchel S; Parsa, Andrew T

    2013-11-01

    Mechanisms of glioma invasion remain to be fully elucidated. Glioma cells within glioblastoma multiforme (GBM) range from well-differentiated tumor cells to less-differentiated brain tumor-initiating cells (BTICs). The β2-subunit of Na(+)/K(+)-ATPase, called the adhesion molecule on glia (AMOG), is highly expressed in normal glia but is thought to be universally downregulated in GBM. To test our hypothesis that expression of AMOG is heterogeneous in GBM and confers a less invasive phenotype, we compared it between BTICs and differentiated cells from patient-matched GBM and then tested GBM invasion in vitro after AMOG overexpression. Immunohistochemistry, immunoblotting, and real-time PCR were used to characterize AMOG protein and mRNA expression in tumor samples, BTICs, and differentiated cells. Matrigel invasion assay, scratch assay, and direct cell counting were used for testing in vitro invasion, migration, and proliferation, respectively. While AMOG expression is heterogeneous in astrocytomas of grades II-IV, it is lost in most GBM. BTICs express higher levels of AMOG mRNA and protein compared with patient-matched differentiated tumor cells. Overexpression of AMOG decreased GBM cell and BTIC invasion without affecting migration or proliferation. Knockdown of AMOG expression in normal human astrocytes increased invasion. AMOG expression inhibits GBM invasion. Its downregulation increases invasion in glial cells and may also represent an important step in BTIC differentiation. These data provide compelling evidence implicating the role of AMOG in glioma invasion and provide impetus for further investigation.

  17. Glioblastoma care in the elderly.

    PubMed

    Jordan, Justin T; Gerstner, Elizabeth R; Batchelor, Tracy T; Cahill, Daniel P; Plotkin, Scott R

    2016-01-15

    Glioblastoma is common among elderly patients, a group in which comorbidities and a poor prognosis raise important considerations when designing neuro-oncologic care. Although the standard of care for nonelderly patients with glioblastoma includes maximal safe surgical resection followed by radiotherapy with concurrent and adjuvant temozolomide, the safety and efficacy of these modalities in elderly patients are less certain given the population's underrepresentation in many clinical trials. The authors reviewed the clinical trial literature for reports on the treatment of elderly patients with glioblastoma to provide evidence-based guidance for practitioners. In elderly patients with glioblastoma, there is a survival advantage for those who undergo maximal safe resection, which likely includes an incremental benefit with increasing completeness of resection. Radiotherapy extends survival in selected patients, and hypofractionation appears to be more tolerable than standard fractionation. In addition, temozolomide chemotherapy is safe and extends the survival of patients with tumors that harbor O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation. The combination of standard radiation with concurrent and adjuvant temozolomide has not been studied in this population. Although many questions remain unanswered regarding the treatment of glioblastoma in elderly patients, the available evidence provides a framework on which providers may base individual treatment decisions. The importance of tumor biomarkers is increasingly apparent in elderly patients, for whom the therapeutic efficacy of any treatment must be weighed against its potential toxicity. MGMT promoter methylation status has specifically demonstrated utility in predicting the efficacy of temozolomide and should be considered in treatment decisions when possible. Cancer 2016;122:189-197. © 2015 American Cancer Society.

  18. Gastrointestinal cancer and brain metastasis: a rare and ominous sign.

    PubMed

    Go, Pauline H; Klaassen, Zachary; Meadows, Michael C; Chamberlain, Ronald S

    2011-08-15

    Metastatic brain tumors represent 20% to 40% of all intracranial neoplasms and are found most frequently in association with lung cancer (50%) and breast cancer (12%). Although brain metastases occur in <4% of all tumors of the gastrointestinal (GI) tract, the incidence of GI brain metastasis is rising in part due to more effective systemic treatments and prolonged survival of patients with GI cancer. Data were collected from 25 studies (11 colorectal, 7 esophageal, 2 gastric, 1 pancreatic, 1 intestinal, 3 all-inclusive GI tract cancer) and 13 case reports (4 pancreatic, 4 gallbladder, and 5 small bowel cancer). Brain metastases are found in 1% of colorectal cancer, 1.2% of esophageal cancer, 0.62% of gastric cancer, and 0.33% of pancreatic cancer cases. Surgical resection with whole brain radiation therapy (WBRT) has been associated with the longest median survival (38.4-262 weeks) compared with surgery alone (16.4-70.8 weeks), stereotactic radiosurgery (20-38 weeks), WBRT alone (7.2-16 weeks), or steroids (4-7 weeks). Survival in patients with brain metastasis from GI cancer was found to be diminished compared with metastases arising from the breast, lung, or kidney. Prolonged survival and improvement in clinical symptoms has been found to be best achieved with surgical resection and WBRT. Although early treatment has been linked to prolonged survival and improved quality of life, brain metastases represent a late manifestation of GI cancers and remain an ominous sign. Copyright © 2011 American Cancer Society.

  19. Targeted delivery of silver nanoparticles and alisertib: in vitro and in vivo synergistic effect against glioblastoma.

    PubMed

    Locatelli, Erica; Naddaka, Maria; Uboldi, Chiara; Loudos, George; Fragogeorgi, Eirini; Molinari, Valerio; Pucci, Andrea; Tsotakos, Theodoros; Psimadas, Dimitrios; Ponti, Jessica; Franchini, Mauro Comes

    2014-05-01

    Targeted biocompatible nanoplatforms presenting multiple therapeutic functions have great potential for the treatment of cancer. Multifunctional nanocomposites formed by polymeric nanoparticles (PNPs) containing two cytotoxic agents - the drug alisertib and silver nanoparticles - were synthesized. These PNPs have been conjugated with a chlorotoxin, an active targeting 36-amino acid-long peptide that specifically binds to MMP-2, a receptor overexpressed by brain cancer cells. The individual and synergistic activity of these two cytotoxic agents against glioblastoma multiforme was tested both in vitro and in vivo. The induced cytotoxicity in a human glioblastoma-astrocytoma epithelial-like cell line (U87MG) was studied in vitro through a trypan blue exclusion test after 48 and 72 h of exposure. Subsequently, the PNPs' biodistribution in healthy animals and their effect on tumor reduction in tumor-bearing mice were studied using PNPs radiolabeled with (99m)Tc. Tumor reduction was achieved in vivo when using silver/alisertib@PNPs-chlorotoxin.

  20. Genes that mediate breast cancer metastasis to the brain.

    PubMed

    Bos, Paula D; Zhang, Xiang H-F; Nadal, Cristina; Shu, Weiping; Gomis, Roger R; Nguyen, Don X; Minn, Andy J; van de Vijver, Marc J; Gerald, William L; Foekens, John A; Massagué, Joan

    2009-06-18

    The molecular basis for breast cancer metastasis to the brain is largely unknown. Brain relapse typically occurs years after the removal of a breast tumour, suggesting that disseminated cancer cells must acquire specialized functions to take over this organ. Here we show that breast cancer metastasis to the brain involves mediators of extravasation through non-fenestrated capillaries, complemented by specific enhancers of blood-brain barrier crossing and brain colonization. We isolated cells that preferentially infiltrate the brain from patients with advanced disease. Gene expression analysis of these cells and of clinical samples, coupled with functional analysis, identified the cyclooxygenase COX2 (also known as PTGS2), the epidermal growth factor receptor (EGFR) ligand HBEGF, and the alpha2,6-sialyltransferase ST6GALNAC5 as mediators of cancer cell passage through the blood-brain barrier. EGFR ligands and COX2 were previously linked to breast cancer infiltration of the lungs, but not the bones or liver, suggesting a sharing of these mediators in cerebral and pulmonary metastases. In contrast, ST6GALNAC5 specifically mediates brain metastasis. Normally restricted to the brain, the expression of ST6GALNAC5 in breast cancer cells enhances their adhesion to brain endothelial cells and their passage through the blood-brain barrier. This co-option of a brain sialyltransferase highlights the role of cell-surface glycosylation in organ-specific metastatic interactions.

  1. Use of in Vivo Two-dimensional MR Spectroscopy to Compare the Biochemistry of the Human Brain to That of Glioblastoma

    PubMed Central

    Ramadan, Saadallah; Andronesi, Ovidiu C.; Stanwell, Peter; Lin, Alexander P.; Sorensen, A. Gregory

    2011-01-01

    Purpose: To develop an in vivo two-dimensional localized correlation spectroscopy technique with which to monitor the biochemistry of the human brain and the pathologic characteristics of diseases in a clinically applicable time, including ascertainment of appropriate postprocessing parameters with which to allow diagnostic and prognostic molecules to be measured, and to investigate how much of the chemical information, known to be available from malignant cultured cells, could be recorded in vivo from human brain. Materials and Methods: The study was approved by the institutional review board and was compliant with HIPAA. With use of a 3.0-T clinical magnetic resonance (MR) unit and a 32-channel head coil, localized correlation spectroscopy was performed in six healthy control subjects and six patients with glioblastoma multiforme (GBM) with an acquisition time of 11 minutes. Two-dimensional spectra were processed and analyzed and peak volume ratios were tabulated. The data used were proved to be normally distributed by passing the Shapiro-Wilk normality test. The first row of the spectra was extracted to examine diagnostic features. The pathologic characteristics and grade of each GBM were determined after biopsy or surgery. Statistically significant differences were assessed by using a t test. Results: The localized correlation spectroscopy method assigned biochemical species from the healthy human brain. The correlation spectra of GBM were of sufficiently high quality that many of the cross peaks, recorded previously from malignant cell models in vitro, were observed, demonstrating a statistically significant difference (P < .05) between the cross peak volumes measured for healthy subjects and those with GBM (which include lipid, alanine, N-acetylaspartate, γ-aminobutyric acid, glutamine and glutamate, glutathione, aspartate, lysine, threonine, total choline, glycerophosphorylcholine, myo-inositol, imidazole, uridine diphosphate glucose, isocitrate, lactate

  2. Use of in vivo two-dimensional MR spectroscopy to compare the biochemistry of the human brain to that of glioblastoma.

    PubMed

    Ramadan, Saadallah; Andronesi, Ovidiu C; Stanwell, Peter; Lin, Alexander P; Sorensen, A Gregory; Mountford, Carolyn E

    2011-05-01

    To develop an in vivo two-dimensional localized correlation spectroscopy technique with which to monitor the biochemistry of the human brain and the pathologic characteristics of diseases in a clinically applicable time, including ascertainment of appropriate postprocessing parameters with which to allow diagnostic and prognostic molecules to be measured, and to investigate how much of the chemical information, known to be available from malignant cultured cells, could be recorded in vivo from human brain. The study was approved by the institutional review board and was compliant with HIPAA. With use of a 3.0-T clinical magnetic resonance (MR) unit and a 32-channel head coil, localized correlation spectroscopy was performed in six healthy control subjects and six patients with glioblastoma multiforme (GBM) with an acquisition time of 11 minutes. Two-dimensional spectra were processed and analyzed and peak volume ratios were tabulated. The data used were proved to be normally distributed by passing the Shapiro-Wilk normality test. The first row of the spectra was extracted to examine diagnostic features. The pathologic characteristics and grade of each GBM were determined after biopsy or surgery. Statistically significant differences were assessed by using a t test. The localized correlation spectroscopy method assigned biochemical species from the healthy human brain. The correlation spectra of GBM were of sufficiently high quality that many of the cross peaks, recorded previously from malignant cell models in vitro, were observed, demonstrating a statistically significant difference (P < .05) between the cross peak volumes measured for healthy subjects and those with GBM (which include lipid, alanine, N-acetylaspartate, γ-aminobutyric acid, glutamine and glutamate, glutathione, aspartate, lysine, threonine, total choline, glycerophosphorylcholine, myo-inositol, imidazole, uridine diphosphate glucose, isocitrate, lactate, and fucose). The first row of the spectra

  3. 'Chemo Brain' Lasts for Months in Many Breast Cancer Survivors

    MedlinePlus

    ... news/fullstory_162990.html 'Chemo Brain' Lasts for Months in Many Breast Cancer Survivors Altered thinking must ... after breast cancer treatment -- can persist for six months, new research shows. The finding comes from one ...

  4. Delivery of Small Interfering RNA to Inhibit Vascular Endothelial Growth Factor in Zebrafish Using Natural Brain Endothelia Cell-Secreted Exosome Nanovesicles for the Treatment of Brain Cancer.

    PubMed

    Yang, Tianzhi; Fogarty, Brittany; LaForge, Bret; Aziz, Salma; Pham, Thuy; Lai, Leanne; Bai, Shuhua

    2017-03-01

    Although small interfering RNA (siRNA) holds great therapeutic promise, its delivery to the disease site remains a paramount obstacle. In this study, we tested whether brain endothelial cell-derived exosomes could deliver siRNA across the blood-brain barrier (BBB) in zebrafish. Natural exosomes were isolated from brain endothelial bEND.3 cell culture media and vascular endothelial growth factor (VEGF) siRNA was loaded in exosomes with the assistance of a transfection reagent. While fluorescence-activated cell flow cytometry and immunocytochemistry staining studies indicated that wild-type exosomes significantly increased the uptake of fluorescence-labeled siRNA in the autologous brain endothelial cells, decreased fluorescence intensity was observed in the cells treated with the tetraspanin CD63 antibody-blocked exosome-delivered formulation (p < 0.05). In the transport study, exosomes also enhanced the permeability of rhodamine 123 in a co-cultured monolayer of brain endothelial bEND.3 cell and astrocyte. Inhibition at the expression of VEGF RNA and protein levels was observed in glioblastoma-astrocytoma U-87 MG cells treated with exosome-delivered siRNAs. Imaging results showed that exosome delivered more siRNAs across the BBB in Tg(fli1:GFP) zebrafish. In a xenotransplanted brain tumor model, exosome-delivered VEGF siRNAs decreased the fluorescence intensity of labeled cancer cells in the brain of zebrafish. Brain endothelial cell-derived exosomes could be potentially used as a natural carrier for the brain delivery of exogenous siRNA.

  5. Suppression of the Eag1 potassium channel sensitizes glioblastoma cells to injury caused by temozolomide

    PubMed Central

    Sales, Thais Torquato; Resende, Fernando Francisco Borges; Chaves, Natália Lemos; Titze-De-Almeida, Simoneide Souza; Báo, Sônia Nair; Brettas, Marcella Lemos; Titze-De-Almeida, Ricardo

    2016-01-01

    Glioblastoma multiforme (GBM) is the most aggressive type of human primary brain tumor. The standard treatment protocol includes radiotherapy in combination with temozolomide (TMZ). Despite advances in GBM treatment, the survival time of patients diagnosed with glioma is 14.5 months. Regarding tumor biology, various types of cancer cell overexpress the ether à go-go 1 (Eag1) potassium channel. Therefore, the present study examined the role of Eag1 in the cell damage caused by TMZ on the U87MG glioblastoma cell line. Eag1 was inhibited using a channel blocker (astemizole) or silenced by a short-hairpin RNA expression vector (pKv10.1-3). pKv10.1-3 (0.2 µg) improved the Eag1 silencing caused by 250 µM TMZ, as determined by reverse transcription-quantitative polymerase chain reaction and immunocytochemistry. Additionally, inhibiting Eag1 with the vector or astemizole (5 µM) reduced glioblastoma cell viability and sensitized cells to TMZ. Cell viability decreased by 63% for pKv10.1-3 + TMZ compared with 34% for TMZ alone, and by 77% for astemizole + TMZ compared with 46% for TMZ alone, as determined by MTT assay. In addition, both the vector and astemizole increased the apoptosis rate of glioblastoma cells triggered by TMZ, as determined by an Annexin V apoptosis assay. Collectively, the current data reveal that Eag1 has a role in the damage caused to glioblastoma by TMZ. Furthermore, suppression of this channel can improve the action of TMZ on U87MG glioblastoma cells. Thus, silencing Eag1 is a promising strategy to improve GBM treatment and merits additional studies in animal models of glioma. PMID:27698831

  6. Suppression of the Eag1 potassium channel sensitizes glioblastoma cells to injury caused by temozolomide.

    PubMed

    Sales, Thais Torquato; Resende, Fernando Francisco Borges; Chaves, Natália Lemos; Titze-De-Almeida, Simoneide Souza; Báo, Sônia Nair; Brettas, Marcella Lemos; Titze-De-Almeida, Ricardo

    2016-10-01

    Glioblastoma multiforme (GBM) is the most aggressive type of human primary brain tumor. The standard treatment protocol includes radiotherapy in combination with temozolomide (TMZ). Despite advances in GBM treatment, the survival time of patients diagnosed with glioma is 14.5 months. Regarding tumor biology, various types of cancer cell overexpress the ether à go-go 1 (Eag1) potassium channel. Therefore, the present study examined the role of Eag1 in the cell damage caused by TMZ on the U87MG glioblastoma cell line. Eag1 was inhibited using a channel blocker (astemizole) or silenced by a short-hairpin RNA expression vector (pKv10.1-3). pKv10.1-3 (0.2 µg) improved the Eag1 silencing caused by 250 µM TMZ, as determined by reverse transcription-quantitative polymerase chain reaction and immunocytochemistry. Additionally, inhibiting Eag1 with the vector or astemizole (5 µM) reduced glioblastoma cell viability and sensitized cells to TMZ. Cell viability decreased by 63% for pKv10.1-3 + TMZ compared with 34% for TMZ alone, and by 77% for astemizole + TMZ compared with 46% for TMZ alone, as determined by MTT assay. In addition, both the vector and astemizole increased the apoptosis rate of glioblastoma cells triggered by TMZ, as determined by an Annexin V apoptosis assay. Collectively, the current data reveal that Eag1 has a role in the damage caused to glioblastoma by TMZ. Furthermore, suppression of this channel can improve the action of TMZ on U87MG glioblastoma cells. Thus, silencing Eag1 is a promising strategy to improve GBM treatment and merits additional studies in animal models of glioma.

  7. MicroRNA-197 inhibits cell proliferation by targeting GAB2 in glioblastoma.

    PubMed

    Tian, Li-Qiang; Liu, En-Qin; Zhu, Xi-De; Wang, Xin-Gong; Li, Jian; Xu, Guang-Ming

    2016-05-01

    Glioblastoma is the most common type of primary brain tumor in adults, and is usually fatal in a short duration. Acquiring a better understanding of the pathogenic mechanisms of glioblastoma is essential to the design of effective therapeutic strategies. Grb2-associated binding protein 2 (GAB2) is a member of the daughter of sevenless/Gab family of scaffolding adapters, and has been reported to be important in the development and progression of human cancer. Previously, it has been reported that GAB2 is expressed at high levels in glioma, and may serve as a useful prognostic marker for glioma and a novel therapeutic target for glioma invasion intervention. Elucidating why GAB2 is overexpressed in glioma, and investigating how to downregulate it will assist in further understanding the pathogenesis and progression of the disease, and to offer novel targets for therapy. The present study used in situ hybridization to detect microRNA (miR)‑197 expression levels and Targetscan to predict that the 3'-UTR of GAB2 was targeted by miR-197. Northern blotting and reverse transcription‑quantitative polymerase chain reaction were also conducted in the current study. miR-197 is downregulated in glioblastoma tissues, compared with adjacent normal tissues, however it involvement continues to be detected in the disease. The results of the present study demonstrated that miR‑197, as a tumor suppressor gene, inhibited proliferation by regulating GAB2 in glioblastoma cells. Furthermore, GAB2 was not only upregulated in glioma, but its expression levels were also associated with the grades of glioma severity. In addition, overexpression of GAB2 suppressed the expression of miR‑197 in glioblastoma cells. Therefore, restoration of miR‑197 and targeting GAB2 may be used, in conjunction with other therapies, to prevent the progression of glioblastoma.

  8. Indirect costs associated with glioblastoma: Experience at one hospital.

    PubMed

    Undabeitia, J; Torres-Bayona, S; Samprón, N; Arrázola, M; Bollar, A; Armendariz, M; Torres, P; Ruiz, I; Caballero, M C; Egaña, L; Querejeta, A; Villanua, J; Pardo, E; Etxegoien, I; Liceaga, G; Urtasun, M; Michan, M; Emparanza, J I; Aldaz, P; Matheu, A; Úrculo, E

    2016-07-20

    Glioblastoma is the most common primary brain tumour. Despite advances in treatment, its prognosis remains dismal, with a mean survival time of about 14 months. Many articles have addressed direct costs, those associated with the diagnosis and treatment of the disease. Indirect costs, those associated with loss of productivity due to the disease, have seldom been described. We conducted a retrospective study in patients diagnosed with glioblastoma at Hospital Universitario Donostia between January 1, 2010 and December 31, 2013. We collected demographics, data regarding the treatment received, and survival times. We calculated the indirect costs with the human capital approach, adjusting the mean salaries of comparable individuals by sex and age and obtaining mortality data for the general population from the Spanish National Statistics Institute. Past salaries were updated to 2015 euros according to the annual inflation rate and we applied a discount of 3.5% compounded yearly to future salaries. We reviewed the records of 99 patients: 46 women (mean age 63.53) and 53 men (mean age 59.94); 29 patients underwent a biopsy and the remaining 70 underwent excisional surgery. Mean survival was 18.092 months for the whole series. The total indirect cost for the series was €11 080 762 (2015). Mean indirect cost per patient was €111 926 (2015). Although glioblastoma is a relatively uncommon type of tumour, accounting for only 4% of all cancers, its poor prognosis and potential sequelae generate disproportionately large morbidity and mortality rates which translate to high indirect costs. Clinicians should be aware of the societal impact of glioblastoma and indirect costs should be taken into account when cost effectiveness studies are performed to better illustrate the overall consequences of this disease. Copyright © 2016 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

  9. Immune Checkpoint Blockade Biology in Mouse Models of Glioblastoma.

    PubMed

    Yeo, Alan T; Charest, Alain

    2017-09-01

    Glioblastoma Multiforme (GBM) is a highly malignant primary brain cancer that is associated with abysmal prognosis. The median survival of GBM patients is ∼15 months and there have not been any significant advance in therapies in over a decade, leaving treatment options limited. There is clearly an unmet need for GBM treatment. Immunotherapies are treatments based on usurping the power of the host's immune system to recognize and eliminate cancer cells. They have recently proven to be a successful strategy for combating a variety of cancers. Of the various types of immunotherapies, checkpoint blockade approaches have thus far produced significant clinical responses in several cancers including melanoma, non small-cell lung cancer, renal cancer, and prostate cancer. This review focuses on the biological rationale for using checkpoint blockade immunotherapeutic approaches in primary brain cancer and an up-to-date summary of current and ongoing checkpoint inhibitors-based clinical trials for malignant glioma. In addition, we expand on new concepts for further improving checkpoint blockade treatments, with a particular focus on the advantages of using genetically engineered mouse models for studies of immunotherapies in GBM. J. Cell. Biochem. 118: 2516-2527, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  10. Caffeine-mediated inhibition of calcium release channel inositol 1,4,5-trisphosphate receptor subtype 3 blocks glioblastoma invasion and extends survival.

    PubMed

    Kang, Sang Soo; Han, Kyung-Seok; Ku, Bo Mi; Lee, Yeon Kyung; Hong, Jinpyo; Shin, Hye Young; Almonte, Antoine G; Woo, Dong Ho; Brat, Daniel J; Hwang, Eun Mi; Yoo, Seung Hyun; Chung, Chun Kee; Park, Sung-Hye; Paek, Sun Ha; Roh, Eun Joo; Lee, Sung Joong; Park, Jae-Yong; Traynelis, Stephen F; Lee, C Justin

    2010-02-01

    Calcium signaling is important in many signaling processes in cancer cell proliferation and motility including in deadly glioblastomas of the brain that aggressively invade neighboring tissue. We hypothesized that disturbing Ca(2+) signaling pathways might decrease the invasive behavior of giloblastoma, extending survival. Evaluating a panel of small-molecule modulators of Ca(2+) signaling, we identified caffeine as an inhibitor of glioblastoma cell motility. Caffeine, which is known to activate ryanodine receptors, paradoxically inhibits Ca(2+) increase by inositol 1,4,5-trisphospate receptor subtype 3 (IP(3)R3), the expression of which is increased in glioblastoma cells. Consequently, by inhibiting IP(3)R3-mediated Ca(2+) release, caffeine inhibited migration of glioblastoma cells in various in vitro assays. Consistent with these effects, caffeine greatly increased mean survival in a mouse xenograft model of glioblastoma. These findings suggest IP(3)R3 as a novel therapeutic target and identify caffeine as a possible adjunct therapy to slow invasive growth of glioblastoma.

  11. Toward intracellular targeted delivery of cancer therapeutics: progress and clinical outlook for brain tumor therapy.

    PubMed

    Pandya, Hetal; Debinski, Waldemar

    2012-08-01

    A number of anti-cancer drugs have their targets localized to particular intracellular compartments. These drugs reach the targets mainly through diffusion, dependent on biophysical and biochemical forces that allow cell penetration. This means that both cancer cells and normal cells will be subjected to such diffusion; hence many of these drugs, like chemotherapeutics, are potentially toxic and the concentration achieved at the site of their action is often suboptimal. The same relates to radiation that indiscriminately affects normal and diseased cells. However, nature-designed systems enable compounds present in the extracellular environment to end up inside the cell and even travel to more specific intracellular compartments. For example, viruses and bacterial toxins can more or less specifically recognize eukaryotic cells, enter these cells, and direct some protein portions to designated intracellular areas. These phenomena have led to creative thinking, such as employing viruses or bacterial toxins for cargo delivery to cells and, more specifically, to cancer cells. Proteins can be genetically engineered in order to not only mimic what viruses and bacterial toxins can do, but also to add new functions, extending or changing the intracellular routes. It is possible to make conjugates or, more preferably, single-chain proteins that recognize cancer cells and deliver cargo inside the cells, even to the desired subcellular compartment. These findings offer new opportunities to deliver drugs/labels only to cancer cells and only to their site of action within the cells. The development of such dual-specificity vectors for targeting cancer cells is an attractive and potentially safer and more efficacious way of delivering drugs. We provide examples of this approach for delivering brain cancer therapeutics, using a specific biomarker on glioblastoma tumor cells.

  12. Evo-Devo and the evolution of cancer: a hypothesis for metamorphic therapies for the cancers of prolactin-influenced tumourigenesis: with special reference to glioblastoma multiforme (GBM).

    PubMed

    Pearson, Roy Douglas

    2009-06-01

    Recalling the remarkable developmental similarities between cancer cells and embryonic tissues, this paper argues that, by the process of retrodifferentiation and heterochronization, stem cells that have become neoplastic could be said to have undergone "cellular heterochrony." It theorizes, therefore, that hormones are the major factor in the non-random regulation of cellular heterochrony in tumourigenesis. Two recent articles confirm that there is low thyroxine and high prolactin in glioblastomas. Thyroxine metamorphoses vertebrates' tissues so as to mature the tissues, e.g., in amphibian metamorphosis. In 1896, thyroxine (horse thyroid extract) was the first successful hormonal product to be used against a fulminating breast cancer. Recent work confirms the important role of prolactin in the induction and progression of mammary, prostate and colorectal tumours. Although the pituitary is the main source of prolactin in vertebrates, there is also placental production of prolactin, and paracrine production of prolactin by tumours themselves. Since tumours produce their own prolactin, shutting down the pituitary source has not proven wholly successful. Research to find prolactin receptor antagonists is ongoing. Therefore, prolactin inhibitors (dopamine agonists), prolactin receptor antagonists, plus thyroxine comprise a plausible metamorphic therapy for shrinking solid tumour mass. By contrast with "differentiation" therapies currently sought by stem cell oncologists, this paper advocates "metamorphic" therapies, to introduce hormonal oncological knowledge of how to modulate signalling pathways that are aberrant in the stem cells that give rise to tumours. Despite subtle differences in these signalling translation pathways and cascades, strategies exist that will allow these evolved populations, going back to their stem precursors, to "metamorphose" or perhaps apoptotically cease proliferation.

  13. From glioblastoma to endothelial cells through extracellular vesicles: messages for angiogenesis.

    PubMed

    Giusti, Ilaria; Delle Monache, Simona; Di Francesco, Marianna; Sanità, Patrizia; D'Ascenzo, Sandra; Gravina, Giovanni Luca; Festuccia, Claudio; Dolo, Vincenza

    2016-09-01

    Glioblastoma has one of the highest mortality rates among cancers, and it is the most common and malignant form of brain cancer. Among the typical features of glioblastoma tumors, there is an aberrant vascularization: all gliomas are among the most vascularized/angiogenic tumors. In recent years, it has become clear that glioblastoma cells can secrete extracellular vesicles which are spherical and membrane-enclosed particles released, in vitro or in vivo, by both normal and tumor cells; they are involved in the regulation of both physiological and pathological processes; among the latter, cancer is the most widely studied. Extracellular vesicles from tumor cells convey messages to other tumor cells, but also to normal stromal cells in order to create a microenvironment that supports cancer growth and progression and are implicated in drug resistance, escape from immunosurveillance and from apoptosis, as well as in metastasis formation; they are also involved in angiogenesis stimulation, inducing endothelial cells proliferation, and other pro-angiogenic activities. To this aim, the present paper assesses in detail the extracellular vesicles phenomenon in the human glioblastoma cell line U251 and evaluates extracellular vesicles ability to promote the processes required to achieve the formation of new blood vessels in human brain microvascular endothelial cells, highlighting that they stimulate proliferation, motility, and tube formation in a dose-response manner. Moreover, a molecular characterization shows that extracellular vesicles are fully equipped for angiogenesis stimulation in terms of proteolytic enzymes (gelatinases and plasminogen activators), pro-angiogenic growth factors (VEGF and TGFβ), and the promoting-angiogenic CXCR4 chemokine receptor.

  14. Heat Shock Factor 1 Depletion Sensitizes A172 Glioblastoma Cells to Temozolomide via Suppression of Cancer Stem Cell-Like Properties

    PubMed Central

    Im, Chang-Nim; Yun, Hye Hyeon; Lee, Jeong-Hwa

    2017-01-01

    Heat shock factor 1 (HSF1), a transcription factor activated by various stressors, regulates proliferation and apoptosis by inducing expression of target genes, such as heat shock proteins and Bcl-2 (B-cell lymphoma 2) interacting cell death suppressor (BIS). HSF1 also directly interacts with BIS, although it is still unclear whether this interaction is critical in the regulation of glioblastoma stem cells (GSCs). In this study, we examined whether small interfering RNA-mediated BIS knockdown decreased protein levels of HSF1 and subsequent nuclear localization under GSC-like sphere (SP)-forming conditions. Consistent with BIS depletion, HSF1 knockdown also reduced sex determining region Y (SRY)-box 2 (SOX2) expression, a marker of stemness, accompanying the decrease in SP-forming ability and matrix metalloprotease 2 (MMP2) activity. When HSF1 or BIS knockdown was combined with temozolomide (TMZ) treatment, a standard drug used in glioblastoma therapy, apoptosis increased, as measured by an increase in poly (ADP-ribose) polymerase (PARP) cleavage, whereas cancer stem-like properties, such as colony-forming activity and SOX2 protein expression, decreased. Taken together, our findings suggest that targeting BIS or HSF1 could be a viable therapeutic strategy for GSCs resistant to conventional TMZ treatment. PMID:28241425

  15. Role of the neural niche in brain metastatic cancer.

    PubMed

    Termini, John; Neman, Josh; Jandial, Rahul

    2014-08-01

    Metastasis is the relentless pursuit of cancer to escape its primary site and colonize distant organs. This malignant evolutionary process is biologically heterogeneous, yet one unifying element is the critical role of the microenvironment for arriving metastatic cells. Historically, brain metastases were rarely investigated because patients with advanced cancer were considered terminal. Fortunately, advances in molecular therapies have led to patients living longer with metastatic cancer. However, one site remains recalcitrant to our treatment efforts, the brain. The central nervous system is the most complex biologic system, which poses unique obstacles but also harbors opportunities for discovery. Much of what we know about the brain microenvironment comes from neuroscience. We suggest that the interrelated cellular responses in traumatic brain injury may guide us toward new perspectives in understanding brain metastases. In this view, brain metastases may be conceptualized as progressive oncologic injury to the nervous system. This review discusses our evolving understanding of bidirectional interactions between the brain milieu and metastatic cancer.

  16. Combining NK cells and mAb9.2.27 to combat NG2-dependent and anti-inflammatory signals in glioblastoma.

    PubMed

    Kmiecik, Justyna; Gras Navarro, Andrea; Poli, Aurelie; Planagumà, Jesús Planagumà; Zimmer, Jacques; Chekenya, Martha

    2014-01-01

    Glioblastoma is a deadly brain cancer with limited treatment options. Targeting chondroitin sulfate proteoglycan 4 (CSPG4, best known as NG2) with the monoclonal antibody mAb9.2.27 and activated natural killer (NK) cells abrogated the tumor growth and prolonged the survival of glioblastoma-bearing animals by favoring the establishment of a pro-inflammatory microenvironment. The combination of NK cells and mAb9.2.27 recruited ED1(+)CCR2(low) macrophages that stimulated ED1(+)ED2(low)MHCII(high) microglial cells to exert robust cytotoxicity. Our findings demonstrate the therapeutic potential of targeting salient tumor associated-antigens.

  17. HMGCR positively regulated the growth and migration of glioblastoma cells.

    PubMed

    Qiu, Zhihua; Yuan, Wen; Chen, Tao; Zhou, Chenzhi; Liu, Chao; Huang, Yongkai; Han, Deqing; Huang, Qinghui

    2016-01-15

    The metabolic program of cancer cells is significant different from the normal cells, which makes it possible to develop novel strategies targeting cancer cells. Mevalonate pathway and its rate-limiting enzyme HMG-CoA reductase (HMGCR) have shown important roles in the progression of several cancer types. However, their roles in glioblastoma cells remain unknown. In this study, up-regulation of HMGCR in the clinical glioblastoma samples was observed. Forced expression of HMGCR promoted the growth and migration of U251 and U373 cells, while knocking down the expression of HMGCR inhibited the growth, migration and metastasis of glioblastoma cells. Molecular mechanism studies revealed that HMGCR positively regulated the expression of TAZ, an important mediator of Hippo pathway, and the downstream target gene connective tissue growth factor (CTGF), suggesting HMGCR might activate Hippo pathway in glioblastoma cells. Taken together, our study demonstrated the oncogenic roles of HMGCR in glioblastoma cells and HMGCR might be a promising therapeutic target.

  18. Systemic analysis of genome-wide expression profiles identified potential therapeutic targets of demethylation drugs for glioblastoma.

    PubMed

    Ning, Tongbo; Cui, Hao; Sun, Feng; Zou, Jidian

    2017-09-05

    Glioblastoma represents one of the most aggressive malignant brain tumors with high morbidity and motility. Demethylation drugs have been developed for its treatment with little efficacy has been observed. The purpose of this study was to screen therapeutic targets of demethylation drugs or bioactive molecules for glioblastoma through systemic bioinformatics analysis. We firstly downloaded genome-wide expression profiles from the Gene Expression Omnibus (GEO) and conducted the primary analysis through R software, mainly including preprocessing of raw microarray data, transformation between probe ID and gene symbol and identification of differential expression genes (DEGs). Secondly, functional enrichment analysis was conducted via the Database for Annotation, Visualization and Integrated Discovery (DAVID) to explore biological processes involved in the development of glioblastoma. Thirdly, we constructed protein-protein interaction (PPI) network of interested genes and conducted cross analysis for multi datasets to obtain potential therapeutic targets for glioblastoma. Finally, we further confirmed the therapeutic targets through real-time RT-PCR. As a result, biological processes that related to cancer development, amino metabolism, immune response and etc. were found to be significantly enriched in genes that differential expression in glioblastoma and regulated by 5'aza-dC. Besides, network and cross analysis identified ACAT2, UFC1 and CYB5R1 as novel therapeutic targets of demethylation drugs which also confirmed by real time RT-PCR. In conclusions, our study identified several biological processes and genes that involved in the development of glioblastoma and regulated by 5'aza-dC, which would be helpful for the treatment of glioblastoma. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. Integrative genome-wide analysis reveals a robust genomic glioblastoma signature associated with copy number driving changes in gene expression.

    PubMed

    de Tayrac, Marie; Etcheverry, Amandine; Aubry, Marc; Saïkali, Stephan; Hamlat, Abderrahmane; Quillien, Veronique; Le Treut, André; Galibert, Marie-Dominique; Mosser, Jean

    2009-01-01

    Glioblastoma multiforme shows multiple chromosomal aberrations, the impact of which on gene expression remains unclear. To investigate this relationship and to identify putative initiating genomic events, we integrated a paired copy number and gene expression survey in glioblastoma using whole human genome arrays. Loci of recurrent copy number alterations were combined with gene expression profiles obtained on the same tumor samples. We identified a set of 406 "cis-acting DNA targeted genes" corresponding to genomic aberrations with direct copy-number-driving changes in gene expression, defined as genes with either significantly concordant or correlated changes in DNA copy number and expression. Functional annotation revealed that these genes participate in key processes of cancer cell biology, providing insights into the genetic mechanisms driving glioblastoma. The robustness of the gene selection was validated on an external microarray data set including 81 glioblastomas and 23 non-neoplastic brain samples. The integration of array CGH and gene expression data highlights a robust cis-acting DNA targeted genes signature that may be critical for glioblastoma progression, with two tumor suppressor genes PCDH9 and STARD13 that could be involved in tumor invasiveness and resistance to etoposide.

  20. Synergistic anti-cancer mechanisms of curcumin and paclitaxel for growth inhibition of human brain tumor stem cells and LN18 and U138MG cells

    PubMed Central

    Hossain, Md. Motarab; Banik, Naren L.; Ray, Swapan K.

    2012-01-01

    Glioblastoma, the deadliest brain tumor in humans, responds poorly to conventional chemotherapeutic agents because of existence of highly chemoresistant human brain tumor stem cells (HBTSC). An effective therapeutic strategy is urgently needed to target HBTSC as well as other glioblastoma cells. We explored synergistic efficacy of a low dose of curcumin (CCM) and a low dose of paclitaxel (PTX) in HBTSC and human glioblastoma LN18 (p53 mutant and PTEN proficient) and U138MG (p53 mutant and PTEN mutant) cells. The highest expression of the cancer stem cell markers aldehyde dehydrogenase 1 (ALDH1) and CD133 occurred in HBTSC when compared with LN18 and U138MG cells. Combination of 20 µM CCM and 10 nM PTX worked synergistically and more effectively than either drug alone in decreasing viability in all cells. Combination of CCM and PTX was highly effective in inducing both morphological and biochemical features of apoptosis. Apoptosis required activation of caspase-8, cleavage of Bid to tBid, increase in Bax:Bcl-2 ratio, and mitochondrial release of cytochrome c, Smac, and apoptosis-inducing factor (AIF). Phosphorylation of Bcl-2 following combination therapy appeared to promote Bax homodimerization and mitochondrial release of proapoptotic factors into the cytosol. Increases in activities cysteine proteases confirmed the completion of apoptotic process. Combination therapy inhibited invasion of cells, reduced expression of survival and proliferation factors and also angiogenic factors, and prevented HBTSC, LN18, and U138MG cells from promoting network formation. Collectively, the combination of CCM and PTX worked as a promising therapy for controlling the growth of HBTSC and other glioblastoma cells. PMID:22910273

  1. Aquaporins and Brain Tumors

    PubMed Central

    Maugeri, Rosario; Schiera, Gabriella; Di Liegro, Carlo Maria; Fricano, Anna; Iacopino, Domenico Gerardo; Di Liegro, Italia

    2016-01-01

    Brain primary tumors are among the most diverse and complex human cancers, and they are normally classified on the basis of the cell-type and/or the grade of malignancy (the most malignant being glioblastoma multiforme (GBM), grade IV). Glioma cells are able to migrate throughout the brain and to stimulate angiogenesis, by inducing brain capillary endothelial cell proliferation. This in turn causes loss of tight junctions and fragility of the blood–brain barrier, which becomes leaky. As a consequence, the most serious clinical complication of glioblastoma is the vasogenic brain edema. Both glioma cell migration and edema have been correlated with modification of the expression/localization of different isoforms of aquaporins (AQPs), a family of water channels, some of which are also involved in the transport of other small molecules, such as glycerol and urea. In this review, we discuss relationships among expression/localization of AQPs and brain tumors/edema, also focusing on the possible role of these molecules as both diagnostic biomarkers of cancer progression, and therapeutic targets. Finally, we will discuss the possibility that AQPs, together with other cancer promoting factors, can be exchanged among brain cells via extracellular vesicles (EVs). PMID:27367682

  2. Brain Cancer in Workers Employed at a Laboratory Research Facility

    PubMed Central

    Collins, James J.; Bender, Thomas John; Bonner, Eileen M.; Bodner, Kenneth M.; Kreft, Alisa M.

    2014-01-01

    Background An earlier study of research facility workers found more brain cancer deaths than expected, but no workplace exposures were implicated. Methods Adding four additional years of vital-status follow-up, we reassessed the risk of death from brain cancer in the same workforce, including 5,284 workers employed between 1963, when the facility opened, and 2007. We compared the work histories of the brain cancer decedents in relationship to when they died and their ages at death. Results As in most other studies of laboratory and research workers, we found low rates of total mortality, total cancers, accidents, suicides, and chronic conditions such as heart disease and diabetes. We found no new brain cancer deaths in the four years of additional follow-up. Our best estimate of the brain cancer standardized mortality ratio (SMR) was 1.32 (95% confidence interval [95% CI] 0.66–2.37), but the SMR might have been as high as 1.69. Deaths from benign brain tumors and other non-malignant diseases of the nervous system were at or below expected levels. Conclusion With the addition of four more years of follow-up and in the absence of any new brain cancers, the updated estimate of the risk of brain cancer death is smaller than in the original study. There was no consistent pattern among the work histories of decedents that indicated a common causative exposure. PMID:25493437

  3. Core Canonical Pathways Involved in Developing Human Glioblastoma Multiforme (GBM).

    PubMed

    Ghosh, Somiranjan; Dutta, Sisir; Thorne, Gabriel; Boston, Ava; Barfield, Alexis; Banerjee, Narendra; Walker, Rayshawn; Banerjee, Hirendra Nath

    2017-02-01

    Glioblastoma multiforme (GBM) is the most common and aggressive type of the primary brain tumors with pathologic hallmarks of necrosis and vascular proliferation. The diagnosis of GBM is currently mostly based on histological examination of brain tumor tissues, after radiological characterization and surgical biopsy. The ability to characterize tumors comprehensively at the molecular level raises the possibility that diagnosis can be made based on molecular profiling with or without histological examination, rather than solely on histological phenotype. The development of novel genomic and proteomic techniques will foster in the identification of such diagnostic and prognostic molecular markers. We analyzed the global differential gene expression of a GBM cell line HTB15 in comparison to normal human Astrocytes, and established a few canonical pathways that are important in determining the molecular mechanisms of cancer using global gene expression microarray, coupled with the Ingenuity Pathway Analysis (IPA®). Overall, we revealed a discrete gene expression profile in the experimental model that resembled progression of GBM cancer. The canonical pathway analysis showed the involvement of genes that differentially expressed in such a disease condition that included Inositol pathway, Polo like kinases, nNOS signaling, and Tetrapyrrole biosynthesis. Our findings established that the gene expression pattern of this dreaded brain cancer will probably help the cancer research community by finding out newer therapeutic strategies to combat this dreaded cancer type that leads to the identification of high-risk population in this category, with almost hundred percent mortality rate.

  4. Novel Nanotechnologies for Brain Cancer Therapeutics and Imaging.

    PubMed

    Ferroni, Letizia; Gardin, Chiara; Della Puppa, Alessandro; Sivolella, Stefano; Brunello, Giulia; Scienza, Renato; Bressan, Eriberto; D'Avella, Domenico; Zavan, Barbara

    2015-11-01

    Despite progress in surgery, radiotherapy, and in chemotherapy, an effective curative treatment of brain cancer, specifically malignant gliomas, does not yet exist. The efficacy of current anti-cancer strategies in brain tumors is limited by the lack of specific therapies against malignant cells. Besides, the delivery of the drugs to brain tumors is limited by the presence of the blood-brain barrier. Nanotechnology today offers a unique opportunity to develop more effective brain cancer imaging and therapeutics. In particular, the development of nanocarriers that can be conjugated with several functional molecules including tumor-specific ligands, anticancer drugs, and imaging probes, can provide new devices which are able to overcome the difficulties of the classical strategies. Nanotechnology-based approaches hold great promise for revolutionizing brain cancer medical treatments, imaging, and diagnosis.

  5. Brain Cancer Stem Cells Display Preferential Sensitivity to Akt Inhibition

    PubMed Central

    Eyler, Christine E.; Foo, Wen-Chi; LaFiura, Katherine M.; McLendon, Roger E.; Hjelmeland, Anita B.; Rich, Jeremy N.

    2009-01-01

    Malignant brain tumors are among the most lethal cancers, and conventional therapies are largely limited to palliation. Novel therapies targeted against specific molecular pathways may offer improved efficacy and reduced toxicity compared to conventional therapies, but initial clinical trials of molecular targeted agents in brain cancer therapy have been frequently disappointing. In brain tumors and other cancers, subpopulations of tumor cells have recently been characterized by their ability to self-renew and initiate tumors. Although these cancer stem cells, or tumor initiating cells, are often only present in small numbers in human tumors, mounting evidence suggests that cancer stem cells contribute to tumor maintenance and therapeutic resistance. Thus, the development of therapies that target cancer stem cell signal transduction and biologies may improve brain tumor patient survival. We now demonstrate that populations enriched for cancer stem cells are preferentially sensitive to an inhibitor of Akt, a prominent cell survival and invasion signaling node. Treatment with an Akt inhibitor more potently reduced the numbers of viable brain cancer stem cells relative to matched non-stem cancer cells associated with a preferential induction of apoptosis and a suppression of neurosphere formation. Akt inhibition also reduced the motility and invasiveness of all tumor cells but had a greater impact on cancer stem cell behaviors. Furthermore, inhibition of Akt activity in cancer stem cells increased survival of immunocompromised mice bearing human glioma xenografts in vivo. Together, these results suggest that Akt inhibitors may function as effective anti-cancer stem cell therapies. PMID:18802038

  6. Incidence of brain metastasis from esophageal cancer.

    PubMed

    Welch, G; Ross, H J; Patel, N P; Jaroszewski, D E; Fleischer, D E; Rule, W G; Paripati, H R; Ramirez, F C; Ashman, J B

    2017-09-01

    We investigated whether the incidence of brain metastasis (BM) from primary esophageal and esophagogastric cancer is increasing. A single-institution retrospective review identified 583 patients treated from January 1997 to January 2016 for stages I through IV cancer of the esophagus and esophagogastric junction (follow-up, ≥3 months). Collected data included demographic information, date and staging at primary diagnosis, histologic subtype, treatment regimen for primary lesion, date of BM diagnosis, presence or absence of central nervous system symptoms, presence or absence of extracranial disease, treatment regimen for intracranial lesions, and date of death. The overall cohort included 495 patients (85%) with adenocarcinoma and 82 (14%) with squamous cell carcinoma (492 [84%] were male; median age at diagnosis, 68 years [range: 26-90 years]). BM was identified in 22 patients (3.8%) (median latency after primary diagnosis, 11 months). Among patients with BM, the primary histology was adenocarcinoma in 21 and squamous cell carcinoma in 1 (P = 0.30). BM developed in 12 who were initially treated for locally advanced disease and in 10 stage IV patients who presented with distant metastases. Overall survival (OS) after BM diagnosis was 18% at 1 year (median, 4 months). No difference in OS after BM diagnosis was observed in patients initially treated for localized disease compared to patients who presented with stage IV disease; however, OS was superior for patients who initially had surgical resection compared to patients treated with whole brain radiotherapy or stereotactic radiosurgery alone (1-year OS, 67% vs. 0%; median OS, 13.5 vs. 3 months; P = 0.003). The incidence of BM is low in patients with esophageal cancer. Outcomes were poor overall for patients with BM, but patients who underwent neurosurgical resection had improved survival. © The Authors 2017. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus

  7. PCDH10 is required for the tumorigenicity of glioblastoma cells

    SciTech Connect

    Echizen, Kanae; Nakada, Mitsutoshi; Hayashi, Tomoatsu; Sabit, Hemragul; Furuta, Takuya; Nakai, Miyuki; Koyama-Nasu, Ryo; Nishimura, Yukiko; Taniue, Kenzui; Morishita, Yasuyuki; Hirano, Shinji; Terai, Kenta; Todo, Tomoki; Ino, Yasushi; Mukasa, Akitake; Takayanagi, Shunsaku; Ohtani, Ryohei; Saito, Nobuhito; Akiyama, Tetsu

    2014-01-31

    Highlights: • PCDH10 is required for the proliferation, survival and self-renewal of glioblastoma cells. • PCDH10 is required for glioblastoma cell migration and invasion. • PCDH10 is required for the tumorigenicity of glioblastoma cells. • PCDH10 may be a promising target for the therapy of glioblastoma. - Abstract: Protocadherin10 (PCDH10)/OL-protocadherin is a cadherin-related transmembrane protein that has multiple roles in the brain, including facilitating specific cell–cell connections, cell migration and axon guidance. It has recently been reported that PCDH10 functions as a tumor suppressor and that its overexpression inhibits proliferation or invasion of multiple tumor cells. However, the function of PCDH10 in glioblastoma cells has not been elucidated. In contrast to previous reports on other tumors, we show here that suppression of the expression of PCDH10 by RNA interference (RNAi) induces the growth arrest and apoptosis of glioblastoma cells in vitro. Furthermore, we demonstrate that knockdown of PCDH10 inhibits the growth of glioblastoma cells xenografted into immunocompromised mice. These results suggest that PCDH10 is required for the proliferation and tumorigenicity of glioblastoma cells. We speculate that PCDH10 may be a promising target for the therapy of glioblastoma.

  8. Association between RAD 51 rs1801320 and susceptibility to glioblastoma.

    PubMed

    Franceschi, S; Tomei, S; Mazzanti, C M; Lessi, F; Aretini, P; La Ferla, M; De Gregorio, V; Pasqualetti, F; Zavaglia, K; Bevilacqua, G; Naccarato, A G

    2016-01-01

    Glioblastoma is the most common and aggressive malignant primary brain tumor. Despite decades of research and the advent of new therapies, patients with glioblastoma continue to have a very poor prognosis. Radiation therapy has a major role as adjuvant treatment for glioblastoma following surgical resection. Many studies have shown that polymorphisms of genes involved in pathways of DNA repair may affect the sensitivity of the cells to treatment. Although the role of these polymorphisms has been investigated in relation to response to radiotherapy, their role as predisposing factors to glioblastoma has not been clarified yet. In the present study, we evaluated the association between polymorphisms in DNA repair genes, namely: XRCC1 rs25487, XRCC3 rs861539 and RAD51 rs1801320, with the susceptibility to develop glioblastoma. Eighty-five glioblastoma patients and 70 matched controls were recruited for this study. Data from the 1000 Genomes Project (98 Tuscans) were also downloaded and used for the association analysis. Subjects carrying RAD51 rs1801320 GC genotype showed an increased risk of glioblastoma (GC vs GG, χ(2) = 10.75; OR 3.0087; p = 0.0010). The C allele was also significantly associated to glioblastoma (χ(2) = 8.66; OR 2.5674; p = 0.0032). Moreover, RAD51 rs1801320 C allele increased the risk to develop glioblastoma also when combined to XRCC1 rs25487 G allele and XRCC3 rs861539 C allele (χ(2) = 6.558; p = 0.0053).

  9. Synthesis of tetrahydrohonokiol derivates and their evaluation for cytotoxic activity against CCRF-CEM leukemia, U251 glioblastoma and HCT-116 colon cancer cells.

    PubMed

    Bernaskova, Marketa; Kretschmer, Nadine; Schuehly, Wolfgang; Huefner, Antje; Weis, Robert; Bauer, Rudolf

    2014-01-20

    Biphenyl neolignans such as honokiol and magnolol, which are the major active constituents of the Asian medicinal plant Magnolia officinalis, are known to exert a multitude of pharmacological and biological activities. Among these, cytotoxic and tumor growth inhibitory activity against various tumour cell lines are well-documented. To further elucidate the cytotoxic effects of honokiol derivatives, derivatizations were performed using tetrahydrohonokiol as a scaffold. The derivatizations comprised the introduction of functional groups, e.g., nitro and amino groups, as well as alkylation. This way, 18 derivatives, of which 13 were previously undescribed compounds, were evaluated against CCRF-CEM leukemia cells, U251 glioblastoma and HCT-116 colon cancer cells. The results revealed no significant cytotoxic effects in any of the three tested cell lines at a test concentration of 10 µM.

  10. Apoptotic effect of atorvastatin in glioblastoma spheroids tumor cultured in fibrin gel.

    PubMed

    Bayat, Neda; Ebrahimi-Barough, Somayeh; Norouzi-Javidan, Abbas; Saberi, Hooshang; Tajerian, Roksana; Ardakan, Mohammad Mehdi Mokhtari; Shirian, Sadegh; Ai, Arman; Ai, Jafar

    2016-12-01

    Glioblastoma multiform (GBM) is one of the most common and highly aggressive primary brain tumors that thought to be of glial cells origin. The new available therapy for glioblastoma is based on better understanding of molecular malignant progression in this tumor. It is better to identify key molecular targets stimulating signaling pathways that lead to initiation of apoptosis for treatment of glioblastoma. Tumorigenesis broadly is controlled by tumor microenvironment and design of best biomimetic culture systems dependency on these conditions allow for in vitro and in vivo tumor modeling for studies of cancer cells behavior to drugs. We engineered three-dimensional (3D) human tumor models using U87 glioma cells in fibrin gel that mimic microenvironmental feature of glioblastoma in vivo. In this study, atorvastatin was used as a kind of statins for induction of apoptosis, and inhibition of migration and invasion in glioma cells. To reach for these aims, 3D model of glioma in fibrin gel was used with different concentrations of atorvastatin (1, 5, 10μM) to assay apoptotic genes expression by real time PCR and Tunel assay. After 24 and 48h exposing with different concentrations of atorvastatin, cell migration and invasion of tumor cells were investigated. The results showed atorvastatin induced apoptosis of glioma spheroids dose- dependently. The most likely mechanisms are the induction of apoptosis by caspase-8- caspase-3 signaling pathway. The invasion and migration of U87 spheroid cells decreased after 48h especially with 10μM concentration of atorvastatin. Finally these results suggest that this biomimetic model with fibrin may provide a vastly applicable 3D culture system to study the effect of anti-cancer drugs such as atrovastatin on tumor malignancy in vitro and in vivo and atorvastatin could be used as anticancer agent for glioblastoma treatment. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  11. Targeting Phosphatidylserine for Radioimmunotherapy of Breast Cancer Brain Metastasis

    DTIC Science & Technology

    2015-12-01

    Award Number: W81XWH-12-1-0316 TITLE: Targeting Phosphatidylserine for Radioimmunotherapy of Breast Cancer Brain Metastasis PRINCIPAL...Cancer Brain Metastasis 5b. GRANT NUMBER W81XWH-12-1-0316 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT NUMBER Rolf A. Brekken...DISTRIBUTION / AVAILABILITY STATEMENT Approved for public release; distribution unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT Brain metastasis occurs in

  12. Targeting Phosphatidylserince for Radioimmunotherapy of Breast Cancer Brain Metastasis

    DTIC Science & Technology

    2014-10-01

    Targeting Phosphatidylserine for Radioimmunotherapy of Breast Cancer Brain Metastasis 5b. GRANT NUMBER W81XWH-12-1-0316 5c. PROGRAM ELEMENT NUMBER 6...SUPPLEMENTARY NOTES 14. ABSTRACT Brain metastasis occurs in ~30% of metastatic breast cancer patients. The prognosis is extremely poor, with a...Introduction Brain metastasis is the most common intracranial malignancy in adults. The prognosis is extremely poor, with a median survival of 4-6 months even

  13. Constitutive activation of signal transducer and activator of transcription 3 (STAT3) and nuclear factor κB signaling in glioblastoma cancer stem cells regulates the Notch pathway.

    PubMed

    Garner, Jo Meagan; Fan, Meiyun; Yang, Chuan He; Du, Ziyun; Sims, Michelle; Davidoff, Andrew M; Pfeffer, Lawrence M

    2013-09-06

    Malignant gliomas are locally aggressive, highly vascular tumors that have a dismal prognosis, and present therapies provide little improvement in the disease course and outcome. Many types of malignancies, including glioblastoma, originate from a population of cancer stem cells (CSCs) that are able to initiate and maintain tumors. Although CSCs only represent a small fraction of cells within a tumor, their high tumor-initiating capacity and therapeutic resistance drives tumorigenesis. Therefore, it is imperative to identify pathways associated with CSCs to devise strategies to selectively target them. In this study, we describe a novel relationship between glioblastoma CSCs and the Notch pathway, which involves the constitutive activation of STAT3 and NF-κB signaling. Glioma CSCs were isolated and maintained in vitro using an adherent culture system, and the biological properties were compared with the traditional cultures of CSCs grown as multicellular spheres under nonadherent culture conditions. Interestingly, both adherent and spheroid glioma CSCs show constitutive activation of the STAT3/NF-κB signaling pathway and up-regulation of STAT3- and NF-κB-dependent genes. Gene expression profiling also identified components of the Notch pathway as being deregulated in glioma CSCs, and the deregulated expression of these genes was sensitive to treatment with STAT3 and NF-κB inhibitors. This finding is particularly important because Notch signaling appears to play a key role in CSCs in a variety of cancers and controls cell fate determination, survival, proliferation, and the maintenance of stem cells. The constitutive activation of STAT3 and NF-κB signaling pathways that leads to the regulation of Notch pathway genes in glioma CSCs identifies novel therapeutic targets for the treatment of glioma.

  14. AT-24PHASE 1/2 TRIAL OF BEVACIZUMAB PLUS TPI 287, A NOVEL BRAIN PENETRABLE ANTI-MICROTUBULE AGENT, FOR THE TREATMENT OF RECURRENT GLIOBLASTOMA

    PubMed Central

    Goldlust, Samuel; Nabors, L. Burt; Duic, J. Paul; Conrad, Charles; Silberman, Sandra; Singer, Samuel; Farmer, George

    2014-01-01

    BACKGROUND: TPI 287, a novel anti-microtubule agent of the taxoid class that readily penetrates the blood-brain barrier, is under investigation for the treatment of recurrent glioblastoma (GBM). A dose-escalation Phase 1/2 trial was designed to determine the maximum tolerated dose (MTD) and efficacy of TPI 287 in combination with bevacizumab. Initial results from the dose escalation stage of the trial are reported here. METHODS: Patients with GBM at first relapse after standard therapy without prior exposure to anti-angiogenic agents are eligible for enrollment. Bevacizumab is administered at 10 mg/kg as an IV infusion once every 2 weeks. TPI 287 is administered as a 1-hour IV infusion every 3 weeks. Employing a standard 3 + 3 design, dose escalation of TPI 287 is planned until a dose-limiting toxicity (DLT) is observed in order to select the recommended Phase 2 dose. MRIs are obtained at the end of every six-week cycle with response assessment via RANO criteria. RESULTS: As of June 2014, a total of 9 subjects have been enrolled in the first 3 dose-escalation cohorts (140, 150, and 160 mg/m2). No DLTs have been observed to date, and no drug-related grade 3/4 adverse events have been reported. Among the 7 patients evaluable for response, 3 achieved a partial response, and 2 had stable disease (1 confirmed, 1 unconfirmed). Four of these first 9 patients remain on study 39 weeks after start of the trial. TPI 287 dose escalation continues. CONCLUSIONS: Preliminary data to date indicate that TPI 287 is safe in combination with bevacizumab for the treatment of recurrent GBM. Evolving safety and efficacy results will be presented.

  15. VEGF promotes tumorigenesis and angiogenesis of human glioblastoma stem cells

    SciTech Connect

    Oka, Naoki; Soeda, Akio . E-mail: ccd29400@nyc.odn.ne.jp; Inagaki, Akihito; Onodera, Masafumi; Maruyama, Hidekazu; Hara, Akira; Kunisada, Takahiro; Mori, Hideki; Iwama, Toru

    2007-08-31

    There is increasing evidence for the presence of cancer stem cells (CSCs) in malignant brain tumors, and these CSCs may play a pivotal role in tumor initiation, growth, and recurrence. Vascular endothelial growth factor (VEGF) promotes the proliferation of vascular endothelial cells (VECs) and the neurogenesis of neural stem cells. Using CSCs derived from human glioblastomas and a retrovirus expressing VEGF, we examined the effects of VEGF on the properties of CSCs in vitro and in vivo. Although VEGF did not affect the property of CSCs in vitro, the injection of mouse brains with VEGF-expressing CSCs led to the massive expansion of vascular-rich GBM, tumor-associated hemorrhage, and high morbidity, suggesting that VEGF promoted tumorigenesis via angiogenesis. These results revealed that VEGF induced the proliferation of VEC in the vascular-rich tumor environment, the so-called stem cell niche.

  16. The role of Octamer binding transcription factors in glioblastoma multiforme

    PubMed Central

    Rooj, AK.; Bronisz, A.

    2016-01-01

    A group of transcription factors (TF) that are master developmental regulators of the establishment and maintenance of pluripotency during embryogenesis play additional roles to control tissue homeostasis and regeneration in adults. Among these TFs, members of the Octamer-binding transcription factor (OCT) gene family are well documented as major regulators controlling the self-renewal and pluripotency of stem cells isolated from different adult organs including the brain. In the last few years a large number of studies show the aberrant expression and dysfunction of OCT in different types of cancers including glioblastoma multiforme (GBM). GBM is the most common malignant primary brain tumor, and contains a subpopulation of undifferentiated stem cells (GSCs), with self-renewal and tumorigenic potential that contribute to tumor initiation, invasion, recurrence, and therapeutic resistance. In this review, we have summarized the current knowledge about OCT family in GBM and their crucial role in the initiation, maintenance and drug resistance properties of GSCs. PMID:26968235

  17. Nanocarriers for the treatment of glioblastoma multiforme: Current state-of-the-art.

    PubMed

    Karim, Reatul; Palazzo, Claudio; Evrard, Brigitte; Piel, Geraldine

    2016-04-10

    Glioblastoma multiforme, a grade IV glioma, is the most frequently occurring and invasive primary tumor of the central nervous system, which causes about 4% of cancer-associated-deaths, making it one of the most fatal cancers. With present treatments, using state-of-the-art technologies, the median survival is about 14 months and 2 year survival rate is merely 3-5%. Hence, novel therapeutic approaches are urgently necessary. However, most drug molecules are not able to cross the blood-brain barrier, which is one of the major difficulties in glioblastoma treatment. This review describes the features of blood-brain barrier, and its anatomical changes with different stages of tumor growth. Moreover, various strategies to improve brain drug delivery i.e. tight junction opening, chemical modification of the drug, efflux transporter inhibition, convection-enhanced delivery, craniotomy-based drug delivery and drug delivery nanosystems are discussed. Nanocarriers are one of the highly potential drug transport systems that have gained huge research focus over the last few decades for site specific drug delivery, including drug delivery to the brain. Properly designed nanocolloids are capable to cross the blood-brain barrier and specifically deliver the drug in the brain tumor tissue. They can carry both hydrophilic and hydrophobic drugs, protect them from degradation, release the drug for sustained period, significantly improve the plasma circulation half-life and reduce toxic effects. Among various nanocarriers, liposomes, polymeric nanoparticles and lipid nanocapsules are the most widely studied, and are discussed in this review. For each type of nanocarrier, a general discussion describing their composition, characteristics, types and various uses is followed by their specific application to glioblastoma treatment. Moreover, some of the main challenges regarding toxicity and standardized evaluation techniques are narrated in brief. Copyright © 2016 Elsevier B.V. All

  18. A Unique Four-Hub Protein Cluster Associates to Glioblastoma Progression

    PubMed Central

    Simeone, Pasquale; Trerotola, Marco; Urbanella, Andrea; Lattanzio, Rossano; Ciavardelli, Domenico; Di Giuseppe, Fabrizio; Eleuterio, Enrica; Sulpizio, Marilisa; Eusebi, Vincenzo; Pession, Annalisa; Piantelli, Mauro; Alberti, Saverio

    2014-01-01

    Gliomas are the most frequent brain tumors. Among them, glioblastomas are malignant and largely resistant to available treatments. Histopathology is the gold standard for classification and grading of brain tumors. However, brain tumor heterogeneity is remarkable and histopathology procedures for glioma classification remain unsatisfactory for predicting disease course as well as response to treatment. Proteins that tightly associate with cancer differentiation and progression, can bear important prognostic information. Here, we describe the identification of protein clusters differentially expressed in high-grade versus low-grade gliomas. Tissue samples from 25 high-grade tumors, 10 low-grade tumors and 5 normal brain cortices were analyzed by 2D-PAGE and proteomic profiling by mass spectrometry. This led to identify 48 differentially expressed protein markers between tumors and normal samples. Protein clustering by multivariate analyses (PCA and PLS-DA) provided discrimination between pathological samples to an unprecedented extent, and revealed a unique network of deranged proteins. We discovered a novel glioblastoma control module centered on four major network hubs: Huntingtin, HNF4α, c-Myc and 14-3-3ζ. Immunohistochemistry, western blotting and unbiased proteome-wide meta-analysis revealed altered expression of this glioblastoma control module in human glioma samples as compared with normal controls. Moreover, the four-hub network was found to cross-talk with both p53 and EGFR pathways. In summary, the findings of this study indicate the existence of a unifying signaling module controlling glioblastoma pathogenesis and malignant progression, and suggest novel targets for development of diagnostic and therapeutic procedures. PMID:25050814

  19. Cediranib Maleate and Whole Brain Radiation Therapy in Patients With Brain Metastases From Non-Small Cell Lung Cancer

    ClinicalTrials.gov

    2013-03-07

    Male Breast Cancer; Stage IV Breast Cancer; Stage IV Melanoma; Stage IV Non-small Cell Lung Cancer; Stage IV Renal Cell Cancer; Stage IVA Colon Cancer; Stage IVA Rectal Cancer; Stage IVB Colon Cancer; Stage IVB Rectal Cancer; Tumors Metastatic to Brain

  20. Lomustine Nanoparticles Enable Both Bone Marrow Sparing and High Brain Drug Levels - A Strategy for Brain Cancer Treatments.

    PubMed

    Fisusi, Funmilola A; Siew, Adeline; Chooi, Kar Wai; Okubanjo, Omotunde; Garrett, Natalie; Lalatsa, Katerina; Serrano, Dolores; Summers, Ian; Moger, Julian; Stapleton, Paul; Satchi-Fainaro, Ronit; Schätzlein, Andreas G; Uchegbu, Ijeoma F

    2016-05-01

    The blood brain barrier compromises glioblastoma chemotherapy. However high blood concentrations of lipophilic, alkylating drugs result in brain uptake, but cause myelosuppression. We hypothesised that nanoparticles could achieve therapeutic brain concentrations without dose-limiting myelosuppression. Mice were dosed with either intravenous lomustine Molecular Envelope Technology (MET) nanoparticles (13 mg kg(-1)) or ethanolic lomustine (6.5 mg kg(-1)) and tissues analysed. Efficacy was assessed in an orthotopic U-87 MG glioblastoma model, following intravenous MET lomustine (daily 13 mg kg(-1)) or ethanolic lomustine (daily 1.2 mg kg(-1) - the highest repeated dose possible). Myelosuppression and MET particle macrophage uptake were also investigated. The MET formulation resulted in modest brain targeting (brain/ bone AUC0-4h ratios for MET and ethanolic lomustine = 0.90 and 0.53 respectively and brain/ liver AUC0-4h ratios for MET and ethanolic lomustine = 0.24 and 0.15 respectively). The MET formulation significantly increased mice (U-87 MG tumours) survival times; with MET lomustine, ethanolic lomustine and untreated mean survival times of 33.2, 22.5 and 21.3 days respectively and there were no material treatment-related differences in blood and femoral cell counts. Macrophage uptake is slower for MET nanoparticles than for liposomes. Particulate drug formulations improved brain tumour therapy without major bone marrow toxicity.

  1. PROX1 is a novel pathway-specific prognostic biomarker for high-grade astrocytomas; results from independent glioblastoma cohorts stratified by age and IDH mutation status.

    PubMed

    Roodakker, Kenney R; Elsir, Tamador; Edqvist, Per-Henrik D; Hägerstrand, Daniel; Carlson, Joseph; Lysiak, Malgorzata; Henriksson, Roger; Pontén, Fredrik; Rosell, Johan; Söderkvist, Peter; Stupp, Roger; Tchougounova, Elena; Nistér, Monica; Malmström, Annika; Smits, Anja

    2016-11-08

    PROX1 is a transcription factor with an essential role in embryonic development and determination of cell fate. In addition, PROX1 has been ascribed suppressive as well as oncogenic roles in several human cancers, including brain tumors. In this study we explored the correlation between PROX1 expression and patient survival in high-grade astrocytomas. For this purpose, we analyzed protein expression in tissue microarrays of tumor samples stratified by patient age and IDH mutation status. We initially screened 86 unselected high-grade astrocytomas, followed by 174 IDH1-R132H1 immunonegative glioblastomas derived from patients aged 60 years and older enrolled in the Nordic phase III trial of elderly patients with newly diagnosed glioblastoma. Representing the younger population of glioblastomas, we studied 80 IDH-wildtype glioblastomas from patients aged 18-60 years. There was no correlation between PROX1 protein and survival for patients with primary glioblastomas included in these cohorts. In contrast, high expression of PROX1 protein predicted shorter survival in the group of patients with IDH-mutant anaplastic astrocytomas and secondary glioblastomas. The prognostic impact of PROX1 in IDH-mutant 1p19q non-codeleted high-grade astrocytomas, as well as the negative findings in primary glioblastomas, was corroborated by gene expression data extracted from the Cancer Genome Atlas. We conclude that PROX1 is a new prognostic biomarker for 1p19q non-codeleted high-grade astrocytomas that have progressed from pre-existing low-grade tumors and harbor IDH mutations.

  2. PROX1 is a novel pathway-specific prognostic biomarker for high-grade astrocytomas; results from independent glioblastoma cohorts stratified by age and IDH mutation status

    PubMed Central

    Edqvist, Per-Henrik D.; Hägerstrand, Daniel; Carlson, Joseph; Lysiak, Malgorzata; Henriksson, Roger; Pontén, Fredrik; Rosell, Johan; Söderkvist, Peter; Stupp, Roger; Tchougounova, Elena; Nistér, Monica; Malmström, Annika; Smits, Anja

    2016-01-01

    PROX1 is a transcription factor with an essential role in embryonic development and determination of cell fate. In addition, PROX1 has been ascribed suppressive as well as oncogenic roles in several human cancers, including brain tumors. In this study we explored the correlation between PROX1 expression and patient survival in high-grade astrocytomas. For this purpose, we analyzed protein expression in tissue microarrays of tumor samples stratified by patient age and IDH mutation status. We initially screened 86 unselected high-grade astrocytomas, followed by 174 IDH1-R132H1 immunonegative glioblastomas derived from patients aged 60 years and older enrolled in the Nordic phase III trial of elderly patients with newly diagnosed glioblastoma. Representing the younger population of glioblastomas, we studied 80 IDH-wildtype glioblastomas from patients aged 18-60 years. There was no correlation between PROX1 protein and survival for patients with primary glioblastomas included in these cohorts. In contrast, high expression of PROX1 protein predicted shorter survival in the group of patients with IDH-mutant anaplastic astrocytomas and secondary glioblastomas. The prognostic impact of PROX1 in IDH-mutant 1p19q non-codeleted high-grade astrocytomas, as well as the negative findings in primary glioblastomas, was corroborated by gene expression data extracted from the Cancer Genome Atlas. We conclude that PROX1 is a new prognostic biomarker for 1p19q non-codeleted high-grade astrocytomas that have progressed from pre-existing low-grade tumors and harbor IDH mutations. PMID:27626492

  3. Pediatric Glioblastoma Therapies Based on Patient-Derived Stem Cell Resources

    DTIC Science & Technology

    2013-10-01

    AD_________________ Award Number: W81XWH-11-1-0756 TITLE: Pediatric Glioblastoma Therapies Based on Patient-Derived Stem Cell Resources PRINCIPAL...TITLE AND SUBTITLE Pediatric Glioblastoma Therapies Based on Patient-Derived Stem Cell Resources 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-11...TERMS Glioblastoma multiforme , glioma stem cell, brain tumor-initiating cell, pediatric brain tumor, RNAi, functional genetics 16. SECURITY

  4. Clinical Applications of a Peptide-Based Vaccine for Glioblastoma

    PubMed Central

    Kanaly, Charles W; Ding, Dale; Heimberger, Amy B.

    2010-01-01

    SYNOPSIS Glioblastoma multiforme (GBM) is a malignant, relentless brain cancer with no known cure, and standard therapies leave significant room for the development of better, more effective treatments. Immunotherapy is a promising approach to the treatment of solid tumors that directs the patient’s own immune system to destroy tumor cells. The most widespread and successful immunologically-based cancer therapy to date involves the passive administration of monoclonal antibodies, but significant antitumor responses have also been generated with active vaccination strategies and cell-transfer therapies as well. This article summarizes the important components of the immune system, discusses the specific difficulty of immunologic privilege in the central nervous system (CNS), and reviews the variety of treatment approaches that are being attempted, with an emphasis on active immunotherapy using peptide vaccines in the treatment of GBM. PMID:19944970

  5. Spitting out the demons: Extracellular vesicles in glioblastoma.

    PubMed

    André-Grégoire, Gwennan; Gavard, Julie

    2017-03-04

    Discovered decades ago, extracellular vesicles (EVs) emerge as dedicated organelles, able to deliver protected, specific cellular cues throughout the organism. While virtually every cell can release EVs, cancer cells co-opted this feature and efficiently unleashed them both in the tumor microenvironment and toward healthy tissues. This might contribute to tumor aggressiveness and spreading. Cancer-derived EVs that contain DNA, mRNA, miRNA, and packed and transmembrane proteins can operate locally or at distance. This review will focus on the high-grade brain tumor (i.e. glioblastoma)-derived EVs, discussing recent reports on i) their phenotype and content, ii) their putative functions, and iii) their clinical potential for improving diagnosis and therapeutics.

  6. Differential Reactions of Microglia to Brain Metastasis of Lung Cancer

    PubMed Central

    He, Bei Ping; Wang, Jian Jun; Zhang, Xian; Wu, Yan; Wang, Miao; Bay, Boon-Huat; Chang, Alex Yuang-Chi

    2006-01-01

    The brain is a common metastatic site for various types of cancers, especially lung cancer. Patients with brain metastases have a poor prognosis in spite of radiotherapy and/or chemotherapy. It is postulated that immune cells in the brain may play a major role in cancer metastasis, dormancy, and relapse. Although microglia may serve as a major component in the brain immune system, the interaction between metastatic cancer cells and microglia is still largely unknown and remains to be elucidated. In this study, we have investigated microglial reactions in brain tissues with metastatic lung cancer cells and evaluated the cytotoxic effects of lipopolysaccharide (LPS)-activated microglia on metastatic lung cancer cells in vitro. In the vicinity of metastatic lung cancer mass in the brain, microglia showed signs of significant activation. There was an obvious increase in the number of microglia labeled with ionized calcium binding adaptor molecule 1 (Iba-1) antibody, a specific marker of microglia. The microglia were observed to form a clear boundary between the tumor mass and normal brain tissue. In the region where the tumor mass was situated, only a few microglia expressed inducible nitric oxide synthase (iNOS) and tumor necrosis factor-α (TNF-α), indicating differential activation in those microglia. The supernatant from LPS-activated microglia induced apoptosis of metastatic lung cancer cells in vitro in a dose- and time-dependent manner. However, at lower concentrations of activated microglial supernatant, trophic effects on cancer cells were observed, some lung cancer cells being insensitive to microglial cytotoxicity. Together with the observation that TNF-α alone induced proliferation of the tumor cells, the findings provide possible clues to the mechanism involved in metastasis of lung cancer cells to the brain. PMID:17088948

  7. Glioblastoma after radiotherapy for craniopharyngioma: case report

    SciTech Connect

    Ushio, Y.; Arita, N.; Yoshimine, T.; Nagatani, M.; Mogami, H.

    1987-07-01

    A 6-year-old girl developed a glioblastoma in the basal ganglia and brain stem 5 years after surgical excision and local irradiation (5460 cGy) for craniopharyngioma. Clinical and histological details are presented, and the literature on radiation-induced gliomas is reviewed.

  8. MiR-224 expression increases radiation sensitivity of glioblastoma cells

    SciTech Connect

    Upraity, Shailendra; Kazi, Sadaf; Padul, Vijay; Shirsat, Neelam Vishwanath

    2014-05-30

    Highlights: • MiR-224 expression in established glioblastoma cell lines and sporadic tumor tissues is low. • Exogenous miR-224 expression was found to increase radiation sensitivity of glioblastoma cells. • MiR-224 expression brought about 55–60% reduction in API5 expression levels. • Transfection with API5 siRNA increased radiation sensitivity of glioblastoma cells. • Low miR-224 and high API5 expression correlated with worse survival of GBM patients. - Abstract: Glioblastoma (GBM) is the most common and highly aggressive primary malignant brain tumor. The intrinsic resistance of this brain tumor limits the efficacy of administered treatment like radiation therapy. In the present study, effect of miR-224 expression on growth characteristics of established GBM cell lines was analyzed. MiR-224 expression in the cell lines as well as in primary GBM tumor tissues was found to be low. Exogenous transient expression of miR-224 using either synthetic mimics or stable inducible expression using doxycycline inducible lentiviral vector carrying miR-224 gene, was found to bring about 30–55% reduction in clonogenic potential of U87 MG cells. MiR-224 expression reduced clonogenic potential of U87 MG cells by 85–90% on irradiation at a dose of 6 Gy, a dose that brought about 50% reduction in clonogenic potential in the absence of miR-224 expression. MiR-224 expression in glioblastoma cells resulted in 55–65% reduction in the expression levels of API5 gene, a known target of miR-224. Further, siRNA mediated down-regulation of API5 was also found to have radiation sensitizing effect on glioblastoma cell lines. Analysis of the Cancer Genome Atlas data showed lower miR-224 expression levels in male GBM patients to correlate with poorer survival. Higher expression levels of miR-224 target API5 also showed significant correlation with poorer survival of GBM patients. Up-regulation of miR-224 or down-regulation of its target API5 in combination with radiation therapy

  9. Sex steroids in human brain tumors and breast cancer.

    PubMed

    von Schoultz, E; Bixo, M; Bäckström, T; Silfvenius, H; Wilking, N; Henriksson, R

    1990-02-15

    The concentrations of three sex steroids, estradiol, progesterone and testosterone, were analyzed by radioimmunoassay after celite chromatography in brain tumor and breast cancer tissues. The concentrations in malignant gliomas and breast cancers showed interindividual variations, especially evident with regard to estradiol. High estradiol concentrations were recorded in two patients with malignant astrocytoma. The concentrations of 1.00 pg/mg and 3.32 pg/mg were 10 to 30 times as high as in normal female brain. In five of ten astrocytomas the estradiol concentration was higher than the lowest breast cancer value. The distribution of progesterone seemed more even, and the level was significantly lower in brain tumors and breast cancers as compared with female brain, perhaps indicating an increased metabolism. Testosterone levels were somewhat higher in brain tumors, as compared with breast cancers, but not different from values in brain tissue. There were no significant age or sex correlation or differences in the concentrations of steroids in the brain tumors. The results suggest that manipulation of sex steroid metabolism in malignant brain tumors can be of beneficial therapeutic value as has been shown for breast cancer and prostatic carcinoma.

  10. Galectin-8 promotes migration and proliferation and prevents apoptosis in U87 glioblastoma cells.

    PubMed

    Metz, Claudia; Döger, Remziye; Riquelme, Elizabeth; Cortés, Priscilla; Holmes, Christopher; Shaughnessy, Ronan; Oyanadel, Claudia; Grabowski, Catalina; González, Alfonso; Soza, Andrea

    2016-07-27

    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 model. 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. 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

  11. [Glioblastomas: gliomagenesis, genetics, angiogenesis, and microenvironment].

    PubMed

    Figarella-Branger, D; Colin, C; Tchoghandjian, A; Baeza, N; Bouvier, C

    2010-12-01

    Glioblastomas are the most malignant gliomas of the central nervous system. Currently, numerous studies are attempting to decipher their genetic and epigenetic modifications, to identify the cells at the origin of gliomagenesis, and to better understand the molecular bases responsible for invasion and angiogenesis processes. This article reviews recent data on the cellular and molecular biology of gliomas delineated by several teams including ours. We and others have underlined the role played by cancer stem cells in gliomagenesis; the Cancer Genome Atlas Network has described most glioblastoma genetic alterations. According to many studies, glioblastomas derive from malignant transformation of stem cells and/or glial precursor cells. Moreover, the topographic microenvironment is important regarding invasion and angiogenesis processes. Finally, it is now well established, thanks to IDH1 mutation identification, that primary and secondary glioblastomas are two different clinical and genetic entities. Interestingly, IDH1 mutation seems to be a very early genomic modification in astrocytoma, oligodendroglioma, and secondary glioblastoma tumorigenic processes. Regarding all these data, we suggest a hypothetical model of glioma initiation, growth, and progression. Moreover, the histomolecular glioma classification has been substantially revised and new therapeutic targets have been identified. Copyright © 2010 Elsevier Masson SAS. All rights reserved.

  12. The NSL Chromatin-Modifying Complex Subunit KANSL2 Regulates Cancer Stem-like Properties in Glioblastoma That Contribute to Tumorigenesis.

    PubMed

    Ferreyra Solari, Nazarena E; Belforte, Fiorella S; Canedo, Lucía; Videla-Richardson, Guillermo A; Espinosa, Joaquín M; Rossi, Mario; Serna, Eva; Riudavets, Miguel A; Martinetto, Horacio; Sevlever, Gustavo; Perez-Castro, Carolina

    2016-09-15

    KANSL2 is an integral subunit of the nonspecific lethal (NSL) chromatin-modifying complex that contributes to epigenetic programs in embryonic stem cells. In this study, we report a role for KANSL2 in regulation of stemness in glioblastoma (GBM), which is characterized by heterogeneous tumor stem-like cells associated with therapy resistance and disease relapse. KANSL2 expression is upregulated in cancer cells, mainly at perivascular regions of tumors. RNAi-mediated silencing of KANSL2 in GBM cells impairs their tumorigenic capacity in mouse xenograft models. In clinical specimens, we found that expression levels of KANSL2 correlate with stemness markers in GBM stem-like cell populations. Mechanistic investigations showed that KANSL2 regulates cell self-renewal, which correlates with effects on expression of the stemness transcription factor POU5F1. RNAi-mediated silencing of POU5F1 reduced KANSL2 levels, linking these two genes to stemness control in GBM cells. Together, our findings indicate that KANSL2 acts to regulate the stem cell population in GBM, defining it as a candidate GBM biomarker for clinical use. Cancer Res; 76(18); 5383-94. ©2016 AACR. ©2016 American Association for Cancer Research.

  13. Neurobehavioral radiation mitigation to standard brain cancer therapy regimens by Mn(III) n-butoxyethylpyridylporphyrin-based redox modifier.

    PubMed

    Weitzel, Douglas H; Tovmasyan, Artak; Ashcraft, Kathleen A; Boico, Alina; Birer, Samuel R; Roy Choudhury, Kingshuk; Herndon, James; Rodriguiz, Ramona M; Wetsel, William C; Peters, Katherine B; Spasojevic, Ivan; Batinic-Haberle, Ines; Dewhirst, Mark W

    2016-06-01

    Combinations of radiotherapy (RT) and chemotherapy have shown efficacy toward brain tumors. However, therapy-induced oxidative stress can damage normal brain tissue, resulting in both progressive neurocognitive loss and diminished quality of life. We have recently shown that MnTnBuOE-2-PyP(5+) (Mn(III)meso-tetrakis(N-n-butoxyethylpyridinium -2-yl)porphyrin) rescued RT-induced white matter damage in cranially-irradiated mice. Radiotherapy is not used in isolation for treatment of brain tumors; temozolomide is the standard-of-care for adult glioblastoma, whereas cisplatin is often used for treatment of pediatric brain tumors. Therefore, we evaluated the brain radiation mitigation ability of MnTnBuOE-2-PyP(5+) after either temozolomide or cisplatin was used singly or in combination with 10 Gy RT. MnTnBuOE-2-PyP(5+) accumulated in brains at low nanomolar levels. Histological and neurobehavioral testing showed a drastic decrease (1) of axon density in the corpus callosum and (2) rotorod and running wheel performance in the RT only treatment group, respectively. MnTnBuOE-2-PyP(5+) completely rescued this phenotype in irradiated animals. In the temozolomide groups, temozolomide/ RT treatment resulted in further decreased rotorod responses over RT alone. Again, MnTnBuOE-2-PyP(5+) treatment rescued the negative effects of both temozolomide ± RT on rotorod performance. While the cisplatin-treated groups did not give similar results as the temozolomide groups, inclusion of MnTnBuOE-2-PyP(5+) did not negatively affect rotorod performance. Additionally, MnTnBuOE-2-PyP(5+) sensitized glioblastomas to either RT ± temozolomide in flank tumor models. Mice treated with both MnTnBuOE-2-PyP(5+) and radio-/chemo-therapy herein demonstrated brain radiation mitigation. MnTnBuOE-2-PyP(5+) may well serve as a normal tissue radio-/chemo-mitigator adjuvant therapy to standard brain cancer treatment regimens. Environ. Mol. Mutagen. 57:372-381, 2016. © 2016 Wiley Periodicals, Inc.

  14. TCGA Workshop: Genomics and Biology of Glioblastoma Multiforme (GBM) - TCGA

    Cancer.gov

    The National Cancer Institute (NCI) and National Human Genome Research Institute (NHGRI) held a workshop entitled, “Genomics and Biology of Glioblastoma Multiforme (GBM),” to review the initial GBM data from the TCGA pilot project.

  15. Evaluation of glioblastomas and lymphomas with whole-brain CT perfusion: Comparison between a delay-invariant singular-value decomposition algorithm and a Patlak plot.

    PubMed

    Hiwatashi, Akio; Togao, Osamu; Yamashita, Koji; Kikuchi, Kazufumi; Yoshimoto, Koji; Mizoguchi, Masahiro; Suzuki, Satoshi O; Yoshiura, Takashi; Honda, Hiroshi

    2016-07-01

    Correction of contrast leakage is recommended when enhancing lesions during perfusion analysis. The purpose of this study was to assess the diagnostic performance of computed tomography perfusion (CTP) with a delay-invariant singular-value decomposition algorithm (SVD+) and a Patlak plot in differentiating glioblastomas from lymphomas. This prospective study included 17 adult patients (12 men and 5 women) with pathologically proven glioblastomas (n=10) and lymphomas (n=7). CTP data were analyzed using SVD+ and a Patlak plot. The relative tumor blood volume and flow compared to contralateral normal-appearing gray matter (rCBV and rCBF derived from SVD+, and rBV and rFlow derived from the Patlak plot) were used to differentiate between glioblastomas and lymphomas. The Mann-Whitney U test and receiver operating characteristic (ROC) analyses were used for statistical analysis. Glioblastomas showed significantly higher rFlow (3.05±0.49, mean±standard deviation) than lymphomas (1.56±0.53; P<0.05). There were no statistically significant differences between glioblastomas and lymphomas in rBV (2.52±1.57 vs. 1.03±0.51; P>0.05), rCBF (1.38±0.41 vs. 1.29±0.47; P>0.05), or rCBV (1.78±0.47 vs. 1.87±0.66; P>0.05). ROC analysis showed the best diagnostic performance with rFlow (Az=0.871), followed by rBV (Az=0.771), rCBF (Az=0.614), and rCBV (Az=0.529). CTP analysis with a Patlak plot was helpful in differentiating between glioblastomas and lymphomas, but CTP analysis with SVD+ was not. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  16. Novel approaches and mechanisms of immunotherapy for glioblastoma.

    PubMed

    Hegde, Meenakshi; Bielamowicz, Kevin J; Ahmed, Nabil

    2014-03-01

    Glioblastoma (GBM) is the most aggressive primary brain tumor. Combination therapy with surgery, radiation, and chemotherapy is not curative at present and carries a significant risk of toxicity. Advancements in the knowledge of tumor biology and tumor microenvironment have led to the development of novel targeted therapies for glioblastoma. In the past 15 years, a vast amount of pre-clinical data has been generated for glioblastoma immunotherapy. Translating these promising results into the clinic is, however, still an evolving process. Early clinical trials have demonstrated the feasibility and safety of several such approaches in patients with recurrent as well as newly diagnosed glioblastoma. Both passive as well as active immunotherapeutic modalities have also shown potential clinical benefit in at least a subset of these patients. This brief review discusses 'why' and 'how' various types of immunotherapies are being employed to treat glioblastoma.

  17. Current data and strategy in glioblastoma multiforme

    PubMed Central

    Dinca, EB

    2009-01-01

    Glioblastoma multiforme (GBM) or astrocytoma grade Ⅳ on WHO classification is the most aggressive and the most frequent of all primary brain tumors. Glioblastoma is multiforme , resistant to therapeutic interventions illustrating the heterogeneity exhibited by this tumor in its every aspect, including clinical presentation, pathology, genetic signature. Current data and treatment strategy in GBM are presented focusing on basic science data and key clinical aspects like surgery, including personal experience; adjuvant modalities: radiotherapy, chemotherapy, but also for experimental approaches. Therapeutic attitude in recurrent GBM is also widely discussed. PMID:20108752

  18. Gamma Knife Surgery for Metastatic Brain Tumors from Gynecologic Cancer.

    PubMed

    Matsunaga, Shigeo; Shuto, Takashi; Sato, Mitsuru

    2016-05-01

    The incidences of metastatic brain tumors from gynecologic cancer have increased. The results of Gamma Knife surgery (GKS) for the treatment of patients with brain metastases from gynecologic cancer (ovarian, endometrial, and uterine cervical cancers) were retrospectively analyzed to identify the efficacy and prognostic factors for local tumor control and survival. The medical records were retrospectively reviewed of 70 patients with 306 tumors who underwent GKS for brain metastases from gynecologic cancer between January 1995 and December 2013 in our institution. The primary cancers were ovarian in 33 patients with 147 tumors and uterine in 37 patients with 159 tumors. Median tumor volume was 0.3 cm(3). Median marginal prescription dose was 20 Gy. The local tumor control rates were 96.4% at 6 months and 89.9% at 1 year. There was no statistically significant difference between ovarian and uterine cancers. Higher prescription dose and smaller tumor volume were significantly correlated with local tumor control. Median overall survival time was 8 months. Primary ovarian cancer, controlled extracranial metastases, and solitary brain metastasis were significantly correlated with satisfactory overall survival. Median activities of daily living (ADL) preservation survival time was 8 months. Primary ovarian cancer, controlled extracranial metastases, and higher Karnofsky Performance Status score were significantly correlated with better ADL preservation. GKS is effective for control of tumor progression in patients with brain metastases from gynecologic cancer, and may provide neurologic benefits and preservation of the quality of life. Copyright © 2016 Elsevier Inc. All rights reserved.

  19. Capturing Changes in the Brain Microenvironment during Initial Steps of Breast Cancer Brain Metastasis

    PubMed Central

    Lorger, Mihaela; Felding-Habermann, Brunhilde

    2010-01-01

    Brain metastases are difficult to treat and mostly develop late during progressive metastatic disease. Patients at risk would benefit from the development of prevention and improved treatments. This requires knowledge of the initial events that lead to brain metastasis. The present study reveals cellular events during the initiation of brain metastasis by breast cancer cells and documents the earliest host responses to incoming cancer cells after carotid artery injection in immunodeficient and immunocompetent mouse models. Our findings capture and characterize heterogeneous astrocytic and microglial reactions to the arrest and extravasation of cancer cells in the brain, showing immediate and drastic changes in the brain microenvironment on arrival of individual cancer cells. We identified reactive astrocytes as the most active host cell population that immediately localizes to individual invading tumor cells and continuously associates with growing metastatic lesions. Up-regulation of matrix metalloproteinase-9 associated with astrocyte activation in the immediate vicinity of extravasating cancer cells might support their progression. Early involvement of different host cell types indicates environmental clues that might codetermine whether a single cancer cell progresses to macrometastasis or remains dormant. Thus, information on the initial interplay between brain homing tumor cells and reactive host cells may help develop strategies for prevention and treatment of symptomatic breast cancer brain metastases. PMID:20382702

  20. Capturing changes in the brain microenvironment during initial steps of breast cancer brain metastasis.

    PubMed

    Lorger, Mihaela; Felding-Habermann, Brunhilde

    2010-06-01

    Brain metastases are difficult to treat and mostly develop late during progressive metastatic disease. Patients at risk would benefit from the development of prevention and improved treatments. This requires knowledge of the initial events that lead to brain metastasis. The present study reveals cellular events during the initiation of brain metastasis by breast cancer cells and documents the earliest host responses to incoming cancer cells after carotid artery injection in immunodeficient and immunocompetent mouse models. Our findings capture and characterize heterogeneous astrocytic and microglial reactions to the arrest and extravasation of cancer cells in the brain, showing immediate and drastic changes in the brain microenvironment on arrival of individual cancer cells. We identified reactive astrocytes as the most active host cell population that immediately localizes to individual invading tumor cells and continuously associates with growing metastatic lesions. Up-regulation of matrix metalloproteinase-9 associated with astrocyte activation in the immediate vicinity of extravasating cancer cells might support their progression. Early involvement of different host cell types indicates environmental clues that might codetermine whether a single cancer cell progresses to macrometastasis or remains dormant. Thus, information on the initial interplay between brain homing tumor cells and reactive host cells may help develop strategies for prevention and treatment of symptomatic breast cancer brain metastases.

  1. Honokiol inhibits U87MG human glioblastoma cell invasion through endothelial cells by regulating membrane permeability and the epithelial-mesenchymal transition.

    PubMed

    Joo, Young Nak; Eun, So Young; Park, Sang Won; Lee, Jae Heun; Chang, Ki Churl; Kim, Hye Jung

    2014-01-01

    Glioblastoma is one of the most lethal and prevalent malignant human brain tumors, with aggressive proliferation and highly invasive properties. There is still no effective cure for patients with glioblastoma. Honokiol, derived from Magnolia officinalis, can cross the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB), making it a strong candidate for an effective drug for the treatment of brain tumors, including glioblastoma. In our previous study, we demonstrated that honokiol effectively induced apoptotic cell death in glioblastoma. Metastasis poses the largest problem to cancer treatment and is the primary cause of death in cancer patients. Thus, in this study, we investigated the effect of honokiol on the cell invasion process of U87MG human glioblastoma cells through brain microvascular endothelial cells (BMECs) and its possible mechanisms. Honokiol dose-dependently inhibited TNF-α-induced VCAM-1 expression in BMECs and adhesion of U87MG to BMECs. Moreover, honokiol effectively blocked U87MG invasion through BMEC-Matrigel-coated transwell membranes. Increased phosphorylation of VE-cadherin and membrane permeability by TNF-α were suppressed by honokiol in BMECs. Furthermore, we investigated the effect of honokiol on the epithelial-mesenchymal transition (EMT) in U87MG cells. Honokiol reduced the expression levels of Snail, N-cadherin and β-catenin, which are mesenchymal markers, but increased E-cadherin, an epithelial marker. In conclusion, these results suggest that honokiol inhibits metastasis by targeting the interaction between U87MG and BMECs, regulating the adhesion of U87MG to BMECs by inhibiting VCAM-1, and regulating the invasion of U87MG through BMECs by reducing membrane permeability and EMT processes of U87MG cells.

  2. Non-coding RNAs in cancer brain metastasis.

    PubMed

    Wu, Kerui; Sharma, Sambad; Venkat, Suresh; Liu, Keqin; Zhou, Xiaobo; Watabe, Kounosuke

    2016-01-01

    More than 90% of cancer death is attributed to metastatic disease, and the brain is one of the major metastatic sites of melanoma, colon, renal, lung and breast cancers. Despite the recent advancement of targeted therapy for cancer, the incidence of brain metastasis is increasing. One reason is that most therapeutic drugs can't penetrate blood-brain-barrier and tumor cells find the brain as sanctuary site. In this review, we describe the pathophysiology of brain metastases to introduce the latest understandings of metastatic brain malignancies. This review also particularly focuses on non-coding RNAs and their roles in cancer brain metastasis. Furthermore, we discuss the roles of the extracellular vesicles as they are known to transport information between cells to initiate cancer cell-microenvironment communication. The potential clinical translation of non-coding RNAs as a tool for diagnosis and for treatment is also discussed in this review. At the end, the computational aspects of non-coding RNA detection, the sequence and structure calculation and epigenetic regulation of non-coding RNA in brain metastasis are discussed.

  3. RO4929097 and Whole-Brain Radiation Therapy or Stereotactic Radiosurgery in Treating Patients With Brain Metastases From Breast Cancer

    ClinicalTrials.gov

    2015-01-22

    Estrogen Receptor-negative Breast Cancer; Extensive Stage Small Cell Lung Cancer; HER2-negative Breast Cancer; HER2-positive Breast Cancer; Male Breast Cancer; Recurrent Breast Cancer; Recurrent Melanoma; Recurrent Non-small Cell Lung Cancer; Recurrent Small Cell Lung Cancer; Stage IV Breast Cancer; Stage IV Melanoma; Stage IV Non-small Cell Lung Cancer; Tumors Metastatic to Brain; Unspecified Adult Solid Tumor, Protocol Specific

  4. JNK contributes to temozolomide resistance of stem-like glioblastoma cells via regulation of MGMT expression.

    PubMed

    Okada, Masashi; Sato, Atsushi; Shibuya, Keita; Watanabe, Eriko; Seino, Shizuka; Suzuki, Shuhei; Seino, Manabu; Narita, Yoshitaka; Shibui, Soichiro; Kayama, Takamasa; Kitanaka, Chifumi

    2014-02-01

    While elimination of the cancer stem cell population is increasingly recognized as a key to successful treatment of cancer, the high resistance of cancer stem cells to conventional chemoradiotherapy remains a therapeutic challenge. O6-methylguanine DNA methyltransferase (MGMT), which is frequently expressed in cancer stem cells of glioblastoma, has been implicated in their resistance to temozolomide, the first-line chemotherapeutic agent against newly diagnosed glioblastoma. However, much remains unknown about the molecular regulation that underlies MGMT expression and temozolomide resistance of glioblastoma cancer stem cells. Here, we identified JNK as a novel player in the control of MGMT expression and temozolomide resistance of glioblastoma cancer stem cells. We showed that inhibition of JNK, either pharmacologically or by RNA interference, in stem-like glioblastoma cells derived directly from glioblastoma tissues reduces their MGMT expression and temozolomide resistance. Importantly, sensitization of stem-like glioblastoma cells to temozolomide by JNK inhibition was dependent on MGMT expression, implying that JNK controls temozolomide resistance of stem-like glioblastoma cells through MGMT expression. Our findings suggest that concurrent use of JNK inhibitors with temozolomide may be a rational therapeutic approach to effectively target the cancer stem cell population in the treatment of glioblastoma.

  5. Gamma Knife Radiosurgery for Brain Metastases From Primary Breast Cancer

    SciTech Connect

    Kased, Norbert; Binder, Devin K.; McDermott, Michael W.; Nakamura, Jean L.; Huang, Kim; Berger, Mitchel S.; Wara, William M.; Sneed, Penny K.

    2009-11-15

    Purpose: The relative roles of stereotactic radiosurgery (SRS) vs. whole brain radiotherapy (WBRT) in the treatment of patients with brain metastases from breast cancer remain undefined. In this study, we reviewed our experience with these patients. Materials and Methods: We retrospectively reviewed all patients treated between 1991 and 2005 with Gamma Knife SRS for brain metastases from breast cancer. The actuarial survival and freedom from progression endpoints were calculated using the Kaplan-Meier method. Results: Between 1991 and 2005, 176 patients underwent SRS for brain metastases from breast cancer. The median survival time was 16.0 months for 95 newly diagnosed patients and 11.7 months for 81 patients with recurrent brain metastases. In the newly diagnosed patients, omission of upfront WBRT did not significantly affect the MST (p = .20), brain freedom from progression (p = .75), or freedom from new brain metastases (p = .83). Longer survival was associated with age <50 years, Karnofsky performance score >=70, primary tumor control, estrogen receptor positivity, and Her2/neu overexpression. No association was found between the number of treated brain metastases and the survival time. Conclusion: We have described prognostic factors for breast cancer patients treated with SRS for newly diagnosed or recurrent brain metastases. Most patient subsets had a median survival time of >=11 months. Unexpectedly, upfront WBRT did not appear to improve brain freedom from progression, and a larger number of brain metastases was not associated with a shorter survival time. Breast cancer might be distinct from other primary sites in terms of prognostic factors and the roles of WBRT and SRS for brain metastases.

  6. Glioblastoma Mimicking an Arteriovenous Malformation

    PubMed Central

    Khanna, Arjun; Venteicher, Andrew S.; Walcott, Brian P.; Kahle, Kristopher T.; Mordes, Daniel A.; William, Christopher M.; Ghogawala, Zoher; Ogilvy, Christopher S.

    2013-01-01

    Abnormal cerebral vasculature can be a manifestation of a vascular malformation or a neoplastic process. We report the case of a patient with angiography-negative subarachnoid hemorrhage (SAH) who re-presented 3 years later with a large intraparenchymal hemorrhage. Although imaging following the intraparenchymal hemorrhage was suggestive of arteriovenous malformation, the patient was ultimately found to have an extensive glioblastoma associated with abnormal tumor vasculature. The case emphasizes the need for magnetic resonance imaging to investigate angiography-negative SAH in suspicious cases to rule out occult etiologies, such as neoplasm. We also discuss diagnostic pitfalls when brain tumors are associated with hemorrhage and abnormal vasculature. PMID:24137154

  7. Secondary Data Analytics of Aquaporin Expression Levels in Glioblastoma Stem-Like Cells.

    PubMed

    Isokpehi, Raphael D; Wollenberg Valero, Katharina C; Graham, Barbara E; Pacurari, Maricica; Sims, Jennifer N; Udensi, Udensi K; Ndebele, Kenneth

    2015-01-01

    Glioblastoma is the most common brain tumor in adults in which recurrence has been attributed to the presence of cancer stem cells in a hypoxic microenvironment. On the basis of tumor formation in vivo and growth type in vitro, two published microarray gene expression profiling studies grouped nine glioblastoma stem-like (GS) cell lines into one of two groups: full (GSf) or restricted (GSr) stem-like phenotypes. Aquaporin-1 (AQP1) and aquaporin-4 (AQP4) are water transport proteins that are highly expressed in primary glial-derived tumors. However, the expression levels of AQP1 and AQP4 have not been previously described in a panel of 92 glioma samples. Therefore, we designed secondary data analytics methods to determine the expression levels of AQP1 and AQP4 in GS cell lines and glioblastoma neurospheres. Our investigation also included a total of 2,566 expression levels from 28 Affymetrix microarray probe sets encoding 13 human aquaporins (AQP0-AQP12); CXCR4 (the receptor for stromal cell derived factor-1 [SDF-1], a potential glioma stem cell therapeutic target]); and PROM1 (gene encoding CD133, the widely used glioma stem cell marker). Interactive visual representation designs for integrating phenotypic features and expression levels revealed that inverse expression levels of AQP1 and AQP4 correlate with distinct phenotypes in a set of cell lines grouped into full and restricted stem-like phenotypes. Discriminant function analysis further revealed that AQP1 and AQP4 expression are better predictors for tumor formation and growth types in glioblastoma stem-like cells than are CXCR4 and PROM1. Future investigations are needed to characterize the molecular mechanisms for inverse expression levels of AQP1 and AQP4 in the glioblastoma stem-like neurospheres.

  8. Secondary Data Analytics of Aquaporin Expression Levels in Glioblastoma Stem-Like Cells

    PubMed Central

    Isokpehi, Raphael D; Wollenberg Valero, Katharina C; Graham, Barbara E; Pacurari, Maricica; Sims, Jennifer N; Udensi, Udensi K; Ndebele, Kenneth

    2015-01-01

    Glioblastoma is the most common brain tumor in adults in which recurrence has been attributed to the presence of cancer stem cells in a hypoxic microenvironment. On the basis of tumor formation in vivo and growth type in vitro, two published microarray gene expression profiling studies grouped nine glioblastoma stem-like (GS) cell lines into one of two groups: full (GSf) or restricted (GSr) stem-like phenotypes. Aquaporin-1 (AQP1) and aquaporin-4 (AQP4) are water transport proteins that are highly expressed in primary glial-derived tumors. However, the expression levels of AQP1 and AQP4 have not been previously described in a panel of 92 glioma samples. Therefore, we designed secondary data analytics methods to determine the expression levels of AQP1 and AQP4 in GS cell lines and glioblastoma neurospheres. Our investigation also included a total of 2,566 expression levels from 28 Affymetrix microarray probe sets encoding 13 human aquaporins (AQP0–AQP12); CXCR4 (the receptor for stromal cell derived factor-1 [SDF-1], a potential glioma stem cell therapeutic target]); and PROM1 (gene encoding CD133, the widely used glioma stem cell marker). Interactive visual representation designs for integrating phenotypic features and expression levels revealed that inverse expression levels of AQP1 and AQP4 correlate with distinct phenotypes in a set of cell lines grouped into full and restricted stem-like phenotypes. Discriminant function analysis further revealed that AQP1 and AQP4 expression are better predictors for tumor formation and growth types in glioblastoma stem-like cells than are CXCR4 and PROM1. Future investigations are needed to characterize the molecular mechanisms for inverse expression levels of AQP1 and AQP4 in the glioblastoma stem-like neurospheres. PMID:26279619

  9. Resveratrol sensitizes glioblastoma-initiating cells to temozolomide by inducing cell apoptosis and promoting differentiation.

    PubMed

    Li, Hao; Liu, Yaodong; Jiao, Yumin; Guo, Anchen; Xu, Xiaoxue; Qu, Xianjun; Wang, Shuo; Zhao, Jizong; Li, Ye; Cao, Yong

    2016-01-01

    Glioblastoma-initiating cells play crucial roles in the origin, growth, and recurrence of glioblastoma multiforme. The elimination of glioblastoma-initiating cells is believed to be a key strategy for achieving long-term survival of glioblastoma patients due to the highly resistant property of glioblastoma-initiating cells to temozolomide. Resveratrol, a naturally occurring polyphenol, has been widely studied as a promising candidate for cancer prevention and treatment. Whether resveratrol could enhance the sensitivity of glioblastoma-initiating cells to temozolomide therapy has not yet been reported. Here, using patient-derived glioblastoma-initiating cell lines, we found that resveratrol sensitized glioblastoma-initiating cells to temozolomide both in vitro and in vivo. Furthermore, we showed that resveratrol enhanced glioblastoma-initiating cells to temozolomide-induced apoptosis through DNA double-stranded breaks/pATM/pATR/p53 pathway activation, and promoted glioblastoma-initiating cell differentiation involving p-STAT3 inactivation. Our results propose that temozolomide and resveratrol combination strategy may be effective in the management of glioblastoma patients, particularly for those patients who have been present with a high abundance of glioblastoma-initiating cells in their tumors and show slight responsiveness to temozolomide.

  10. Cholesterol: An Achilles' Heel for Glioblastoma?

    PubMed

    An, Zhenyi; Weiss, William A

    2016-11-14

    In this issue of Cancer Cell, Villa et al. report that survival of glioblastoma cells is dependent on uptake of cholesterol. A synthetic agonist of the Liver X receptor depleted cholesterol in GBM cells, slowing growth of GBM xenografts.

  11. Oncogenic activity of SOX1 in glioblastoma

    PubMed Central

    Garcia, Idoia; Aldaregia, Juncal; Marjanovic Vicentic, Jelena; Aldaz, Paula; Moreno-Cugnon, Leire; Torres-Bayona, Sergio; Carrasco-Garcia, Estefania; Garros-Regulez, Laura; Egaña, Larraitz; Rubio, Angel; Pollard, Steven; Stevanovic, Milena; Sampron, Nicolas; Matheu, Ander

    2017-01-01

    Glioblastoma remains the most common and deadliest type of brain tumor and contains a population of self-renewing, highly tumorigenic glioma stem cells (GSCs), which contributes to tumor initiation and treatment resistance. Developmental programs participating in tissue development and homeostasis re-emerge in GSCs, supporting the development and progression of glioblastoma. SOX1 plays an important role in neural development and neural progenitor pool maintenance. Its impact on glioblastoma remains largely unknown. In this study, we have found that high levels of SOX1 observed in a subset of patients correlate with lower overall survival. At the cellular level, SOX1 expression is elevated in patient-derived GSCs and it is also higher in oncosphere culture compared to differentiation conditions in conventional glioblastoma cell lines. Moreover, genetic inhibition of SOX1 in patient-derived GSCs and conventional cell lines decreases self-renewal and proliferative capacity in vitro and tumor initiation and growth in vivo. Contrarily, SOX1 over-expression moderately promotes self-renewal and proliferation in GSCs. These functions seem to be independent of its activity as Wnt/β-catenin signaling regulator. In summary, these results identify a functional role for SOX1 in regulating glioma cell heterogeneity and plasticity, and suggest SOX1 as a potential target in the GSC population in glioblastoma. PMID:28425506

  12. Leptomeningeal metastasis from gynecologic cancers diagnosed by brain MRI.

    PubMed

    Toyoshima, Masafumi; Tsuji, Keita; Shigeta, Shogo; Tokunaga, Hideki; Ito, Kiyoshi; Watanabe, Yoh; Yoshinaga, Kosuke; Otsuki, Takeo; Niikura, Hitoshi; Yaegashi, Nobuo

    Leptomeningeal metastasis (LM) is rarely observed in gynecologic cancers. As gadolinium-enhanced magnetic resonance imaging (Gd-MRI) is highly effective for diagnosing LM, the aim of this study is to describe the clinical behaviors and outcomes of LM patients who were diagnosed by Gd-MRI. After securing institutional review board approvals, we retrospectively reviewed patient records. Eight patients were found to have LM from gynecological malignancies. Primary tumors included three ovarian cancers, one tubal cancer, one peritoneal cancer, two endometrial cancers, and one cervical cancer. Gd-MRI of the brain and the spine is indicated as the high-priority inspection for the diagnosis of this devastating complication.

  13. Improving Goals of Care Discussion in Advanced Cancer Patients

    ClinicalTrials.gov

    2016-12-20

    Primary Stage IV Hepatobiliary; Esophageal; Colorectal Cancer; Glioblastoma; Cancer of Stomach; Cancer of Pancreas; Melanoma; Head or Neck Cancer; Stage III; Stage IV; Lung Cancers; Pancreatic Cancers

  14. Glioblastoma Mimicking Meningioma: Report of 2 Cases.

    PubMed

    Patel, Mohit; Nguyen, Ha Son; Doan, Ninh; Gelsomino, Michael; Shabani, Saman; Mueller, Wade

    2016-11-01

    Glioblastoma can mimic various pathologies, including arteriovenous malformation, hemorrhage from ischemic stroke, cerebral contusion, metastatic disease, lymphoma, and infection. The literature is limited regarding diagnostic confusion with meningioma. Herein, we present 2 patients that exhibited imaging, including cerebral angiography during preoperative embolization, which was consistent with meningioma, but where final surgical diagnosis revealed glioblastoma. Case 1 was a 57-year-old woman presenting with headache, ataxia, and memory lapses for the past month. Brain magnetic resonance imaging (MRI) demonstrated a heterogeneous-enhancing right temporoparietal mass with broad contact along the right tentorium, cerebrospinal fluid (CSF) cleft sign, and dural tail sign-consistent with meningioma. Patient underwent angiography with successful polyvinyl alcohol foam (PVA) particle embolization of the petrosquamosal branch of the right middle meningeal artery (MMA) and meningeal branch of the right occipital artery, resulting in significant devascularization of the tumor blush. Subsequently, the patient underwent tumor resection, where pathology revealed glioblastoma. Case 2 was a 60-year-old man presenting with right hemiparesis. Brain MRI demonstrated a left parasagittal, heterogeneous-enhancing mass abutting the falx with a dural tail sign-consistent with meningioma. Patient underwent angiography with successful PVA particle embolization of the left MMA, resulting in significant devascularization of the tumor blush. Patient underwent a tumor resection where pathology revealed glioblastoma. Glioblastoma can mimic meningioma on MRI with dural tail sign, CSF cleft sign, and broad dural contact. Moreover, cerebral angiography can reveal tumor feeders commonly associated with meningioma. These features can contribute to diagnostic confusion. Based on these 2 cases, preoperative embolization of tumor feeders is possible with glioblastoma. Copyright © 2016 The Author

  15. MicroRNA-206 Inhibited the Progression of Glioblastoma Through BCL-2.

    PubMed

    Hao, Wenjiong; Luo, Wei; Bai, Mangmang; Li, Jian; Bai, Xiaobin; Guo, Jie; Wu, Jinsong; Wang, Maode

    2016-12-01

    Gliomas are the most common type of brain tumor and have a poor prognosis. MicroRNAs (miRNAs) are a class of small, endogenous, and non-coding RNAs that play crucial roles in cell proliferation, survival, and invasion. Deregulated expression of miR-206 has been investigated in many cancers. However, the role of miR-206 in glioblastoma is still unclear. In the present study, we found that the expression of miR-206 was decreased in cancer tissues compared with normal tissues. However, the expression level of BCL-2 was higher in cancer tissues than that in normal tissues (all p < 0.001). Statistically, the expression level of BCL-2 was inversely correlated with the miR-206. In addition, the overall survival of glioblastoma patients with lower miR-206 expression was significantly shorter than those with high miR-206 expression (p < 0.001). Besides, the expression of miR-206 was also decreased in U87 and U251 cells. In vitro assays showed that ectopic miR-206 expression affected the proliferation, cell cycle, and invasion in U87 and U251 cells. Importantly, we identified BCL-2 as a direct target of miR-206 in U87 and U251 cells using luciferase assay. Overexpression of BCL-2 partially attenuated the miR-206-mediated cell proliferation. In vivo, overexpression of miR-206 suppressed the progression of glioblastoma cells using mice xenograft model. In conclusion, this study suggested that miR-206 could act as a tumor suppressor gene through inhibiting BCL-2 in the development of glioblastoma.

  16. Applications of dendrimers for brain delivery and cancer therapy.

    PubMed

    Somani, Sukrut; Dufès, Christine

    2014-10-01

    Dendrimers are emerging as potential nonviral vectors for the efficient delivery of drugs and nucleic acids to the brain and cancer cells. These polymers are highly branched, 3D macromolecules with modifiable surface functionalities and available internal cavities that make them attractive as delivery systems for drug and gene delivery applications. This article highlights the recent therapeutic advances resulting from the use of dendrimers for brain targeting and cancer treatment.

  17. Adaptive Chromatin Remodeling Drives Glioblastoma Stem Cell Plasticity and Drug Tolerance.

    PubMed

    Liau, Brian B; Sievers, Cem; Donohue, Laura K; Gillespie, Shawn M; Flavahan, William A; Miller, Tyler E; Venteicher, Andrew S; Hebert, Christine H; Carey, Christopher D; Rodig, Scott J; Shareef, Sarah J; Najm, Fadi J; van Galen, Peter; Wakimoto, Hiroaki; Cahill, Daniel P; Rich, Jeremy N; Aster, Jon C; Suvà, Mario L; Patel, Anoop P; Bernstein, Bradley E

    2017-02-02

    Glioblastoma, the most common and aggressive malignant brain tumor, is propagated by stem-like cancer cells refractory to existing therapies. Understanding the molecular mechanisms that control glioblastoma stem cell (GSC) proliferation and drug resistance may reveal opportunities for therapeutic interventions. Here we show that GSCs can reversibly transition to a slow-cycling, persistent state in response to targeted kinase inhibitors. In this state, GSCs upregulate primitive developmental programs and are dependent upon Notch signaling. This transition is accompanied by widespread redistribution of repressive histone methylation. Accordingly, persister GSCs upregulate, and are dependent on, the histone demethylases KDM6A/B. Slow-cycling cells with high Notch activity and histone demethylase expression are present in primary glioblastomas before treatment, potentially contributing to relapse. Our findings illustrate how cancer cells may hijack aspects of native developmental programs for deranged proliferation, adaptation, and tolerance. They also suggest strategies for eliminating refractory tumor cells by targeting epigenetic and developmental pathways.

  18. EGFR Signals through a DOCK180-MLK3 Axis to Drive Glioblastoma Cell Invasion.

    PubMed

    Misek, Sean A; Chen, Jian; Schroeder, Laura; Rattanasinchai, Chotirat; Sample, Ashley; Sarkaria, Jann N; Gallo, Kathleen A

    2017-08-01

    A hallmark of glioblastoma (GBM) tumors is their highly invasive behavior. Tumor dissemination into surrounding brain tissue is responsible for incomplete surgical resection, and subsequent tumor recurrence. Identification of targets that control GBM cell dissemination is critical for developing effective therapies to treat GBM. A majority of GBM tumors have dysregulated EGFR signaling, due most frequently to EGFR amplification or the presence of a constitutively active EGFRvIII mutant. Mixed lineage kinase 3 (MLK3) is a mitogen-activated protein kinase kinase kinase (MAP3K) that can activate multiple MAPK pathways. In this study, evidence is provided that MLK3 is essential for GBM cell migration and invasion, and that an MLK inhibitor blocks EGF-induced migration and invasion. MLK3 silencing or MLK inhibition blocks EGF-induced JNK activation, suggesting that MLK3-JNK signaling promotes invasion of GBM cells. Mechanistically, it is demonstrated that DOCK180, a RAC1 guanine nucleotide exchange factor (GEF) overexpressed in invasive GBM cells, activates the MLK3-JNK signaling axis in a RAC1-dependent manner. In summary, this investigation identifies an EGFR-DOCK180-RAC1-MLK3-JNK signaling axis that drives glioblastoma cell migration and dissemination.Implications: On the basis of these findings, MLK3 emerges as a potential therapeutic target for the treatment of glioblastoma. Mol Cancer Res; 15(8); 1085-95. ©2017 AACR. ©2017 American Association for Cancer Research.

  19. Nanomedicine based curcumin and doxorubicin combination treatment of glioblastoma with scFv-targeted micelles: In vitro evaluation on 2D and 3D tumor models.

    PubMed

    Sarisozen, Can; Dhokai, Shekhar; Tsikudo, Edcar G; Luther, Ed; Rachman, Ilya M; Torchilin, Vladimir P

    2016-11-01

    NF-κB is strongly associated with poor prognosis of different cancer types and an important factor responsible for the malignant phenotype of glioblastoma. Overcoming chemotherapy-induced resistance caused by activation of PI3K/Akt and NF-κB pathways is crucial for successful glioblastoma therapy. We developed an all-in-one nanomedicine formulation for co-delivery of a chemotherapeutic agent (topoisomerase II inhibitor, doxorubicin) and a multidrug resistance modulator (NF-κB inhibitor, curcumin) for treatment of glioblastoma due to their synergism. Both agents were incorporated into PEG-PE-based polymeric micelles. The glucose transporter-1 (GLUT1) is overexpressed in many tumors including glioblastoma. The micellar system was decorated with GLUT1 antibody single chain fragment variable (scFv) as the ligand to promote blood brain barrier transport and glioblastoma targeting. The combination treatment was synergistic (combination index, CI of 0.73) against U87MG glioblastoma cells. This synergism was improved by micellar encapsulation (CI: 0.63) and further so with GLUT1 targeting (CI: 0.46). Compared to non-targeted micelles, GLUT1 scFv surface modification increased the association of micelles (>20%, P<0.01) and the nuclear localization of doxorubicin (∼3-fold) in U87MGcells, which also translated into enhanced cytotoxicity. The increased caspase 3/7 activation by targeted micelles indicates successful apoptosis enhancement by combinatory treatment. Moreover, GLUT1 targeted micelles resulted in deeper penetration into the 3D spheroid model. The increased efficacy of combination nanoformulations on the spheroids compared to a single agent loaded, or to non-targeted formulations, reinforces the rationale for selection of this combination and successful utilization of GLUT1 scFv as a targeting agent for glioblastoma treatment. Copyright © 2016 Elsevier B.V. All rights reserved.

  20. BC3EE2,9B, a synthetic carbazole derivative, upregulates autophagy and synergistically sensitizes human GBM8901 glioblastoma cells to temozolomide

    PubMed Central

    CHEN, CHIEN-MIN; SYU, JHIH-PU; WAY, TZONG-DER; HUANG, LI-JIAU; KUO, SHENG-CHU; LIN, CHUNG-TIEN; LIN, CHIH-LI

    2015-01-01

    Glioblastoma multiforme (GBM) is the most fatal form of human brain cancer. Although temozolomide (TMZ), an oral alkylating chemotherapeutic agent, improves the survival rate, the prognosis of patients with GBM remains poor. Naturally occurring carbazole alkaloids isolated from curry leaves (Murraya koenigii Spreng.) have been shown to possess a wide range of anticancer properties. However, the effects of carbazole derivatives on glioblastoma cells remain poorly understood. In the present study, anti-glioblastoma profiles of a series of synthetic carbazole derivatives were evaluated in vitro. The most promising derivative in this series was BC3EE2,9B, which showed significant anti-proliferative effects in GBM8401 and GBM8901 cells. BC3EE2,9B also triggered cell-cycle arrest, most prominently at the G1 stage, and suppressed glioblastoma cell invasion and migration. Furthermore, BC3EE2,9B induced autophagy-mediated cell death and synergistically sensitized GBM cells to TMZ cytotoxicity. The possible mechanism underlying BC3EE2,9B-induced autophagy may involve activation of adenosine monophosphate-activated protein kinase and the attenuation of the Akt and mammalian target of the rapamycin downstream signaling pathway. Taken together, the present results provide molecular evidence for the mode of action governing the ability of BC3EE2,9B to sensitize drug-resistant glioblastoma cells to the chemotherapeutic agent TMZ. PMID:26329365

  1. Integrative Network Analysis Combined with Quantitative Phosphoproteomics Reveals Transforming Growth Factor-beta Receptor type-2 (TGFBR2) as a Novel Regulator of Glioblastoma Stem Cell Properties*

    PubMed Central

    Narushima, Yuta; Kozuka-Hata, Hiroko; Koyama-Nasu, Ryo; Tsumoto, Kouhei; Inoue, Jun-ichiro; Akiyama, Tetsu; Oyama, Masaaki

    2016-01-01

    Glioblastoma is one of the most malignant brain tumors with poor prognosis and their development and progression are known to be driven by glioblastoma stem cells. Although glioblastoma stem cells lose their cancer stem cell properties during cultivation in serum-containing medium, little is known about the molecular mechanisms regulating signaling alteration in relation to reduction of stem cell-like characteristics. To elucidate the global phosphorylation-related signaling events, we performed a SILAC-based quantitative phosphoproteome analysis of serum-induced dynamics in glioblastoma stem cells established from the tumor tissues of the patient. Among a total of 2876 phosphorylation sites on 1584 proteins identified in our analysis, 732 phosphorylation sites on 419 proteins were regulated through the alteration of stem cell-like characteristics. The integrative computational analyses based on the quantified phosphoproteome data revealed the relevant changes of phosphorylation levels regarding the proteins associated with cytoskeleton reorganization such as Rho family GTPase and Intermediate filament signaling, in addition to transforming growth factor-β receptor type-2 (TGFBR2) as a prominent upstream regulator involved in the serum-induced phosphoproteome regulation. The functional association of transforming growth factor-β receptor type-2 with stem cell-like properties was experimentally validated through signaling perturbation using the corresponding inhibitors, which indicated that transforming growth factor-β receptor type-2 could play an important role as a novel cell fate determinant in glioblastoma stem cell regulation. PMID:26670566

  2. Ganging Up on Brain Metastases | Center for Cancer Research

    Cancer.gov

    When primary tumors metastasize to the brain, the prognosis for patients is poor. The currently accepted treatment is whole-brain radiation therapy, and the median survival time is several months. Since these types of tumors form in 10 to 30 percent of adult cancer patients, improvements in treatment methods are a necessity.  

  3. Bevacizumab in recurrent glioblastoma: five informative patient scenarios.

    PubMed

    Mason, Warren P

    2015-05-01

    Glioblastoma is the most common and malignant primary brain tumour in adults. Maximum feasible surgical resection, radiotherapy and temozolomide chemotherapy at initial diagnosis have improved prognosis but rapid recurrence is typical and survival remains brief. There is an urgent need for effective new treatments and approval of the antiangiogenic agent bevacizumab for recurrent glioblastoma by Health Canada in 2009 has been the most notable recent therapeutic advance for this disease. This review with illustrative case studies highlights how bevacizumab has been incorporated into the treatment of glioblastoma in Canada and describes the ongoing controversies surrounding its clinical application.

  4. Time-Frequency Analysis of Peptide Microarray Data: Application to Brain Cancer Immunosignatures

    PubMed Central

    O’Donnell, Brian; Maurer, Alexander; Papandreou-Suppappola, Antonia; Stafford, Phillip

    2015-01-01

    One of the gravest dangers facing cancer patients is an extended symptom-free lull between tumor initiation and the first diagnosis. Detection of tumors is critical for effective intervention. Using the body’s immune system to detect and amplify tumor-specific signals may enable detection of cancer using an inexpensive immunoassay. Immunosignatures are one such assay: they provide a map of antibody interactions with random-sequence peptides. They enable detection of disease-specific patterns using classic train/test methods. However, to date, very little effort has gone into extracting information from the sequence of peptides that interact with disease-specific antibodies. Because it is difficult to represent all possible antigen peptides in a microarray format, we chose to synthesize only 330,000 peptides on a single immunosignature microarray. The 330,000 random-sequence peptides on the microarray represent 83% of all tetramers and 27% of all pentamers, creating an unbiased but substantial gap in the coverage of total sequence space. We therefore chose to examine many relatively short motifs from these random-sequence peptides. Time-variant analysis of recurrent subsequences provided a means to dissect amino acid sequences from the peptides while simultaneously retaining the antibody–peptide binding intensities. We first used a simple experiment in which monoclonal antibodies with known linear epitopes were exposed to these random-sequence peptides, and their binding intensities were used to create our algorithm. We then demonstrated the performance of the proposed algorithm by examining immunosignatures from patients with Glioblastoma multiformae (GBM), an aggressive form of brain cancer. Eight different frameshift targets were identified from the random-sequence peptides using this technique. If immune-reactive antigens can be identified using a relatively simple immune assay, it might enable a diagnostic test with sufficient sensitivity to detect tumors

  5. Glioblastoma multiforme in a child with tuberous sclerosis complex.

    PubMed

    Vignoli, Aglaia; Lesma, Elena; Alfano, Rosa Maria; Peron, Angela; Scornavacca, Giulia Federica; Massimino, Maura; Schiavello, Elisabetta; Ancona, Silvia; Cerati, Michele; Bulfamante, Gaetano; Gorio, Alfredo; Canevini, Maria Paola

    2015-10-01

    Tuberous Sclerosis Complex (TSC) is characterized by the presence of benign tumors in the brain, kidneys, heart, eyes, lungs, and skin. The typical brain lesions are cortical tubers, subependimal nodules and subependymal giant-cell astrocytomas. The occurrence of malignant astrocytomas such as glioblastoma is rare. We report on a child with a clinical diagnosis of TSC and a rapidly evolving glioblastoma multiforme. Genetic analysis identified a de novo mutation in TSC2. Molecular characterization of the tumor was performed and discussed, as well as a review of the literature where cases of TSC and glioblastoma multiforme are described. Although the co-occurrence of TSC and glioblastoma multiforme seems to be rare, this possible association should be kept in mind, and proper clinical and radiological follow up should be recommended in these patients.

  6. Brain metastasis in patients with uterine cervical cancer.

    PubMed

    Hwang, Jong Ha; Yoo, Heon Jong; Lim, Myong Cheol; Seo, Sang-Soo; Kang, Sokbom; Kim, Joo-Young; Park, Sang-Yoon

    2013-01-01

    The purpose of this study was to describe the features of patients with brain metastasis from cervical cancer. The medical records of patients with cervical cancer between February 2001 and June 2011 were reviewed retrospectively. Clinical characteristics, symptoms, treatment and survival in patients with brain metastasis were analyzed.   Eleven patients with brain metastasis from cervical cancer were identified, representing an incidence of brain metastasis in the study population of 0.45%. Median patient age at initial diagnosis of cervical cancer was 50 years (range 33-75 years). Non-squamous cell carcinoma was diagnosed in six (54.5%) of the 11 patients, with small cell carcinoma diagnosed in two patients. Ten of the 11 patients had lung-related metastasis at presentation; eight patients had lung metastasis, one had mediastinal lymph node metastasis, and one had pleural metastasis. The median interval from diagnosis of cervical cancer to identification of brain metastasis was 15.4 months (range 3.4-83.3 months). Nine patients presented with neurologic symptoms, such as headache, nausea, vomiting, seizure and extremity weakness. Initially, six patients received whole brain radiotherapy: three patients received chemotherapy; one underwent surgery; and one patient refused treatment. The median survival time after diagnosis of the brain metastases was 5.9 months (range 0.7-19 months). The prognosis after diagnosis of the brain metastasis in patients with uterine cervical cancer is poor. The small cell type and lung metastasis seem to be related with brain metastasis and may be regarded as risk factors. © 2012 The Authors. Journal of Obstetrics and Gynaecology Research © 2012 Japan Society of Obstetrics and Gynecology.

  7. Brain metastasis from ovarian cancer: a systematic review.

    PubMed

    Pakneshan, Shabnam; Safarpour, Damoun; Tavassoli, Fattaneh; Jabbari, Bahman

    2014-08-01

    To review the existing literature on brain metastasis (BM) from ovarian cancer and to assess the frequency, anatomical, clinical and paraclinical information and factors associated with prognosis. Ovarian cancer is a rare cause of brain metastasis with a recently reported increasing prevalence. Progressive neurologic disability and poor prognosis is common. A comprehensive review on this subject has not been published previously. This systematic literature search used the Pubmed and Yale library. A total of 66 publications were found, 57 of which were used representing 591 patients with BM from ovarian cancer. The median age of the patients was 54.3 years (range 20-81). A majority of patients (57.3 %) had multiple brain lesions. The location of the lesion was cerebellar (30 %), frontal (20 %), parietal (18 %) and occipital (11 %). Extracranial metastasis was present in 49.8 % of cases involving liver (20.7 %), lung (20.4 %), lymph nodes (12.6 %), bones (6.6 %) and pelvic organs (4.3 %). The most common symptoms were weakness (16 %), seizures (11 %), altered mentality (11 %) visual disturbances (9 %) and dizziness (8 %). The interval from diagnosis of breast cancer to BM ranged from 0 to 133 months (median 24 months) and median survival was 8.2 months. Local radiation, surgical resection, stereotactic radiosurgery and medical therapy were used. Factors that significantly increased the survival were younger age at the time of ovarian cancer diagnosis and brain metastasis diagnosis, lower grade of the primary tumor, higher KPS score and multimodality treatment for the brain metastases. Ovarian cancer is a rare cause of brain metastasis. Development of brain metastasis among older patients and lower KPS score correlate with less favorable prognosis. The more prolonged survival after using multimodality treatment for brain metastasis is important due to potential impact on management of brain metastasis in future.

  8. Limited advances in therapy of glioblastoma trigger re-consideration of research policy.

    PubMed

    Frosina, Guido

    2015-11-01

    Glioblastoma (GB - WHO grade IV) is the most frequent and lethal primary brain tumour with median overall survival of 7-15 months after diagnosis. As in other cancer research areas, an overwhelming amount of pre-clinical research acquisitions in the GB field have not been translated to patients' benefit, potentially due to inappropriate treatment schedules and/or trial designs in the clinical setting. The recent failure of promising anti-VEGF bevacizumab to improve GB patients' overall survival recapitulates this sense of frustration. The following measures are proposed. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  9. Micro-masters of glioblastoma biology and therapy: increasingly recognized roles for microRNAs

    PubMed Central

    Floyd, Desiree; Purow, Benjamin

    2014-01-01

    MicroRNAs are small noncoding RNAs encoded in eukaryotic genomes that have been found to play critical roles in most biological processes, including cancer. This is true for glioblastoma, the most common and lethal primary brain tumor, for which microRNAs have been shown to strongly influence cell viability, stem cell characteristics, invasiveness, angiogenesis, metabolism, and immune evasion. Developing microRNAs as prognostic markers or as therapeutic agents is showing increasing promise and has potential to reach the clinic in the next several years. This succinct review summarizes current progress and future directions in this exciting and steadily expanding field. PMID:24723563

  10. BI-03GLIOBLASTOMA-SPECIFIC AND GLIOBLASTOMA STEM CELL SUBTYPE-SPECIFIC SIGNATURES OF LONG, NON-CODING RNAs

    PubMed Central

    Bronisz, Agnieszka; Mineo, Marco; Ansari, Khairul; Rooj, Arun; Nakano, Ichiro; Antonio Chiocca, E.; Godlewski, Jakub

    2014-01-01

    Long-non coding RNAs (lncRNAs) are large and heterogeneous group of non-protein coding RNAs larger than 200nt. They regulate the expression of their target genes by multiple mechanisms including regulation of transcription, splicing, translation and epigenetic regulation. There is growing evidence of important role of lncRNAs in carcinogenesis, including glioblastoma multiforme (GBM). To profile lncRNAs in GBM patient samples and cells, we designed a platform using NanoString system to detect 73 lncRNAs that has been implicated in cancer pathophysiology. We used our collection of matched samples (i.e. from the same patient) of GBM tumors and adjacent brain tissue. We showed that 27-lncRNA signature (10 GBM-low and 17 GBM-high) clustered these samples. Glioblastoma stem cells (GSCs) are highly tumorigenic and therapy-resistant sub-population of glioblastoma. We characterized our large collection of patient-derived GSCs maintained in serum-free culture. Based on 10-gene signature we ascribed them to either proneural (PN), mesenchymal (MES) subtype. We demonstrated that 28-lncRNA signature (7 PN-low and 21 PN-high) clustered PN and MES GSCs. Testing the functionality of lncRNAs, we showed that PN-MES subtype switch achieved by de-regulation of important regulator of GSC self-renewal - miR-128, was concurrent with the shift in lncRNA signature. Finally, based on 29-lncRNA signature, we were able to establish that, irradiated PN GSCs acquired more mesenchymal characteristics. Our results thus suggest broad involvement of lncRNAs in the regulation of pathophysiological processes in GBM/GSC cells.

  11. The interplay between intracellular progesterone receptor and PKC plays a key role in migration and invasion of human glioblastoma cells.

    PubMed

    Marquina-Sánchez, Brenda; González-Jorge, Jesús; Hansberg-Pastor, Valeria; Wegman-Ostrosky, Talia; Baranda-Ávila, Noemi; Mejía-Pérez, Sonia; Camacho-Arroyo, Ignacio; González-Arenas, Aliesha

    2017-09-01

    Intracellular progesterone receptors (PRs) and protein kinases C (PKCs) are known regulators of cancer cell proliferation and metastasis. Both PRs and PKCs are found overexpressed in grade IV human astrocytomas, also known as glioblastomas, which are the most frequent and aggressive brain tumors. In the present study, we investigated whether PR activation by PKC induces the migration and invasion of glioblastoma derived cell lines and if PKCα and δ isoforms are involved in PR activation. We observed that PKC activation with tetradecanoylphorbol acetate (TPA) increases the migration and invasion capacity of two human glioblastoma derived human cell lines (U251 MG and U87) and that the treatment with the PR receptor antagonist RU486 blocks these processes. Interestingly, the pharmacological inhibition of the isoenzymes PKCα and PKCδ also resulted in a blocked PR transcriptional activity. Also, TPA-dependent PR activation increases the expression of progesterone-induced blocking factor (PIBF), a known PR target gene. These results hint to an existing cross-talk between PKCs and PRs in regulating the infiltration process of human glioblastomas. Copyright © 2016 Elsevier Ltd. All rights reserved.

  12. Characterization of PTEN mutations in brain cancer reveals that pten mono-ubiquitination promotes protein stability and nuclear localization.

    PubMed

    Yang, Jr-M; Schiapparelli, P; Nguyen, H-N; Igarashi, A; Zhang, Q; Abbadi, S; Amzel, L M; Sesaki, H; Quiñones-Hinojosa, A; Iijima, M

    2017-03-06

    PTEN is a PIP3 phosphatase that antagonizes oncogenic PI3-kinase signalling. Due to its critical role in suppressing the potent signalling pathway, it is one of the most mutated tumour suppressors, especially in brain tumours. It is generally thought that PTEN deficiencies predominantly result from either loss of expression or enzymatic activity. By analysing PTEN in malignant glioblastoma primary cells derived from 16 of our patients, we report mutations that block localization of PTEN at the plasma membrane and nucleus without affecting lipid phosphatase activity. Cellular and biochemical analyses as well as structural modelling revealed that two mutations disrupt intramolecular interaction of PTEN and open its conformation, enhancing polyubiquitination of PTEN and decreasing protein stability. Moreover, promoting mono-ubiquitination increases protein stability and nuclear localization of mutant PTEN. Thus, our findings provide a molecular mechanism for cancer-associated PTEN defects and may lead to a brain cancer treatment that targets PTEN mono-ubiquitination.Oncogene advance online publication, 6 March 2017; doi:10.1038/onc.2016.493.

  13. Concurrent therapy to enhance radiotherapeutic outcomes in glioblastoma

    PubMed Central

    2016-01-01

    Glioblastoma is one of the most fatal and incurable human cancers characterized by nuclear atypia, mitotic activity, intense microvascular proliferation and necrosis. The current standard of care includes maximal safe surgical resection followed by radiation therapy (RT) with concurrent and adjuvant temozolomide (TMZ). The prognosis remains poor with median survival of 14.6 months with RT plus TMZ. Majority will have a recurrence within 2 years from diagnosis despite adequate treatment. Radiosensitizers, radiotherapy dose escalation and altered fractionation have failed to improve outcome. The molecular biology of glioblastoma is complex and poses treatment challenges. High rate of mutation, genotypic and phenotypic heterogeneity, rapid development of resistance, existence of blood-brain barrier (BBB), multiple intracellular and intercellular signalling pathways, over-expression of growth factor receptors, angiogenesis and antigenic diversity renders the tumor cells differentially susceptible to various treatment modalities. Thus, the treatment strategies require personalised or individualized approach based on the characteristics of tumor. Several targeted agents have been evaluated in clinical trials but the results have been modest despite these advancements. This review summarizes the current standard of care, results of concurrent chemoradiation trials, evolving innovative treatments that use targeted therapy with standard chemoradiation or RT alone, outcome of various recent trials and future outlook. PMID:26904576

  14. Management of glioblastoma after recurrence: A changing paradigm.

    PubMed

    Mallick, Supriya; Benson, Rony; Hakim, Abdul; Rath, Goura K

    2016-12-01

    Glioblastoma remains the most common primary brain tumor after the age of 40years. Maximal safe surgery followed by adjuvant chemoradiotherapy has remained the standard treatment for glioblastoma (GBM). But recurrence is an inevitable event in the natural history of GBM with most patients experiencing it after 6-9months of primary treatment. Recurrent GBM poses great challenge to manage with no well-defined management protocols. The challenge starts from differentiating radiation necrosis from true local progression. A fine balance needs to be maintained on improving survival and assuring a better quality of life. Treatment options are limited and ranges from re-excision, re-irradiation, systemic chemotherapy or a combination of these. Re-excision and re-irradiation must be attempted in selected patients and has been shown to improve survival outcomes. To facilitate the management of GBM recurrences, a treatment algorithm is proposed. Copyright © 2016 National Cancer Institute, Cairo University. Production and hosting by Elsevier B.V. All rights reserved.

  15. PARP-1 protein expression in glioblastoma multiforme

    PubMed Central

    Galia, A.; Calogero, A.E.; Condorelli, R.A.; Fraggetta, F.; La Corte, C.; Ridolfo, F.; Bosco, P.; Castiglione, R.; Salemi, M.

    2012-01-01

    One of the most common type of primary brain tumors in adults is the glioblastoma multiforme (GBM) (World Health Organization grade IV astrocytoma). It is the most common malignant and aggressive form of glioma and it is among the most lethal ones. Poly (ADP-ribose) polymerase 1 (PARP-1) gene, located to 1q42, plays an important role for the efficient maintenance of genome integrity. PARP-1 protein is required for the apoptosis-inducing factor (AIF) translocation from the mitochondria to the nucleus. PARP-1 is proteolytically cleaved at the onset of apoptosis by caspase-3. Microarray analysis of PARP-1 gene expression in more than 8000 samples revealed that PARP-1 is more highly expressed in several types of cancer compared with the equivalent normal tissues. Overall, the most differences in PARP-1 gene expression have been observed in breast, ovarian, endometrial, lung, and skin cancers, and non-Hodgkin's lymphoma. We evaluated the expression of PARP-1 protein in normal brain tissues and primary GBM by immunohistochemistry. Positive nuclear PARP-1 staining was found in all samples with GBM, but not in normal neurons from controls (n=4) and GBM patients (n=27). No cytoplasmic staining was observed in any sample. In conclusion, PARP-1 gene is expressed in GBM. This finding may be envisioned as an attempt to trigger apoptosis in this tumor, as well as in many other malignancies. The presence of the protein exclusively at the nucleus further support the function played by this gene in genome integrity maintenance and apoptosis. Finally, PARP-1 staining may be used as GBM cell marker. PMID:22472897

  16. Role of the neural niche in brain metastatic cancer

    PubMed Central

    Termini, John; Neman, Josh; Jandial, Rahul

    2014-01-01

    Metastasis is the relenteless pursuit of cancer to escape its primary site and colonize distant organs. This malignant evolutionary process is biologically heterogeneous, yet one unifying element is the critical role of the microenvironment for arriving metastatic cells. Historically brain metastases were rarely investigated since patients with advanced cancer were considered terminal. Fortunately, advances in molecular therapies have led to patients living longer with metastatic cancer. However, one site remains recalcitrant to our treatment efforts – the brain. The central nervous system is the most complex biological system, which poses unique obstacles but also harbors opportunities for discovery. Much of what we know about the brain microenvironment comes from neuroscience. We suggest that the interrelated cellular responses in traumatic brain injury may guide us towards new perspectives in understanding brain metastases. In this view, brain metastases may be conceptualized as progressive oncologic injury to the nervous system. This review discusses our evolving understanding of the bidirectional interactions between the brain milieu and metastatic cancer. PMID:25035392

  17. Patterns of DNA damage response in intracranial germ cell tumors versus glioblastomas reflect cell of origin rather than brain environment: implications for the anti-tumor barrier concept and treatment.

    PubMed

    Bartkova, Jirina; Hoei-Hansen, Christina E; Krizova, Katerina; Hamerlik, Petra; Skakkebæk, Niels E; Rajpert-De Meyts, Ewa; Bartek, Jiri

    2014-12-01

    The DNA damage response (DDR) machinery becomes commonly activated in response to oncogenes and during early stages of development of solid malignancies, with an exception of testicular germ cell tumors (TGCTs). The active DDR signaling evokes cell death or senescence but this anti-tumor barrier can be breached by defects in DDR factors, such as the ATM-Chk2-p53 pathway, thereby allowing tumor progression. The DDR barrier is strongly activated in brain tumors, particularly gliomas, due to oxidative damage and replication stress. Here, we took advantage of rare human primary intracranial germ cell tumors (PIGCTs), to address the roles of cell-intrinsic factors including cell of origin, versus local tissue environment, in the constitutive DDR activation in vivo. Immunohistochemical analysis of 7 biomarkers on a series of 21 PIGCTs (germinomas and other subtypes), 20 normal brain specimens and 20 glioblastomas, revealed the following: i) The overall DDR signaling (γH2AX) and activation of the ATM-Chk2-p53 pathway were very low among the PIGCTs, reminiscent of TGCTs, and contrasting sharply with strong DDR activation in glioblastomas; ii) Except for one case of embryonal carcinoma, there were no clear aberrations in the ATM-Chk2-p53 pathway components among the PIGCT cohort; iii) Subsets of PIGCTs showed unusual cytosolic localization of Chk2 and/or ATM. Collectively, these results show that PIGCTs mimic the DDR activation patterns of their gonadal germ cell tumor counterparts, rather than the brain tumors with which they share the tissue environment. Hence cell-intrinsic factors and cell of origin dictate the extent of DDR barrier activation and also the ensuing pressure to select for DDR defects. Our data provide conceptually important insights into the role of DNA damage checkpoints in intracranial tumorigenesis, with implications for the differential biological responses of diverse tumor types to endogenous stress as well as to genotoxic treatments such as

  18. Robust Cell Segmentation for Histological Images of Glioblastoma

    PubMed Central

    Kong, Jun; Zhang, Pengyue; Liang, Yanhui; Teodoro, George; Brat, Daniel J.; Wang, Fusheng

    2016-01-01

    Glioblastoma (GBM) is a malignant brain tumor with uniformly dismal prognosis. Quantitative analysis of GBM cells is an important avenue to extract latent histologic disease signatures to correlate with molecular underpinnings and clinical outcomes. As a prerequisite, a robust and accurate cell segmentation is required. In this paper, we present an automated cell segmentation method that can satisfactorily address segmentation of overlapped cells commonly seen in GBM histology specimens. This method first detects cells with seed connectivity, distance constraints, image edge map, and a shape-based voting image. Initialized by identified seeds, cell boundaries are deformed with an improved variational level set method that can handle clumped cells. We test our method on 40 histological images of GBM with human annotations. The validation results suggest that our cell segmentation method is promising and represents an advance in quantitative cancer research.

  19. Master regulators, regulatory networks, and pathways of glioblastoma subtypes.

    PubMed

    Bozdag, Serdar; Li, Aiguo; Baysan, Mehmet; Fine, Howard A

    2014-01-01

    Glioblastoma multiforme (GBM) is the most common malignant brain tumor. GBM samples are classified into subtypes based on their transcriptomic and epigenetic profiles. Despite numerous studies to better characterize GBM biology, a comprehensive study to identify GBM subtype- specific master regulators, gene regulatory networks, and pathways is missing. Here, we used FastMEDUSA to compute master regulators and gene regulatory networks for each GBM subtype. We also ran Gene Set Enrichment Analysis and Ingenuity Pathway Analysis on GBM expression dataset from The Cancer Genome Atlas Project to compute GBM- and GBM subtype-specific pathways. Our analysis was able to recover some of the known master regulators and pathways in GBM as well as some putative novel regulators and pathways, which will aide in our understanding of the unique biology of GBM subtypes.

  20. Cancer Stem Cell-Secreted Macrophage Migration Inhibitory Factor Stimulates Myeloid Derived Suppressor Cell Function and Facilitates Glioblastoma Immune Evasion.

    PubMed

    Otvos, Balint; Silver, Daniel J; Mulkearns-Hubert, Erin E; Alvarado, Alvaro G; Turaga, Soumya M; Sorensen, Mia D; Rayman, Patricia; Flavahan, William A; Hale, James S; Stoltz, Kevin; Sinyuk, Maksim; Wu, Qiulian; Jarrar, Awad; Kim, Sung-Hak; Fox, Paul L; Nakano, Ichiro; Rich, Jeremy N; Ransohoff, Richard M; Finke, James; Kristensen, Bjarne W; Vogelbaum, Michael A; Lathia, Justin D

    2016-08-01

    Shifting the balance away from tumor-mediated immune suppression toward tumor immune rejection is the conceptual foundation for a variety of immunotherapy efforts currently being tested. These efforts largely focus on activating antitumor immune responses but are confounded by multiple immune cell populations, including myeloid-derived suppressor cells (MDSCs), which serve to suppress immune system function. We have identified immune-suppressive MDSCs in the brains of GBM patients and found that they were in close proximity to self-renewing cancer stem cells (CSCs). MDSCs were selectively depleted using 5-flurouracil (5-FU) in a low-dose administration paradigm, which resulted in prolonged survival in a syngeneic mouse model of glioma. In coculture studies, patient-derived CSCs but not nonstem tumor cells selectively drove MDSC-mediated immune suppression. A cytokine screen revealed that CSCs secreted multiple factors that promoted this activity, including macrophage migration inhibitory factor (MIF), which was produced at high levels by CSCs. Addition of MIF increased production of the immune-suppressive enzyme arginase-1 in MDSCs in a CXCR2-dependent manner, whereas blocking MIF reduced arginase-1 production. Similarly to 5-FU, targeting tumor-derived MIF conferred a survival advantage to tumor-bearing animals and increased the cytotoxic T cell response within the tumor. Importantly, tumor cell proliferation, survival, and self-renewal were not impacted by MIF reduction, demonstrating that MIF is primarily an indirect promoter of GBM progression, working to suppress immune rejection by activating and protecting immune suppressive MDSCs within the GBM tumor microenvironment. Stem Cells 2016;34:2026-2039.

  1. The European Organisation for Research and Treatment of Cancer strategy for new drug development in brain tumors.

    PubMed

    Lacombe, Denis; Brandes, Alba A; van den Bent, Martin

    2003-12-01

    The European Organisation for Research and Treatment of Cancer (EORTC) has carried out clinical trials for nearly 30 years. During this time, several disease-oriented groups within the EORTC have been shaped by rapidly changing regulations in the area of drug development. Continual networking, dissemination of knowledge, and the establishment of specialized administrative units have allowed the EORTC to play a leading role in the development of improved treatment options for patients with brain tumors. Recently, the EORTC Brain Tumor Group and the EORTC New Drug Development Group have been integrated to create a network of institutions dedicated to screening new chemotherapy agents for the treatment of high-grade gliomas. Indeed, several new regimens and agents have already been investigated by this collaboration. Most notable are the recently closed study on temozolomide (Temodar [US], Temodal [international]; Schering-Plough Corporation, Kenilworth, NJ) in the adjuvant setting and in combination with radiotherapy in patients newly diagnosed with glioblastoma multiforme, and the ongoing study on oral STI571 for the treatment of gliomas. Within the current networks, a well-defined strategy has been implemented to select specific and targeted agents for the drug screening process. By sharing their expertise with the EORTC networks, medical oncologists, neuro-oncologists, and radiologists can assist in the clinical development of potentially active agents in patients with brain tumors.

  2. Hippocampal-Sparing Whole-Brain Radiotherapy for Lung Cancer.

    PubMed

    Zhao, Ren; Kong, Wei; Shang, Jun; Zhe, Hong; Wang, Yan-Yang

    2017-03-01

    Brain metastases occur in 20% to 40% of lung cancer patients. Whole-brain radiotherapy (WBRT) has long been considered the treatment of choice for many patients with lung cancer, because of its wide availability, ease of delivery, and effectiveness in prolonging survival. However, WBRT is also associated with several side effects, such as decline in memory and other cognitive functions. There exists significant preclinical and clinical evidence that radiation-induced injury to the hippocampus correlates with neurocognitive decline of patients who receive WBRT. Technological advances in treatment planning and delivery facilitate the use of hippocampal-sparing (HS) WBRT as prophylactic cranial irradiation or the primary treatment modality for lung cancer patients with brain metastases. In this review, we provide a detailed and comprehensive discussion of the safety profile, techniques for hippocampus-sparing, and the clinical evidence of HS-WBRT for lung cancer patients.

  3. A tree shrew glioblastoma model recapitulates features of human glioblastoma.

    PubMed

    Tong, Yaohui; Hao, Junjun; Tu, Qiu; Yu, Hualin; Yan, Lanzhen; Li, Yuan; Lv, Longbao; Wang, Fei; Iavarone, Antonio; Zhao, Xudong

    2017-03-14

    Tupaia belangeri (tree shrew), an animal species whose genome has significantly higher similarity to primates than rodents, has been used in biomedical research. To generate animal models that reproduce the human tumors more faithfully than rodents, we present the first report of a cancer model mimicking human tumor genetics in tree shrew. By engineering a lentiviral system for the transduction of mutant H-Ras and a shRNA against tree shrew p53, we successfully generated malignant glioma in tree shrew. The tree shrew glioma exhibited aggressive behavior and a relatively short latency, and markedly reduced animal survival. Remarkably, the biological features of human high-grade glioma (necrosis, microvascular proliferation, pseudopalisading) were all present in tree shrew glioma. Furthermore, genetic analysis of tree shrew glioma revealed that the tumors were clustered within the mesenchymal subgroup of human glioblastoma multiforme. Compared with the corresponding mouse glioma, tree shrew gliomas were markedly more similar to human glioblastoma at gene expression profile. The tree shrew glioma model provides colleagues working in the field of gliomas and cancer in general with a more accurate animal model.

  4. Breast Cancer Resistance Protein and P-glycoprotein in Brain Cancer: Two Gatekeepers Team Up

    PubMed Central

    Agarwal, Sagar; Hartz, Anika M.S.; Elmquist, William F.; Bauer, Björn

    2012-01-01

    Brain cancer is a devastating disease. Despite extensive research, treatment of brain tumors has been largely ineffective and the diagnosis of brain cancer remains uniformly fatal. Failure of brain cancer treatment may be in part due to limitations in drug delivery, influenced by the ABC drug efflux transporters P-gp and BCRP at the blood-brain and blood-tumor barriers, in brain tumor cells, as well as in brain tumor stem-like cells. P-gp and BCRP limit various anti-cancer drugs from entering the brain and tumor tissues, thus rendering chemotherapy ineffective. To overcome this obstacle, two strategies – targeting transporter regulation and direct transporter inhibition – have been proposed. In this review, we focus on these strategies. We first introduce the latest findings on signaling pathways that could potentially be targeted to down-regulate P-gp and BCRP expression and/or transport activity. We then highlight in detail the new paradigm of P-gp and BCRP working as a “cooperative team of gatekeepers” at the blood-brain barrier, discuss its ramifications for brain cancer therapy, and summarize the latest findings on dual P-gp/BCRP inhibitors. Finally, we provide a brief summary with conclusions and outline the perspectives for future research endeavors in this field. PMID:21827403

  5. γ knife radiosurgery of brain metastasis from breast cancer.

    PubMed

    Padovani, Laetitia; Muracciole, Xavier; Régis, Jean

    2012-01-01

    The incidence of brain metastasis in patients with metastatic breast cancer ranges from 14 to 16%.Age, number of metastatic sites, short disease-free survival and molecular subtypes are associated with the occurrence of brain metastasis. Patients classified in the triple-negative group more frequently presented brain metastasis as the first site (26%) than those in the human epidermal growth factor receptor 2 (HER2)-positive (6%) or luminal (12%) subtypes. Whole brain radiation therapy (WBRT) is still the standard treatment for breast cancer patients with brain metastasis. The 1- and 2-year survival rates of patients with brain metastasis were 25 and 10%, respectively, with a median survival of 6 months. In selected patients with single brain metastasis, majority of lung cancer, three randomized controlled trials underlined the significant survival benefit in adding local treatment such as surgery or stereotactic radio surgery to WBRT. Similarly, the upfront stereotactic radiosurgery (SRS) alone did not affect survival rate in three other randomized studies and represents an alternative treatment for patients with stage 1-4. Metastatic breast cancer patients with Karnofsky Performance Scale ≥70, single or oligometastatic brain metastases and well-controlled extracranial disease or favorable disease-specific graded prognostic assessment group presented a median overall survival of 16 months. Delaying WBRT could spare patients of neurocognitive toxicity due to full-dose whole brain irradiation. Nevertheless, the real WBRT neurocognitive impact is still unclear. These patients should be followed with serial magnetic resonance image every 3 months and treated with WBRT or additional SRS at recurrence to control brain disease.

  6. CD151-α3β1 integrin complexes are prognostic markers of glioblastoma and cooperate with EGFR to drive tumor cell motility and invasion.

    PubMed

    Zhou, Pengcheng; Erfani, Sonia; Liu, Zeyi; Jia, Changhe; Chen, Yecang; Xu, Bingwei; Deng, Xinyu; Alfáro, Jose E; Chen, Li; Napier, Dana; Lu, Michael; Huang, Jian-An; Liu, Chunming; Thibault, Olivier; Segal, Rosalind; Zhou, Binhua P; Kyprianou, Natasha; Horbinski, Craig; Yang, Xiuwei H

    2015-10-06

    Glioblastoma, one of the most aggressive forms of brain cancer, is featured by high tumor cell motility and invasiveness, which not only fuel tumor infiltration, but also enable escape from surgical or other clinical interventions. Thus, better understanding of how these malignant traits are controlled will be key to the discovery of novel biomarkers and therapies against this deadly disease. Tetraspanin CD151 and its associated α3β1 integrin have been implicated in facilitating tumor progression across multiple cancer types. How these adhesion molecules are involved in the progression of glioblastoma, however, remains largely unclear. Here, we examined an in-house tissue microarray-based cohort of 96 patient biopsies and TCGA dataset to evaluate the clinical significance of CD151 and α3β1 integrin. Functional and signaling analyses were also conducted to understand how these molecules promote the aggressiveness of glioblastoma at molecular and cellular levels. Results from our analyses showed that CD151 and α3 integrin were significantly elevated in glioblastomas at both protein and mRNA levels, and exhibited strong inverse correlation with patient survival (p < 0.006). These adhesion molecules also formed tight protein complexes and synergized with EGF/EGFR to accelerate tumor cell motility and invasion. Furthermore, disruption of such complexes enhanced the survival of tumor-bearing mice in a xenograft model, and impaired activation of FAK and small GTPases. Also, knockdown- or pharmacological agent-based attenuation of EGFR, FAK or Graf (ARHGAP26)/small GTPase-mediated pathways markedly mitigated the aggressiveness of glioblastoma cells. Collectively, our findings provide clinical, molecular and cellular evidence of CD151-α3β1 integrin complexes as promising prognostic biomarkers and therapeutic targets for glioblastoma.

  7. CD151-α3β1 integrin complexes are prognostic markers of glioblastoma and cooperate with EGFR to drive tumor cell motility and invasion

    PubMed Central

    Xu, Bingwei; Deng, Xinyu; Alfáro, Jose E.; Chen, Li; Napier, Dana; Lu, Michael; Huang, Jian-An; Liu, Chunming; Thibault, Olivier; Segal, Rosalind; Zhou, Binhua P.; Kyprianou, Natasha; Horbinski, Craig; Yang, Xiuwei H.

    2015-01-01

    Glioblastoma, one of the most aggressive forms of brain cancer, is featured by high tumor cell motility and invasiveness, which not only fuel tumor infiltration, but also enable escape from surgical or other clinical interventions. Thus, better understanding of how these malignant traits are controlled will be key to the discovery of novel biomarkers and therapies against this deadly disease. Tetraspanin CD151 and its associated α3β1 integrin have been implicated in facilitating tumor progression across multiple cancer types. How these adhesion molecules are involved in the progression of glioblastoma, however, remains largely unclear. Here, we examined an in-house tissue microarray-based cohort of 96 patient biopsies and TCGA dataset to evaluate the clinical significance of CD151 and α3β1 integrin. Functional and signaling analyses were also conducted to understand how these molecules promote the aggressiveness of glioblastoma at molecular and cellular levels. Results from our analyses showed that CD151 and α3 integrin were significantly elevated in glioblastomas at both protein and mRNA levels, and exhibited strong inverse correlation with patient survival (p < 0.006). These adhesion molecules also formed tight protein complexes and synergized with EGF/EGFR to accelerate tumor cell motility and invasion. Furthermore, disruption of such complexes enhanced the survival of tumor-bearing mice in a xenograft model, and impaired activation of FAK and small GTPases. Also, knockdown- or pharmacological agent-based attenuation of EGFR, FAK or Graf (ARHGAP26)/small GTPase-mediated pathways markedly mitigated the aggressiveness of glioblastoma cells. Collectively, our findings provide clinical, molecular and cellular evidence of CD151-α3β1 integrin complexes as promising prognostic biomarkers and therapeutic targets for glioblastoma. PMID:26377974

  8. Strategies in Gene Therapy for Glioblastoma

    PubMed Central

    Kwiatkowska, Aneta; Nandhu, Mohan S.; Behera, Prajna; Chiocca, E. Antonio; Viapiano, Mariano S.

    2013-01-01

    Glioblastoma (GBM) is the most aggressive form of brain cancer, with a dismal prognosis and extremely low percentage of survivors. Novel therapies are in dire need to improve the clinical management of these tumors and extend patient survival. Genetic therapies for GBM have been postulated and attempted for the past twenty years, with variable degrees of success in pre-clinical models and clinical trials. Here we review the most common approaches to treat GBM by gene therapy, including strategies to deliver tumor-suppressor genes, suicide genes, immunomodulatory cytokines to improve immune response, and conditionally-replicating oncolytic viruses. The review focuses on the strategies used for gene delivery, including the most common and widely used vehicles (i.e., replicating and non-replicating viruses) as well as novel therapeutic approaches such as stem cell-mediated therapy and nanotechnologies used for gene delivery. We present an overview of these strategies, their targets, different advantages, and challenges for success. Finally, we discuss the potential of gene therapy-based strategies to effectively attack such a complex genetic target as GBM, alone or in combination with conventional therapy. PMID:24202446

  9. Curcumin decreases malignant characteristics of glioblastoma stem cells via induction of reactive oxygen species.

    PubMed

    Gersey, Zachary C; Rodriguez, Gregor A; Barbarite, Eric; Sanchez, Anthony; Walters, Winston M; Ohaeto, Kelechi C; Komotar, Ricardo J; Graham, Regina M

    2017-02-04

    Glioblastoma Multiforme (GBM) is the most common and lethal form of primary brain tumor in adults. Following standard treatment of surgery, radiation and chemotherapy, patients are expected to survive 12-14 months. Theorized cause of disease recurrence in these patients is tumor cell repopulation through the proliferation of treatment-resistant cancer stem cells. Current research has revealed curcumin, the principal ingredient in turmeric, can modulate multiple signaling pathways important for cancer stem cell self-renewal and survival. Following resection, tumor specimens were dissociated and glioblastoma stem cells (GSCs) were propagated in neurosphere media and characterized via immunocytochemistry. Cell viability was determined with MTS assay. GSC proliferation, sphere forming and colony forming assays were conducted through standard counting methods. Reactive oxygen species (ROS) production was examined using the fluorescent molecular probe CM-H2DCFA. Effects on cell signaling pathways were elucidated by western blot. We evaluate the effects of curcumin on patient-derived GSC lines. We demonstrate a curcumin-induced dose-dependent decrease in GSC viability with an approximate IC50 of 25 μM. Treatment with sub-toxic levels (2.5 μM) of curcumin significantly decreased GSC proliferation, sphere forming ability and colony forming potential. Curcumin induced ROS, promoted MAPK pathway activation, downregulated STAT3 activity and IAP family members. Inhibition of ROS with the antioxidant N-acetylcysteine reversed these effects indicating a ROS dependent mechanism. Discoveries made in this investigation may lead to a non-toxic intervention designed to prevent recurrence in glioblastoma by targeting glioblastoma stem cells.

  10. Mathematical Modelling of a Brain Tumour Initiation and Early Development: A Coupled Model of Glioblastoma Growth, Pre-Existing Vessel Co-Option, Angiogenesis and Blood Perfusion.

    PubMed

    Cai, Yan; Wu, Jie; Li, Zhiyong; Long, Quan

    2016-01-01

    We propose a coupled mathematical modelling system to investigate glioblastoma growth in response to dynamic changes in chemical and haemodynamic microenvironments caused by pre-existing vessel co-option, remodelling, collapse and angiogenesis. A typical tree-like architecture network with different orders for vessel diameter is designed to model pre-existing vasculature in host tissue. The chemical substances including oxygen, vascular endothelial growth factor, extra-cellular matrix and matrix degradation enzymes are calculated based on the haemodynamic environment which is obtained by coupled modelling of intravascular blood flow with interstitial fluid flow. The haemodynamic changes, including vessel diameter and permeability, are introduced to reflect a series of pathological characteristics of abnormal tumour vessels including vessel dilation, leakage, angiogenesis, regression and collapse. Migrating cells are included as a new phenotype to describe the migration behaviour of malignant tumour cells. The simulation focuses on the avascular phase of tumour development and stops at an early phase of angiogenesis. The model is able to demonstrate the main features of glioblastoma growth in this phase such as the formation of pseudopalisades, cell migration along the host vessels, the pre-existing vasculature co-option, angiogenesis and remodelling. The model also enables us to examine the influence of initial conditions and local environment on the early phase of glioblastoma growth.

  11. Mathematical Modelling of a Brain Tumour Initiation and Early Development: A Coupled Model of Glioblastoma Growth, Pre-Existing Vessel Co-Option, Angiogenesis and Blood Perfusion

    PubMed Central

    Cai, Yan; Wu, Jie; Li, Zhiyong; Long, Quan

    2016-01-01

    We propose a coupled mathematical modelling system to investigate glioblastoma growth in response to dynamic changes in chemical and haemodynamic microenvironments caused by pre-existing vessel co-option, remodelling, collapse and angiogenesis. A typical tree-like architecture network with different orders for vessel diameter is designed to model pre-existing vasculature in host tissue. The chemical substances including oxygen, vascular endothelial growth factor, extra-cellular matrix and matrix degradation enzymes are calculated based on the haemodynamic environment which is obtained by coupled modelling of intravascular blood flow with interstitial fluid flow. The haemodynamic changes, including vessel diameter and permeability, are introduced to reflect a series of pathological characteristics of abnormal tumour vessels including vessel dilation, leakage, angiogenesis, regression and collapse. Migrating cells are included as a new phenotype to describe the migration behaviour of malignant tumour cells. The simulation focuses on the avascular phase of tumour development and stops at an early phase of angiogenesis. The model is able to demonstrate the main features of glioblastoma growth in this phase such as the formation of pseudopalisades, cell migration along the host vessels, the pre-existing vasculature co-option, angiogenesis and remodelling. The model also enables us to examine the influence of initial conditions and local environment on the early phase of glioblastoma growth. PMID:26934465

  12. The NSL chromatin-modifying complex subunit KANSL2 regulates cancer stem-like properties in glioblastoma that contribute to tumorigenesis

    PubMed Central

    Ferreyra-Solari, Nazarena; Belforte, Fiorella S.; Canedo, Lucía; Videla-Richardson, Guillermo A.; Espinosa, Joaquín M.; Rossi, Mario; Serna, Eva; Riudavets, Miguel A.; Martinetto, Horacio; Sevlever, Gustavo; Perez-Castro, Carolina

    2016-01-01

    KANSL2 is an integral subunit of the Non-Specific Lethal (NSL) chromatin-modifying complex which contributes to epigenetic programs in embryonic stem cells. In this study, we report a role for KANSL2 in regulation of stemness in glioblastoma (GBM), which is characterized by heterogeneous tumor stem-like cells associated with therapy resistance and disease relapse. KANSL2 expression is upregulated in cancer cells, mainly at perivascular regions of tumors. RNAi-mediated silencing of KANSL2 in GBM cells impairs their tumorigenic capacity in mouse xenograft models. In clinical specimens, we found that expression levels of KANSL2 correlate with stemness markers in GBM stem-like cell populations. Mechanistic investigations showed that KANSL2 regulates cell self-renewal, which correlates with effects on expression of the stemness transcription factor POU5F1. RNAi-mediated silencing of POU5F1 reduced KANSL2 levels, linking these two genes to stemness control in GBM cells. Together, our findings indicate that KANSL2 acts to regulate the stem cell population in GBM, defining it as a candidate GBM biomarker for clinical use. PMID:27406830

  13. Degradable Organically-Derivatized Polyoxometalate with Enhanced Activity against Glioblastoma Cell Line

    NASA Astrophysics Data System (ADS)

    She, Shan; Bian, Shengtai; Huo, Ruichao; Chen, Kun; Huang, Zehuan; Zhang, Jiangwei; Hao, Jian; Wei, Yongge

    2016-09-01

    High efficacy and low toxicity are critical for cancer treatment. Polyoxometalates (POMs) have been reported as potential candidates for cancer therapy. On accounts of the slow clearance of POMs, leading to long-term toxicity, the clinical application of POMs in cancer treatment is restricted. To address this problem, a degradable organoimido derivative of hexamolybdate is developed by modifying it with a cleavable organic group, leading to its degradation. Of note, this derivative exhibits favourable pharmacodynamics towards human malignant glioma cell (U251), the ability to penetrate across blood brain barrier and low toxicity towards rat pheochromocytoma cell (PC12). This line of research develops an effective POM-based agent for glioblastoma inhibition and will pave a new way to construct degradable anticancer agents for clinical cancer therapy.

  14. Degradable Organically-Derivatized Polyoxometalate with Enhanced Activity against Glioblastoma Cell Line

    PubMed Central

    She, Shan; Bian, Shengtai; Huo, Ruichao; Chen, Kun; Huang, Zehuan; Zhang, Jiangwei; Hao, Jian; Wei, Yongge

    2016-01-01

    High efficacy and low toxicity are critical for cancer treatment. Polyoxometalates (POMs) have been reported as potential candidates for cancer therapy. On accounts of the slow clearance of POMs, leading to long-term toxicity, the clinical application of POMs in cancer treatment is restricted. To address this problem, a degradable organoimido derivative of hexamolybdate is developed by modifying it with a cleavable organic group, leading to its degradation. Of note, this derivative exhibits favourable pharmacodynamics towards human malignant glioma cell (U251), the ability to penetrate across blood brain barrier and low toxicity towards rat pheochromocytoma cell (PC12). This line of research develops an effective POM-based agent for glioblastoma inhibition and will pave a new way to construct degradable anticancer agents for clinical cancer therapy. PMID:27658479

  15. Brain abscess mimicking brain metastasis in breast cancer.

    PubMed

    Khullar, Pooja; Datta, Niloy R; Wahi, Inderjeet Kaur; Kataria, Sabeena

    2016-03-01

    61 year old female presented with chief complaints of headache for 30 days, fever for 10 days, altered behavior for 10 days and convulsion for 2 days. She was diagnosed and treated as a case of carcinoma of left breast 5 years ago. MRI brain showed a lobulated lesion in the left frontal lobe. She came to our hospital for whole brain radiation as a diagnosed case of carcinoma of breast with brain metastasis. Review of MRI brain scan, revealed metastasis or query infective pathology. MR spectroscopy of the lesion revealed choline: creatinine and choline: NAA (N-Acetylaspartate) ratios of ∼1.6 and 1.5 respectively with the presence of lactate within the lesion suggestive of infective pathology. She underwent left fronto temporal craniotomy and evacuation of abscess and subdural empyema. Gram stain showed gram positive cocci. After 1 month of evacuation and treatment she was fine. This case suggested a note of caution in every case of a rapidly evolving space-occupying lesion independent of the patient's previous history. Copyright © 2015 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

  16. Microtubule actin cross-linking factor 1, a novel target in glioblastoma.

    PubMed

    Afghani, Najlaa; Mehta, Toral; Wang, Jialiang; Tang, Nan; Skalli, Omar; Quick, Quincy A

    2017-01-01

    Genetic heterogeneity is recognized as a major contributing factor of glioblastoma resistance to clinical treatment modalities and consequently low overall survival rates. This genetic diversity results in variations in protein expression, both intratumorally and between individual glioblastoma patients. In this regard, the spectraplakin protein, microtubule actin cross-linking factor 1 (MACF1), was examined in glioblastoma. An expression analysis of MACF1 in various types of brain tumor tissue revealed that MACF1 was predominately present in grade III-IV astroctyomas and grade IV glioblastoma, but not in normal brain tissue, normal human astrocytes and lower grade brain tumors. Subsequent genetic inhibition experiments showed that suppression of MACF1 selectively inhibited glioblastoma cell proliferation and migration in cell lines established from patient derived xenograft mouse models and immortalized glioblastoma cell lines that were associated with downregulation of the Wnt-signaling mediators, Axin1 and β-catenin. Additionally, concomitant MACF1 silencing with the chemotherapeutic agent temozolomide (TMZ) used for the clinical treatment of glioblastomas cooperatively reduced the proliferative capacity of glioblastoma cells. In conclusion, the present study represents the first investigation on the functional role of MACF1 in tumor cell biology, as well as demonstrates its potential as a unique biomarker that can be targeted synergistically with TMZ as part of a combinatorial therapeutic approach for the treatment of genetically multifarious glioblastomas.

  17. Drug Resistance in Glioblastoma: A Mini Review

    PubMed Central

    Haar, Catherine P.; Hebbar, Preetha; Wallace, Gerald C.; Das, Arabinda; Vandergrift, William A.; Smith, Joshua A.; Giglio, Pierre; Patel, Sunil J.; Ray, Swapan K.; Banik, Naren L.

    2015-01-01

    Glioblastoma multiforme (GBM) is recognized as the most common and lethal form of central nervous system cancer. Currently used surgical techniques, chemotherapeutic agents, and radiotherapy strategies have done very little in extending the life expectancies of patients diagnosed with GBM. The difficulty in treating this malignant disease lies both in its inherent complexity and numerous mechanisms of drug resistance. In this review, we summarize several of the primary mechanisms of drug resistance. We reviewed available published literature in the English language regarding drug resistance in glioblastoma. The reasons for drug resistance in glioblastoma include drug efflux, hypoxic areas of tumor cells, cancer stem cells, DNA damage repair, and miRNAs. Many potential therapies target these mechanisms, including a series of investigated alternative and plant-derived agents. Future research and clinical trials in glioblastoma patients should pursue combination of therapies to help combat drug resistance. The emerging new data on the potential of plant-derived therapeutics should also be closely considered and further investigated. PMID:22228201

  18. Drug resistance in glioblastoma: a mini review.

    PubMed

    Haar, Catherine P; Hebbar, Preetha; Wallace, Gerald C; Das, Arabinda; Vandergrift, William A; Smith, Joshua A; Giglio, Pierre; Patel, Sunil J; Ray, Swapan K; Banik, Naren L

    2012-06-01

    Glioblastoma multiforme (GBM) is recognized as the most common and lethal form of central nervous system cancer. Currently used surgical techniques, chemotherapeutic agents, and radiotherapy strategies have done very little in extending the life expectancies of patients diagnosed with GBM. The difficulty in treating this malignant disease lies both in its inherent complexity and numerous mechanisms of drug resistance. In this review, we summarize several of the primary mechanisms of drug resistance. We reviewed available published literature in the English language regarding drug resistance in glioblastoma. The reasons for drug resistance in glioblastoma include drug efflux, hypoxic areas of tumor cells, cancer stem cells, DNA damage repair, and miRNAs. Many potential therapies target these mechanisms, including a series of investigated alternative and plant-derived agents. Future research and clinical trials in glioblastoma patients should pursue combination of therapies to help combat drug resistance. The emerging new data on the potential of plant-derived therapeutics should also be closely considered and further investigated.

  19. Targeted Therapies for Brain Metastases from Breast Cancer

    PubMed Central

    Venur, Vyshak Alva; Leone, José Pablo

    2016-01-01

    The discovery of various driver pathways and targeted small molecule agents/antibodies have revolutionized the management of metastatic breast cancer. Currently, the major targets of clinical utility in breast cancer include the human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF) receptor, mechanistic target of rapamycin (mTOR) pathway, and the cyclin-dependent kinase 4/6 (CDK-4/6) pathway. Brain metastasis, however, remains a thorn in the flesh, leading to morbidity, neuro-cognitive decline, and interruptions in the management of systemic disease. Approximately 20%–30% of patients with metastatic breast cancer develop brain metastases. Surgery, whole brain radiation therapy, and stereotactic radiosurgery are the traditional treatment options for patients with brain metastases. The therapeutic paradigm is changing due to better understanding of the blood brain barrier and the advent of tyrosine kinase inhibitors and monoclonal antibodies. Several of these agents are in clinical practice and several others are in early stage clinical trials. In this article, we will review the common targetable pathways in the management