WorldWideScience

Sample records for gbm tumor cells

  1. Liposomal TriCurin, A Synergistic Combination of Curcumin, Epicatechin Gallate and Resveratrol, Repolarizes Tumor-Associated Microglia/Macrophages, and Eliminates Glioblastoma (GBM) and GBM Stem Cells.

    Science.gov (United States)

    Mukherjee, Sumit; Baidoo, Juliet N E; Sampat, Samay; Mancuso, Andrew; David, Lovena; Cohen, Leah S; Zhou, Shuiqin; Banerjee, Probal

    2018-01-18

    Glioblastoma (GBM) is a deadly brain tumor with a current mean survival of 12-15 months. Despite being a potent anti-cancer agent, the turmeric ingredient curcumin (C) has limited anti-tumor efficacy in vivo due to its low bioavailability. We have reported earlier a strategy involving the use two other polyphenols, epicatechin gallate (E) from green tea and resveratrol (R) from red grapes at a unique, synergistic molar ratio with C (C:E:R: 4:1:12.5, termed TriCurin) to achieve superior potency against HPV+ tumors than C alone at C:E:R (μM): 32:8:100 (termed 32 μM+ TriCurin). We have now prepared liposomal TriCurin (TrLp) and demonstrated that TrLp boosts activated p53 in cultured GL261 mouse GBM cells to trigger apoptosis of GBM and GBM stem cells in vitro. TrLp administration into mice yielded a stable plasma concentration of 210 nM C for 60 min, which, though sub-lethal for cultured GL261 cells, was able to cause repolarization of M2-like tumor (GBM)-associated microglia/macrophages to the tumoricidal M1-like phenotype and intra-GBM recruitment of activated natural killer cells. The intratumor presence of such tumoricidal immune cells was associated with concomitant suppression of tumor-load, and apoptosis of GBM and GBM stem cells. Thus, TrLp is a potential onco-immunotherapeutic agent against GBM tumors.

  2. Liposomal TriCurin, A Synergistic Combination of Curcumin, Epicatechin Gallate and Resveratrol, Repolarizes Tumor-Associated Microglia/Macrophages, and Eliminates Glioblastoma (GBM and GBM Stem Cells

    Directory of Open Access Journals (Sweden)

    Sumit Mukherjee

    2018-01-01

    Full Text Available Glioblastoma (GBM is a deadly brain tumor with a current mean survival of 12–15 months. Despite being a potent anti-cancer agent, the turmeric ingredient curcumin (C has limited anti-tumor efficacy in vivo due to its low bioavailability. We have reported earlier a strategy involving the use two other polyphenols, epicatechin gallate (E from green tea and resveratrol (R from red grapes at a unique, synergistic molar ratio with C (C:E:R: 4:1:12.5, termed TriCurin to achieve superior potency against HPV+ tumors than C alone at C:E:R (μM: 32:8:100 (termed 32 μM+ TriCurin. We have now prepared liposomal TriCurin (TrLp and demonstrated that TrLp boosts activated p53 in cultured GL261 mouse GBM cells to trigger apoptosis of GBM and GBM stem cells in vitro. TrLp administration into mice yielded a stable plasma concentration of 210 nM C for 60 min, which, though sub-lethal for cultured GL261 cells, was able to cause repolarization of M2-like tumor (GBM-associated microglia/macrophages to the tumoricidal M1-like phenotype and intra-GBM recruitment of activated natural killer cells. The intratumor presence of such tumoricidal immune cells was associated with concomitant suppression of tumor-load, and apoptosis of GBM and GBM stem cells. Thus, TrLp is a potential onco-immunotherapeutic agent against GBM tumors.

  3. Simulation of glioblastoma multiforme (GBM) tumor cells using ising model on the Creutz Cellular Automaton

    Science.gov (United States)

    Züleyha, Artuç; Ziya, Merdan; Selçuk, Yeşiltaş; Kemal, Öztürk M.; Mesut, Tez

    2017-11-01

    Computational models for tumors have difficulties due to complexity of tumor nature and capacities of computational tools, however, these models provide visions to understand interactions between tumor and its micro environment. Moreover computational models have potential to develop strategies for individualized treatments for cancer. To observe a solid brain tumor, glioblastoma multiforme (GBM), we present a two dimensional Ising Model applied on Creutz cellular automaton (CCA). The aim of this study is to analyze avascular spherical solid tumor growth, considering transitions between non tumor cells and cancer cells are like phase transitions in physical system. Ising model on CCA algorithm provides a deterministic approach with discrete time steps and local interactions in position space to view tumor growth as a function of time. Our simulation results are given for fixed tumor radius and they are compatible with theoretical and clinic data.

  4. Establishment and Biological Characterization of a Panel of Glioblastoma Multiforme (GBM) and GBM Variant Oncosphere Cell Lines.

    Science.gov (United States)

    Binder, Zev A; Wilson, Kelli M; Salmasi, Vafi; Orr, Brent A; Eberhart, Charles G; Siu, I-Mei; Lim, Michael; Weingart, Jon D; Quinones-Hinojosa, Alfredo; Bettegowda, Chetan; Kassam, Amin B; Olivi, Alessandro; Brem, Henry; Riggins, Gregory J; Gallia, Gary L

    2016-01-01

    Human tumor cell lines form the basis of the majority of present day laboratory cancer research. These models are vital to studying the molecular biology of tumors and preclinical testing of new therapies. When compared to traditional adherent cell lines, suspension cell lines recapitulate the genetic profiles and histologic features of glioblastoma multiforme (GBM) with higher fidelity. Using a modified neural stem cell culture technique, here we report the characterization of GBM cell lines including GBM variants. Tumor tissue samples were obtained intra-operatively and cultured in neural stem cell conditions containing growth factors. Tumor lines were characterized in vitro using differentiation assays followed by immunostaining for lineage-specific markers. In vivo tumor formation was assayed by orthotopic injection in nude mice. Genetic uniqueness was confirmed via short tandem repeat (STR) DNA profiling. Thirteen oncosphere lines derived from GBM and GBM variants, including a GBM with PNET features and a GBM with oligodendroglioma component, were established. All unique lines showed distinct genetic profiles by STR profiling. The lines assayed demonstrated a range of in vitro growth rates. Multipotency was confirmed using in vitro differentiation. Tumor formation demonstrated histologic features consistent with high grade gliomas, including invasion, necrosis, abnormal vascularization, and high mitotic rate. Xenografts derived from the GBM variants maintained histopathological features of the primary tumors. We have generated and characterized GBM suspension lines derived from patients with GBMs and GBM variants. These oncosphere cell lines will expand the resources available for preclinical study.

  5. Comparative analyses of gene copy number and mRNA expression in GBM tumors and GBM xenografts

    Energy Technology Data Exchange (ETDEWEB)

    Hodgson, J. Graeme; Yeh, Ru-Fang; Ray, Amrita; Wang, Nicholas J.; Smirnov, Ivan; Yu, Mamie; Hariono, Sujatmi; Silber, Joachim; Feiler, Heidi S.; Gray, Joe W.; Spellman, Paul T.; Vandenberg, Scott R.; Berger, Mitchel S.; James, C. David

    2009-04-03

    Development of model systems that recapitulate the molecular heterogeneity observed among glioblastoma multiforme (GBM) tumors will expedite the testing of targeted molecular therapeutic strategies for GBM treatment. In this study, we profiled DNA copy number and mRNA expression in 21 independent GBM tumor lines maintained as subcutaneous xenografts (GBMX), and compared GBMX molecular signatures to those observed in GBM clinical specimens derived from the Cancer Genome Atlas (TCGA). The predominant copy number signature in both tumor groups was defined by chromosome-7 gain/chromosome-10 loss, a poor-prognosis genetic signature. We also observed, at frequencies similar to that detected in TCGA GBM tumors, genomic amplification and overexpression of known GBM oncogenes, such as EGFR, MDM2, CDK6, and MYCN, and novel genes, including NUP107, SLC35E3, MMP1, MMP13, and DDX1. The transcriptional signature of GBMX tumors, which was stable over multiple subcutaneous passages, was defined by overexpression of genes involved in M phase, DNA replication, and chromosome organization (MRC) and was highly similar to the poor-prognosis mitosis and cell-cycle module (MCM) in GBM. Assessment of gene expression in TCGA-derived GBMs revealed overexpression of MRC cancer genes AURKB, BIRC5, CCNB1, CCNB2, CDC2, CDK2, and FOXM1, which form a transcriptional network important for G2/M progression and/or checkpoint activation. Our study supports propagation of GBM tumors as subcutaneous xenografts as a useful approach for sustaining key molecular characteristics of patient tumors, and highlights therapeutic opportunities conferred by this GBMX tumor panel for testing targeted therapeutic strategies for GBM treatment.

  6. Tumor associated CD70 expression is involved in promoting tumor migration and macrophage infiltration in GBM.

    Science.gov (United States)

    Ge, Haitao; Mu, Luyan; Jin, Linchun; Yang, Changlin; Chang, Yifan Emily; Long, Yu; DeLeon, Gabriel; Deleyrolle, Loic; Mitchell, Duane A; Kubilis, Paul S; Lu, Dunyue; Qi, Jiping; Gu, Yunhe; Lin, Zhiguo; Huang, Jianping

    2017-10-01

    Tumor migration/metastasis and immunosuppression are major obstacles in effective cancer therapy. Incidentally, these 2 hurdles usually coexist inside tumors, therefore making therapy significantly more complicated, as both oncogenic mechanisms must be addressed for successful therapeutic intervention. Our recent report highlights that the tumor expression of a TNF family member, CD70, is correlated with poor survival for primary gliomas. In this study, we investigated how CD70 expression by GBM affects the characteristics of tumor cells and the tumor microenvironment. We found that the ablation of CD70 in primary GBM decreased CD44 and SOX2 gene expression, and inhibited tumor migration, growth and the ability to attract monocyte-derived M2 macrophages in vitro. In the tumor microenvironment, CD70 was associated with immune cell infiltrates, such as T cells; myeloid-derived suppressor cells; and monocytes/macrophages based on the RNA-sequencing profile. The CD163+ macrophages were far more abundant than T cells were. This overwhelming level of macrophages was identified only in GBM and not in low-grade gliomas and normal brain specimens, implying their tumor association. CD70 was detected only on tumor cells, not on macrophages, and was highly correlated with CD163 gene expression in primary GBM. Additionally, the co-expression of the CD70 and CD163 genes was found to correlate with decreased survival for patients with primary GBM. Together, these data suggest that CD70 expression is involved in promoting tumor aggressiveness and immunosuppression via tumor-associated macrophage recruitment/activation. Our current efforts to target this molecule using chimeric antigen receptor T cells hold great potential for treating patients with GBM. © 2017 UICC.

  7. A Unique Model System for Tumor Progression in GBM Comprising Two Developed Human Neuro-Epithelial Cell Lines with Differential Transforming Potential and Coexpressing Neuronal and Glial Markers

    Directory of Open Access Journals (Sweden)

    Anjali Shiras

    2003-11-01

    Full Text Available The molecular mechanisms involved in tumor progression from a low-grade astrocytoma to the most malignant glioblastoma multiforme (GBM have been hampered due to lack of suitable experimental models. We have established a model of tumor progression comprising of two cell lines derived from the same astrocytoma tumor with a set of features corresponding to low-grade glioma (as in HNGC-1 and high-grade GBM (as in HNGC-2. The HNGC-1 cell line is slowgrowing, contact-inhibited, nontumorigenic, and noninvasive, whereas HNGC-2 is a rapidly proliferating, anchorage-independent, highly tumorigenic, and invasive cell line. The proliferation of cell lines is independent of the addition of exogenous growth factors. Interestingly, the HNGC-2 cell line displays a near-haploid karyotype except for a disomy of chromosome 2. The two cell lines express the neuronal precursor and progenitor markers vimentin, nestin, MAP-2, and NFP160, as well as glial differentiation protein S100μ. The HNGC-1 cell line also expresses markers of mature neurons like Tuj1 and GFAP, an astrocytic differentiation marker, hence contributing toward a more morphologically differentiated phenotype with a propensity for neural differentiation in vitro. Additionally, overexpression of epidermal growth factor receptor and c-erbB2, and loss of fibronectin were observed only in the HNGC-2 cell line, implicating the significance of these pathways in tumor progression. This in vitro model system assumes importance in unraveling the cellular and molecular mechanisms in differentiation, transformation, and gliomagenesis.

  8. GBM secretome induces transient transformation of human neural precursor cells.

    Science.gov (United States)

    Venugopal, Chitra; Wang, X Simon; Manoranjan, Branavan; McFarlane, Nicole; Nolte, Sara; Li, Meredith; Murty, Naresh; Siu, K W Michael; Singh, Sheila K

    2012-09-01

    Glioblastoma (GBM) is the most aggressive primary brain tumor in humans, with a uniformly poor prognosis. The tumor microenvironment is composed of both supportive cellular substrates and exogenous factors. We hypothesize that exogenous factors secreted by brain tumor initiating cells (BTICs) could predispose normal neural precursor cells (NPCs) to transformation. When NPCs are grown in GBM-conditioned media, and designated as "tumor-conditioned NPCs" (tcNPCs), they become highly proliferative and exhibit increased stem cell self-renewal, or the unique ability of stem cells to asymmetrically generate another stem cell and a daughter cell. tcNPCs also show an increased transcript level of stem cell markers such as CD133 and ALDH and growth factor receptors such as VEGFR1, VEGFR2, EGFR and PDGFRα. Media analysis by ELISA of GBM-conditioned media reveals an elevated secretion of growth factors such as EGF, VEGF and PDGF-AA when compared to normal neural stem cell-conditioned media. We also demonstrate that tcNPCs require prolonged or continuous exposure to the GBM secretome in vitro to retain GBM BTIC characteristics. Our in vivo studies reveal that tcNPCs are unable to form tumors, confirming that irreversible transformation events may require sustained or prolonged presence of the GBM secretome. Analysis of GBM-conditioned media by mass spectrometry reveals the presence of secreted proteins Chitinase-3-like 1 (CHI3L1) and H2A histone family member H2AX. Collectively, our data suggest that GBM-secreted factors are capable of transiently altering normal NPCs, although for retention of the transformed phenotype, sustained or prolonged secretome exposure or additional transformation events are likely necessary.

  9. Recruitment of bone marrow derived cells during anti-angiogenic therapy in GBM : Bone marrow derived cell in GBM

    NARCIS (Netherlands)

    Boer, Jennifer C.; Walenkamp, Annemiek M. E.; den Dunnen, Wilfred F. A.

    2014-01-01

    Glioblastoma (GBM) is a highly vascular tumor characterized by rapid and invasive tumor growth, followed by oxygen depletion, hypoxia and neovascularization, which generate a network of disorganized, tortuous and permeable vessels. Recruitment of bone marrow derived cells (BMDC) is crucial for

  10. Anti-SEMA3A Antibody: A Novel Therapeutic Agent to Suppress GBM Tumor Growth.

    Science.gov (United States)

    Lee, Jaehyun; Shin, Yong Jae; Lee, Kyoungmin; Cho, Hee Jin; Sa, Jason K; Lee, Sang-Yun; Kim, Seok-Hyung; Lee, Jeongwu; Yoon, Yeup; Nam, Do-Hyun

    2017-11-10

    Glioblastoma (GBM) is classified as one of the most aggressive and lethal brain tumor. Great strides have been made in understanding the genomic and molecular underpinnings of GBM, which translated into development of new therapeutic approaches to combat such deadly disease. However, there are only few therapeutic agents that can effectively inhibit GBM invasion in a clinical framework. In an effort to address such challenges, we have generated anti-SEMA3A monoclonal antibody as a potential therapeutic antibody against GBM progression. We employed public glioma datasets, Repository of Molecular Brain Neoplasia Data and The Cancer Genome Atlas, to analyze SEMA3A mRNA expression in human GBM specimens. We also evaluated for protein expression level of SEMA3A via tissue microarray (TMA) analysis. Cell migration and proliferation kinetics were assessed in various GBM patient-derived cells (PDCs) and U87-MG cell-line for SEMA3A antibody efficacy. GBM patient-derived xenograft (PDX) models were generated to evaluate tumor inhibitory effect of anti-SEMA3A antibody in vivo. By combining bioinformatics and TMA analysis, we discovered that SEMA3A is highly expressed in human GBM specimens compared to non-neoplastic tissues. We developed three different anti-SEMA3A antibodies, in fully human IgG form, through screening phage-displayed synthetic antibody library using a classical panning method. Neutralization of SEMA3A significantly reduced migration and proliferation capabilities of PDCs and U87-MG cell-line in vitro. In PDX models, treatment with anti-SEMA3A antibody exhibited notable tumor inhibitory effect through down-regulation of cellular proliferative kinetics and tumor-associated macrophages recruitment. In present study, we demonstrated tumor inhibitory effect of SEMA3A antibody in GBM progression and present its potential relevance as a therapeutic agent in a clinical framework.

  11. Selective anti-tumor activity of the novel fluoropyrimidine polymer F10 towards G48a orthotopic GBM tumors.

    Science.gov (United States)

    Gmeiner, William H; Lema-Tome, Carla; Gibo, Denise; Jennings-Gee, Jamie; Milligan, Carol; Debinski, Waldemar

    2014-02-01

    F10 is a novel anti-tumor agent with minimal systemic toxicity in vivo and which displays strong cytotoxicity towards glioblastoma (GBM) cells in vitro. Here we investigate the cytotoxicity of F10 towards GBM cells and evaluate the anti-tumor activity of locally-administered F10 towards an orthotopic xenograft model of GBM. The effects of F10 on thymidylate synthase (TS) inhibition and Topoisomerase 1 (Top1) cleavage complex formation were evaluated using TS activity assays and in vivo complex of enzyme bioassays. Cytotoxicity of F10 towards normal brain was evaluated using cortices from embryonic (day 18) mice. F10 displays minimal penetrance of the blood-brain barrier and was delivered by intra-cerebral (i.c.) administration and prospective anti-tumor response towards luciferase-expressing G48a human GBM tumors in nude mice was evaluated using IVIS imaging. Histological examination of tumor and normal brain tissue was used to assess the selectivity of anti-tumor activity. F10 is cytotoxic towards G48a, SNB-19, and U-251 MG GBM cells through dual targeting of TS and Top1. F10 is not toxic to murine primary neuronal cultures. F10 is well-tolerated upon i.c. administration and induces significant regression of G48a tumors that is dose-dependent. Histological analysis from F10-treated mice revealed tumors were essentially completely eradicated in F10-treated mice while vehicle-treated mice displayed substantial infiltration into normal tissue. F10 displays strong efficacy for GBM treatment with minimal toxicity upon i.c. administration establishing F10 as a promising drug-candidate for treating GBM in human patients.

  12. A Large-Scale RNAi Screen Identifies SGK1 as a Key Survival Kinase for GBM Stem Cells.

    Science.gov (United States)

    Kulkarni, Shreya; Goel-Bhattacharya, Surbhi; Sengupta, Sejuti; Cochran, Brent H

    2018-01-01

    Glioblastoma multiforme (GBM) is the most common type of primary malignant brain cancer and has a very poor prognosis. A subpopulation of cells known as GBM stem-like cells (GBM-SC) have the capacity to initiate and sustain tumor growth and possess molecular characteristics similar to the parental tumor. GBM-SCs are known to be enriched in hypoxic niches and may contribute to therapeutic resistance. Therefore, to identify genetic determinants important for the proliferation and survival of GBM stem cells, an unbiased pooled shRNA screen of 10,000 genes was conducted under normoxic as well as hypoxic conditions. A number of essential genes were identified that are required for GBM-SC growth, under either or both oxygen conditions, in two different GBM-SC lines. Interestingly, only about a third of the essential genes were common to both cell lines. The oxygen environment significantly impacts the cellular genetic dependencies as 30% of the genes required under hypoxia were not required under normoxic conditions. In addition to identifying essential genes already implicated in GBM such as CDK4, KIF11 , and RAN , the screen also identified new genes that have not been previously implicated in GBM stem cell biology. The importance of the serum and glucocorticoid-regulated kinase 1 (SGK1) for cellular survival was validated in multiple patient-derived GBM stem cell lines using shRNA, CRISPR, and pharmacologic inhibitors. However, SGK1 depletion and inhibition has little effect on traditional serum grown glioma lines and on differentiated GBM-SCs indicating its specific importance in GBM stem cell survival. Implications: This study identifies genes required for the growth and survival of GBM stem cells under both normoxic and hypoxic conditions and finds SGK1 as a novel potential drug target for GBM. Mol Cancer Res; 16(1); 103-14. ©2017 AACR . ©2017 American Association for Cancer Research.

  13. EVA1A inhibits GBM cell proliferation by inducing autophagy and apoptosis

    Energy Technology Data Exchange (ETDEWEB)

    Shen, Xue; Kan, Shifeng; Liu, Zhen [Department of Cell Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191 (China); Lu, Guang [Department of Cell Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191 (China); Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597 (Singapore); Zhang, Xiaoyan [Department of Cell Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191 (China); Chen, Yingyu [Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191 (China); Peking University Center for Human Disease Genomics, Beijing 100191 (China); Bai, Yun, E-mail: baiyun@bjmu.edu.cn [Department of Cell Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191 (China)

    2017-03-01

    Eva-1 homolog A (EVA1A) is a novel lysosome and endoplasmic reticulum-associated protein involved in autophagy and apoptosis. In this study, we constructed a recombinant adenovirus 5-EVA1A vector (Ad5-EVA1A) to overexpress EVA1A in glioblastoma (GBM) cell lines and evaluated its anti-tumor activities in vitro and in vivo. We found that overexpression of EVA1A in three GBM cell lines (U251, U87 and SHG44) resulted in a suppression of tumor cell growth via activation of autophagy and induction of cell apoptosis in a dose- and time-dependent manner. EVA1A-mediated autophagy was associated with inactivation of the mTOR/RPS6KB1 signaling pathway. Furthermore in vivo, overexpression of EVA1A successfully inhibited tumor growth in NOD/SCID mice. Our data suggest that EVA1A-induced autophagy and apoptosis play a role in suppressing the development of GBM and their up-regulation may be an effective method for treating this form of cancer. - Highlights: • Overexpression of EVA1A suppresses GBM cell growth. • EVA1A induces autophagy through the mTOR/RPS6KB1 pathway. • EVA1A induces GBM cell apoptosis. • EVA1A inhibits the development of GBM in vivo.

  14. Ultrastructural characterization of primary cilia in pathologically characterized human glioblastoma multiforme (GBM) tumors.

    Science.gov (United States)

    Moser, Joanna J; Fritzler, Marvin J; Rattner, Jerome B

    2014-01-01

    Primary cilia are non-motile sensory cytoplasmic organelles that are involved in cell cycle progression. Ultrastructurally, the primary cilium region is complex, with normal ciliogenesis progressing through five distinct morphological stages in human astrocytes. Defects in early stages of ciliogenesis are key features of astrocytoma/glioblastoma cell lines and provided the impetus for the current study which describes the morphology of primary cilia in molecularly characterized human glioblastoma multiforme (GBM) tumors. Seven surgically resected human GBM tissue samples were molecularly characterized according to IDH1/2 mutation status, EGFR amplification status and MGMT promoter methylation status and were examined for primary cilia expression and structure using indirect immunofluorescence and electron microscopy. We report for the first time that primary cilia are disrupted in the early stages of ciliogenesis in human GBM tumors. We confirm that immature primary cilia and basal bodies/centrioles have aberrant ciliogenesis characteristics including absent paired vesicles, misshaped/swollen vesicular hats, abnormal configuration of distal appendages, and discontinuity of centriole microtubular blades. Additionally, the transition zone plate is able to form in the absence of paired vesicles on the distal end of the basal body and when a cilium progresses beyond the early stages of ciliogenesis, it has electron dense material clumped along the transition zone and a darkening of the microtubules at the proximal end of the cilium. Primary cilia play a role in a variety of human cancers. Previously primary cilia structure was perturbed in cultured cell lines derived from astrocytomas/glioblastomas; however there was always some question as to whether these findings were a cell culture phenomena. In this study we confirm that disruptions in ciliogenesis at early stages do occur in GBM tumors and that these ultrastructural findings bear resemblance to those previously

  15. USP1 targeting impedes GBM growth by inhibiting stem cell maintenance and radioresistance.

    Science.gov (United States)

    Lee, Jin-Ku; Chang, Nakho; Yoon, Yeup; Yang, Heekyoung; Cho, Heejin; Kim, Eunhee; Shin, Yongjae; Kang, Wonyoung; Oh, Young Taek; Mun, Gyeong In; Joo, Kyeung Min; Nam, Do-Hyun; Lee, Jeongwu

    2016-01-01

    Clinical benefits from standard therapies against glioblastoma (GBM) are limited in part due to intrinsic radio- and chemoresistance of GBM and inefficient targeting of GBM stem-like cells (GSCs). Novel therapeutic approaches that overcome treatment resistance and diminish stem-like properties of GBM are needed. We determined the expression levels of ubiquitination-specific proteases (USPs) by transcriptome analysis and found that USP1 is highly expressed in GBM. Using the patient GBM-derived primary tumor cells, we inhibited USP1 by shRNA-mediated knockdown or its specific inhibitor pimozide and evaluated the effects on stem cell marker expression, proliferation, and clonogenic growth of tumor cells. USP1 was highly expressed in gliomas relative to normal brain tissues and more preferentially in GSC enrichment marker (CD133 or CD15) positive cells. USP1 positively regulated the protein stability of the ID1 and CHEK1, critical regulators of DNA damage response and stem cell maintenance. Targeting USP1 by RNA interference or treatment with a chemical USP1 inhibitor attenuated clonogenic growth and survival of GSCs and enhanced radiosensitivity of GBM cells. Finally, USP1 inhibition alone or in combination with radiation significantly prolonged the survival of tumor-bearing mice. USP1-mediated protein stabilization promotes GSC maintenance and treatment resistance, thereby providing a rationale for USP1 inhibition as a potential therapeutic approach against GBM. © 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.

  16. Surprisal analysis of Glioblastoma Multiform (GBM) microRNA dynamics unveils tumor specific phenotype.

    Science.gov (United States)

    Zadran, Sohila; Remacle, Francoise; Levine, Raphael

    2014-01-01

    Gliomablastoma multiform (GBM) is the most fatal form of all brain cancers in humans. Currently there are limited diagnostic tools for GBM detection. Here, we applied surprisal analysis, a theory grounded in thermodynamics, to unveil how biomolecule energetics, specifically a redistribution of free energy amongst microRNAs (miRNAs), results in a system deviating from a non-cancer state to the GBM cancer -specific phenotypic state. Utilizing global miRNA microarray expression data of normal and GBM patients tumors, surprisal analysis characterizes a miRNA system response capable of distinguishing GBM samples from normal tissue biopsy samples. We indicate that the miRNAs contributing to this system behavior is a disease phenotypic state specific to GBM and is therefore a unique GBM-specific thermodynamic signature. MiRNAs implicated in the regulation of stochastic signaling processes crucial in the hallmarks of human cancer, dominate this GBM-cancer phenotypic state. With this theory, we were able to distinguish with high fidelity GBM patients solely by monitoring the dynamics of miRNAs present in patients' biopsy samples. We anticipate that the GBM-specific thermodynamic signature will provide a critical translational tool in better characterizing cancer types and in the development of future therapeutics for GBM.

  17. Investigating a signature of temozolomide resistance in GBM cell lines using metabolomics.

    Science.gov (United States)

    St-Coeur, Patrick-Denis; Poitras, Julie J; Cuperlovic-Culf, Miroslava; Touaibia, Mohamed; Morin, Pier

    2015-10-01

    Glioblastoma multiforme (GBM) is the most common form of malignant glioma. Current therapeutic approach to treat this malignancy involves a combination of surgery, radiotherapy and chemotherapy with temozolomide. Numerous mechanisms contributing to inherent and acquired resistance to this chemotherapeutic agent have been identified and can lead to treatment failure. This study undertook a metabolomics-based approach to characterize the metabolic profiles observed in temozolomide-sensitive and temozolomide-resistant GBM cell lines as well as in a small sub-set of primary GBM tumors. This approach was also utilized to explore the metabolic changes modulated upon cell treatment with temozolomide and lomeguatrib, an MGMT inhibitor with temozolomide-sensitizing potential. Metabolites previously explored for their potential role in chemoresistance including glucose, citrate and isocitrate demonstrated elevated levels in temozolomide-resistant GBM cells. In addition, a signature of metabolites comprising alanine, choline, creatine and phosphorylcholine was identified as up-regulated in sensitive GBM cell line across different treatments. These results present the metabolic profiles associated with temozolomide response in selected GBM models and propose interesting leads that could be leveraged for the development of therapeutic or diagnostic tools to impact temozolomide response in GBMs.

  18. Ficus carica latex prevents invasion through induction of let-7d expression in GBM cell lines.

    Science.gov (United States)

    Tezcan, Gulcin; Tunca, Berrin; Bekar, Ahmet; Yalcin, Murat; Sahin, Saliha; Budak, Ferah; Cecener, Gulsah; Egeli, Unal; Demir, Cevdet; Guvenc, Gokcen; Yilmaz, Gozde; Erkan, Leman Gizem; Malyer, Hulusi; Taskapilioglu, Mevlut Ozgur; Evrensel, Turkkan; Bilir, Ayhan

    2015-03-01

    Glioblastoma multiforme (GBM) is one of the deadliest human malignancies. A cure for GBM remains elusive, and the overall survival time is less than 1 year. Thus, the development of more efficient therapeutic approaches for the treatment of these patients is required. Induction of tumor cell death by certain phytochemicals derived from medicinal herbs and dietary plants has become a new frontier for cancer therapy research. Although the cancer suppressive effect of Ficus carica (fig) latex (FCL) has been determined in a few cancer types, the effect of this latex on GBM tumors has not been investigated. Therefore, in the current study, the anti-proliferative activity of FCL and the effect of the FCL-temozolomide (TMZ) combination were tested in the T98G, U-138 MG, and U-87 MG GBM cell lines using the WST-1 assay. The mechanism of cell death was analyzed using Annexin-V/FITC and TUNEL assays, and the effect of FCL on invasion was tested using the chick chorioallantoic membrane assay. To determine the effect of FCL on GBM progression, the expression levels of 40 GBM associated miRNAs were analyzed in T98G cells using RT-qPCR. According to the obtained data, FCL causes cell death in GBM cells with different responses to TMZ, and this effect is synergistically increased in combination with TMZ. In addition, the current study is the first to demonstrate the effect of FCL on modulation of let-7d expression, which may be an important underlying mechanism of the anti-invasive effect of this extract.

  19. CADrx for GBM Brain Tumors: Predicting Treatment Response from Changes in Diffusion-Weighted MRI

    Directory of Open Access Journals (Sweden)

    Matthew S. Brown

    2009-11-01

    Full Text Available The goal of this study was to develop a computer-aided therapeutic response (CADrx system for early prediction of drug treatment response for glioblastoma multiforme (GBM brain tumors with diffusion weighted (DW MR images. In conventional Macdonald assessment, tumor response is assessed nine weeks or more post-treatment. However, we will investigate the ability of DW-MRI to assess response earlier, at five weeks post treatment. The apparent diffusion coefficient (ADC map, calculated from DW images, has been shown to reveal changes in the tumor’s microenvironment preceding morphologic tumor changes. ADC values in treated brain tumors could theoretically both increase due to the cell kill (and thus reduced cell density and decrease due to inhibition of edema. In this study, we investigated the effectiveness of features that quantify changes from pre- and post-treatment tumor ADC histograms to detect treatment response. There are three parts to this study: first, tumor regions were segmented on T1w contrast enhanced images by Otsu’s thresholding method, and mapped from T1w images onto ADC images by a 3D region of interest (ROI mapping tool using DICOM header information; second, ADC histograms of the tumor region were extracted from both pre- and five weeks post-treatment scans, and fitted by a two-component Gaussian mixture model (GMM. The GMM features as well as standard histogram-based features were extracted. Finally, supervised machine learning techniques were applied for classification of responders or non-responders. The approach was evaluated with a dataset of 85 patients with GBM under chemotherapy, in which 39 responded and 46 did not, based on tumor volume reduction. We compared adaBoost, random forest and support vector machine classification algorithms, using ten-fold cross validation, resulting in the best accuracy of 69.41% and the corresponding area under the curve (Az of 0.70.

  20. The effect of silver nanoparticles (AgNPs) on proliferation and apoptosis of in ovo cultured glioblastoma multiforme (GBM) cells.

    Science.gov (United States)

    Urbańska, Kaja; Pająk, Beata; Orzechowski, Arkadiusz; Sokołowska, Justyna; Grodzik, Marta; Sawosz, Ewa; Szmidt, Maciej; Sysa, Paweł

    2015-01-01

    Recently, it has been shown that silver nanoparticles (AgNPs) provide a unique approach to the treatment of tumors, especially those of neuroepithelial origin. Thus, the aim of this study was to evaluate the impact of AgNPs on proliferation and activation of the intrinsic apoptotic pathway of glioblastoma multiforme (GBM) cells cultured in an in ovo model. Human GBM cells, line U-87, were placed on chicken embryo chorioallantoic membrane. After 8 days, the tumors were divided into three groups: control (non-treated), treated with colloidal AgNPs (40 μg/ml), and placebo (tumors supplemented with vehicle only). At the end of the experiment, all tumors were isolated. Assessment of cell proliferation and cell apoptosis was estimated by histological, immunohistochemical, and Western blot analyses. The results show that AgNPs can influence GBM growth. AgNPs inhibit proliferation of GBM cells and seem to have proapoptotic properties. Although there were statistically significant differences between control and AgNP groups in the AI and the levels of active caspase 9 and active caspase 3, the level of these proteins in GBM cells treated with AgNPs seems to be on the border between the spontaneous apoptosis and the induced. Our results indicate that the antiproliferative properties of silver nanoparticles overwhelm proapoptotic ones. Further research focused on the cytotoxic effect of AgNPs on tumor and normal cells should be conducted.

  1. Differential Expression and Clinical Significance of Transforming Growth Factor-Beta Isoforms in GBM Tumors.

    Science.gov (United States)

    Roy, Laurent-Olivier; Poirier, Marie-Belle; Fortin, David

    2018-04-08

    Glioblastoma (GBM) represents the most common and aggressive malignant primary brain tumors in adults. Response to standard treatment is transitory and the survival of clinical trial cohorts are little more than 14 months. GBM are characterized by excessive proliferation, invasiveness, and radio-/chemoresistance features; which are strongly upregulated by transforming growth factor-beta (TGF-β). We hypothesized that TGF-β gene expression could correlate with overall survival (OS) and serve as a prognostic biomarker. TGF-β₁ and -β₂ expression were analyzed by qPCR in 159 GBM tumor specimens. Kaplan-Meier and multivariate analyses were used to correlate expression with OS and progression-free survival (PFS). In GBM, TGF-β₁ and -β₂ levels were 33- and 11-fold higher respectively than in non-tumoral samples. Kaplan-Meier and multivariate analyses revealed that high to moderate expressions of TGF-β₁ significantly conferred a strikingly poorer OS and PFS in newly diagnosed patients. Interestingly, at relapse, neither isoforms had meaningful impact on clinical evolution. We demonstrate that TGF-β₁ is the dominant isoform in newly diagnosed GBM rather than the previously acknowledged TGF-β₂. We believe our study is the first to unveil a significant relationship between TGF-β₁ expression and OS or PFS in newly diagnosed GBM. TGF-β₁ could serve as a prognostic biomarker or target affecting treatment planning and patient follow-up.

  2. Differential Expression and Clinical Significance of Transforming Growth Factor-Beta Isoforms in GBM Tumors

    Directory of Open Access Journals (Sweden)

    Laurent-Olivier Roy

    2018-04-01

    Full Text Available Glioblastoma (GBM represents the most common and aggressive malignant primary brain tumors in adults. Response to standard treatment is transitory and the survival of clinical trial cohorts are little more than 14 months. GBM are characterized by excessive proliferation, invasiveness, and radio-/chemoresistance features; which are strongly upregulated by transforming growth factor-beta (TGF-β. We hypothesized that TGF-β gene expression could correlate with overall survival (OS and serve as a prognostic biomarker. TGF-β1 and -β2 expression were analyzed by qPCR in 159 GBM tumor specimens. Kaplan–Meier and multivariate analyses were used to correlate expression with OS and progression-free survival (PFS. In GBM, TGF-β1 and -β2 levels were 33- and 11-fold higher respectively than in non-tumoral samples. Kaplan–Meier and multivariate analyses revealed that high to moderate expressions of TGF-β1 significantly conferred a strikingly poorer OS and PFS in newly diagnosed patients. Interestingly, at relapse, neither isoforms had meaningful impact on clinical evolution. We demonstrate that TGF-β1 is the dominant isoform in newly diagnosed GBM rather than the previously acknowledged TGF-β2. We believe our study is the first to unveil a significant relationship between TGF-β1 expression and OS or PFS in newly diagnosed GBM. TGF-β1 could serve as a prognostic biomarker or target affecting treatment planning and patient follow-up.

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

    Science.gov (United States)

    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. The Potential Impact of Biofield Treatment on Human Brain Tumor Cells: A Time-Lapse Video Microscopy

    OpenAIRE

    Trivedi, Mahendra

    2015-01-01

    Study background: Glioblastoma (GBM) is the most common subtype of primary brain tumor in adults. The aim was to evaluate the impact of biofield treatment potential on human GBM and non-GBM brain cells using two time-lapse video microscopy technique. Methods: The human brain tumor, GBM cultured cells were divided into two groups viz. GBM control and GBM treatment. Similarly, human normal brain cultured cells (non-GBM) were taken and divided into two groups viz. non- GBM control and non-GB...

  5. Identification of a novel set of genes reflecting different in vivo invasive patterns of human GBM cells

    Directory of Open Access Journals (Sweden)

    Monticone Massimiliano

    2012-08-01

    Full Text Available Abstract Background Most patients affected by Glioblastoma multiforme (GBM, grade IV glioma experience a recurrence of the disease because of the spreading of tumor cells beyond surgical boundaries. Unveiling mechanisms causing this process is a logic goal to impair the killing capacity of GBM cells by molecular targeting. We noticed that our long-term GBM cultures, established from different patients, may display two categories/types of growth behavior in an orthotopic xenograft model: expansion of the tumor mass and formation of tumor branches/nodules (nodular like, NL-type or highly diffuse single tumor cell infiltration (HD-type. Methods We determined by DNA microarrays the gene expression profiles of three NL-type and three HD-type long-term GBM cultures. Subsequently, individual genes with different expression levels between the two groups were identified using Significance Analysis of Microarrays (SAM. Real time RT-PCR, immunofluorescence and immunoblot analyses, were performed for a selected subgroup of regulated gene products to confirm the results obtained by the expression analysis. Results Here, we report the identification of a set of 34 differentially expressed genes in the two types of GBM cultures. Twenty-three of these genes encode for proteins localized to the plasma membrane and 9 of these for proteins are involved in the process of cell adhesion. Conclusions This study suggests the participation in the diffuse infiltrative/invasive process of GBM cells within the CNS of a novel set of genes coding for membrane-associated proteins, which should be thus susceptible to an inhibition strategy by specific targeting. Massimiliano Monticone and Antonio Daga contributed equally to this work

  6. Identification of a novel set of genes reflecting different in vivo invasive patterns of human GBM cells.

    Science.gov (United States)

    Monticone, Massimiliano; Daga, Antonio; Candiani, Simona; Romeo, Francesco; Mirisola, Valentina; Viaggi, Silvia; Melloni, Ilaria; Pedemonte, Simona; Zona, Gianluigi; Giaretti, Walter; Pfeffer, Ulrich; Castagnola, Patrizio

    2012-08-17

    Most patients affected by Glioblastoma multiforme (GBM, grade IV glioma) experience a recurrence of the disease because of the spreading of tumor cells beyond surgical boundaries. Unveiling mechanisms causing this process is a logic goal to impair the killing capacity of GBM cells by molecular targeting.We noticed that our long-term GBM cultures, established from different patients, may display two categories/types of growth behavior in an orthotopic xenograft model: expansion of the tumor mass and formation of tumor branches/nodules (nodular like, NL-type) or highly diffuse single tumor cell infiltration (HD-type). We determined by DNA microarrays the gene expression profiles of three NL-type and three HD-type long-term GBM cultures. Subsequently, individual genes with different expression levels between the two groups were identified using Significance Analysis of Microarrays (SAM). Real time RT-PCR, immunofluorescence and immunoblot analyses, were performed for a selected subgroup of regulated gene products to confirm the results obtained by the expression analysis. Here, we report the identification of a set of 34 differentially expressed genes in the two types of GBM cultures. Twenty-three of these genes encode for proteins localized to the plasma membrane and 9 of these for proteins are involved in the process of cell adhesion. This study suggests the participation in the diffuse infiltrative/invasive process of GBM cells within the CNS of a novel set of genes coding for membrane-associated proteins, which should be thus susceptible to an inhibition strategy by specific targeting.Massimiliano Monticone and Antonio Daga contributed equally to this work.

  7. Identification of a novel set of genes reflecting different in vivo invasive patterns of human GBM cells

    International Nuclear Information System (INIS)

    Monticone, Massimiliano; Giaretti, Walter; Pfeffer, Ulrich; Daga, Antonio; Candiani, Simona; Romeo, Francesco; Mirisola, Valentina; Viaggi, Silvia; Melloni, Ilaria; Pedemonte, Simona; Zona, Gianluigi

    2012-01-01

    Most patients affected by Glioblastoma multiforme (GBM, grade IV glioma) experience a recurrence of the disease because of the spreading of tumor cells beyond surgical boundaries. Unveiling mechanisms causing this process is a logic goal to impair the killing capacity of GBM cells by molecular targeting. We noticed that our long-term GBM cultures, established from different patients, may display two categories/types of growth behavior in an orthotopic xenograft model: expansion of the tumor mass and formation of tumor branches/nodules (nodular like, NL-type) or highly diffuse single tumor cell infiltration (HD-type). We determined by DNA microarrays the gene expression profiles of three NL-type and three HD-type long-term GBM cultures. Subsequently, individual genes with different expression levels between the two groups were identified using Significance Analysis of Microarrays (SAM). Real time RT-PCR, immunofluorescence and immunoblot analyses, were performed for a selected subgroup of regulated gene products to confirm the results obtained by the expression analysis. Here, we report the identification of a set of 34 differentially expressed genes in the two types of GBM cultures. Twenty-three of these genes encode for proteins localized to the plasma membrane and 9 of these for proteins are involved in the process of cell adhesion. This study suggests the participation in the diffuse infiltrative/invasive process of GBM cells within the CNS of a novel set of genes coding for membrane-associated proteins, which should be thus susceptible to an inhibition strategy by specific targeting. Massimiliano Monticone and Antonio Daga contributed equally to this work

  8. SOX4 inhibits GBM cell growth and induces G0/G1 cell cycle arrest through Akt-p53 axis.

    Science.gov (United States)

    Zhang, Jing; Jiang, Huawei; Shao, Jiaofang; Mao, Ruifang; Liu, Jie; Ma, Yingying; Fang, Xuefeng; Zhao, Na; Zheng, Shu; Lin, Biaoyang

    2014-11-01

    SOX4 is a transcription factor required for tissue development and differentiation in vertebrates. Overexpression of SOX4 has been reported in many cancers including glioblastoma multiforme (GBM), however, the underlying mechanism of actions has not been studied. In this study, we investigated the role of SOX4 in GBM. Kaplan-Meier analysis was performed to assess the association between SOX4 expression levels and survival times in primary GBM samples. Cre/lox P system was used to generate gain or loss of SOX4 in GBM cells, and microarray analysis uncovered the regulation network of SOX4 in GBM cells. High SOX4 expression was significantly associated with good prognosis of primary GBMs. SOX4 inhibited the growth of GBM cell line LN229, A172G and U87MG, partly via the activation of p53-p21 signaling and down-regulation of phosphorylated AKT1. Gene expression profiling and subsequent gene ontology analysis showed that SOX4 influenced several key pathways including the Wnt/ beta-catenin and TGF-beta signaling pathways. Our study found that SOX4 acts as a tumor suppressor in GBM cells by induce cell cycle arrest and inhibiting cell growth.

  9. miR-139-5p suppresses cancer cell migration and invasion through targeting ZEB1 and ZEB2 in GBM.

    Science.gov (United States)

    Yue, Sihai; Wang, Lihua; Zhang, Hui; Min, Youhui; Lou, Yongli; Sun, Hongshan; Jiang, Yu; Zhang, Wenjin; Liang, Aming; Guo, Yongkun; Chen, Ping; Lv, Guowei; Wang, Liuxiang; Zong, Qinghua; Li, Yong

    2015-09-01

    Invasion and migration of glioblastoma multiforme (GBM) is a multistep process and an important phenotype that causes this disease to invade surrounding tissues in the brain. Recent studies have highlighted that miRNAs play a pivotal role in controlling GBM cell plasticity. In this report, we used wound healing and transwell assays to identify a novel role of miR-139-5p in inhibition of GBM cell migration and invasion. Bioinformatics coupled with luciferase and Western blot assays also revealed that miR-139-5p inhibited expression of ZEB1 and ZEB2, which are master regulators of tumor metastasis. MiR-139-5p specifically interacts with the 3'-UTR regions of ZEB1 and ZEB2, attenuating their expression in GBM cells. To corroborate this finding, we rescued ZEB1 and ZEB2 expression and found partial but significant increases in miR-139-5p-suppressed invasion of GBM cells. The biological relevance of our study was validated by analyzing levels of miR-139-5p in GBM tissue. We found that its expression significantly downregulated compared to normal tissue and shorter overall survival rates in patients with lower miR-139-5p expression. These results confirm that miR-139-5p suppresses GBM migration and invasion and highlight its potential as a biomarker and therapeutic target for treating GBM.

  10. Demethoxycurcumin Retards Cell Growth and Induces Apoptosis in Human Brain Malignant Glioma GBM 8401 Cells

    Directory of Open Access Journals (Sweden)

    Tzuu-Yuan Huang

    2012-01-01

    Full Text Available Demethoxycurcumin (DMC; a curcumin-related demethoxy compound has been recently shown to display antioxidant and antitumor activities. It has also produced a potent chemopreventive action against cancer. In the present study, the antiproliferation (using the MTT assay, DMC was found to have cytotoxic activities against GBM 8401 cell with IC50 values at 22.71 μM and induced apoptosis effects of DMC have been investigated in human brain malignant glioma GBM 8401 cells. We have studied the mitochondrial membrane potential (MMP, DNA fragmentation, caspase activation, and NF-κB transcriptional factor activity. By these approaches, our results indicated that DMC has produced an inhibition of cell proliferation as well as the activation of apoptosis in GBM 8401 cells. Both effects were observed to increase in proportion with the dosage of DMC treatment, and the apoptosis was induced by DMC in human brain malignant glioma GBM 8401 cells via mitochondria- and caspase-dependent pathways.

  11. Olea europaea leaf extract improves the treatment response of GBM stem cells by modulating miRNA expression.

    Science.gov (United States)

    Tezcan, Gulcin; Tunca, Berrin; Bekar, Ahmet; Budak, Ferah; Sahin, Saliha; Cecener, Gulsah; Egeli, Unal; Taskapılıoglu, Mevlut Ozgur; Kocaeli, Hasan; Tolunay, Sahsine; Malyer, Hulusi; Demir, Cevdet; Tumen, Gulendam

    2014-01-01

    The stem-like cells of Glioblastoma multiforme (GBM) tumors (GSCs) are one of the important determinants of recurrence and drug resistance. The aims of the current study were to evaluate the anticancer effect of Olea europaea leaf extract (OLE) on GBM cell lines, the association between OLE and TMZ responses, and the effect of OLE and the OLE-TMZ combination in GSCs and to clarify the molecular mechanism of this effect on the expression of miRNAs related to cell death. The anti-proliferative activity of OLE and the effect of the OLE-TMZ combination were tested in the T98G, U-138MG and U-87MG GBM cell lines using WST-1 assay. The mechanism of cell death was analyzed with Annexin V/FITC and TUNEL assays. The effects of OLE on the expression levels of miR-181b, miR-153, miR-145 and miR-137 and potential mRNA targets were analyzed in GSCs using RT-qPCR. OLE exhibited anti-proliferative effects via apoptosis and necrosis in the GBM cell lines. In addition, OLE significantly induced the expression of miR-153, miR-145, and miR-137 and decreased the expression of the target genes of these miRNAs in GSCs (p GBM cells with different TMZ responses, and this effect is synergistically increased when the cells are treated with a combination of OLE and TMZ. This is the first study to indicate that OLE may interfere with the pluripotency of GSCs by modulating miRNA expression. Further studies are required, but we suggest that OLE may have a potential for advanced therapeutic cancer drug studies in GBM.

  12. Study Protocol: Early Stereotactic Gamma Knife Radiosurgery to Residual Tumor After Surgery of Newly Diagnosed Glioblastoma (Gamma-GBM).

    Science.gov (United States)

    Brehmer, Stefanie; Grimm, Mario Alexander; Förster, Alex; Seiz-Rosenhagen, Marcel; Welzel, Grit; Stieler, Florian; Wenz, Frederik; Groden, Christoph; Mai, Sabine; Hänggi, Daniel; Giordano, Frank Anton

    2018-04-24

    Glioblastoma (GBM) is the most common malignant brain tumor in adult patients. Tumor recurrence commonly occurs around the resection cavity, especially after subtotal resection (STR). Consequently, the extent of resection correlates with overall survival (OS), suggesting that depletion of postoperative tumor remnants will improve outcome. To assess safety and efficacy of adding stereotactic radiosurgery (SRS) to the standard treatment of GBM in patients with postoperative residual tumor. Gamma-GBM is a single center, open-label, prospective, single arm, phase II study that includes patients with newly diagnosed GBM (intraoperative via frozen sections) who underwent STR (residual tumor will be identified by native and contrast enhanced T1-weighted magnetic resonance imaging scans). All patients will receive SRS with 15 Gy (prescribed to the 50% isodose enclosing all areas of residual tumor) early (within 24-72 h) after surgery. Thereafter, all patients undergo standard-of-care therapy for GBM (radiochemotherapy with 60 Gy external beam radiotherapy [EBRT] plus concomitant temozolomide and 6 cycles of adjuvant temozolomide chemotherapy). The primary outcome is median progression-free survival, secondary outcomes are median OS, occurrence of radiation induced acute (3 mo post-SRS) neurotoxicity and incidence of symptomatic radionecrosis. We expect to detect efficacy and safety signals by the immediate application of SRS to standard-of-care therapy in newly diagnosed GBM. Early postoperative SRS to areas of residual tumor could bridge the therapeutic gap between surgery and adjuvant therapies.

  13. Tumor and Endothelial Cell Hybrids Participate in Glioblastoma Vasculature

    Directory of Open Access Journals (Sweden)

    Soufiane El Hallani

    2014-01-01

    Full Text Available Background. Recently antiangiogenic therapy with bevacizumab has shown a high but transient efficacy in glioblastoma (GBM. Indeed, GBM is one of the most angiogenic human tumors and endothelial proliferation is a hallmark of the disease. We therefore hypothesized that tumor cells may participate in endothelial proliferation of GBM. Materials and Methods. We used EGFR FISH Probe to detect EGFR amplification and anti-CD31, CD105, VE-cadherin, and vWF to identify endothelial cells. Endothelial and GBM cells were grown separately, labeled with GFP and DsRed lentiviruses, and then cocultured with or without contact. Results. In a subset of GBM tissues, we found that several tumor endothelial cells carry EGFR amplification, characteristic of GBM tumor cells. This observation was reproduced in vitro: when tumor stem cells derived from GBM were grown in the presence of human endothelial cells, a fraction of them acquired endothelial markers (CD31, CD105, VE-cadherin, and vWF. By transduction with GFP and DsRed expressing lentiviral vectors, we demonstrate that this phenomenon is due to cell fusion and not transdifferentiation. Conclusion. A fraction of GBM stem cells thus has the capacity to fuse with endothelial cells and the resulting hybrids may participate in tumor microvascular proliferation and in treatment resistance.

  14. MAXIMIZATION OF DNA DAMAGE TO MGMT(+ EGFR(+ GBM CELLS USING OPTIMAL COMBINATION OF TEMOZOLOMIDE-ANTI EGFR MONOCLONAL ANTIBODY NIMOTUZUMAB

    Directory of Open Access Journals (Sweden)

    M. A. M. Inggas

    2015-09-01

    Full Text Available Background: Glioblastoma multiforme (GBM is the most aggressive primary brain tumor in adultswith dismal prognosis due to the unavailability of an effective therapy. Up to now, there had been no definitive studies published on EGFR inhibition therapy as a chemosensitizer for GBM therapy using Temozolomide (TMZ. This study aims to reveal the most effective method and timing to administer TMZ-anti EGFR targeted therapy which causes maximal DNA damage on GBM cells.Methods: Various regimens of anti EGFR monoclonal antibody Nimotuzumab (NMZ was administered in different combinations with TMZ, performed on U87MG MGMT(+ EGFR(+ cells. The effectiveness of the combinations were evaluated by measuring yH2AX levels which reflects the degree of DNA damage. One-way Anova and LSD tests were performed to determine the effects of each treatment with p<0.05. Results and discussion: the mean SD of yH2AX of each treatment was: 11,90±1,25 for the control group; 29.33±1.91 for NMZ alone; 28.13±1.58 for TMZ alone; 41.53±3.51 for concurrent use; 35.67 ±2.65 for NMZ after 24 hours TMZ; 31.87±2.94 for NMZ after 48 hours TMZ; 39.57±4.2 for TMZ after 24 hours NMZ; and 35.93 ±3.56 for TMZ after 48 hours NMZ. The administration of TMZ concurrent with or after 24 hours NMZ gives the highest amount of DNA damage to GBM cells. Conclusion: The administration of Nimotuzumab targeted therapy up to 24 hours before Temozolomide chemotherapy has been proven to be effective in maximizing the amount of DNA damage done to GBM cells in vitro. 

  15. Characterization of Metabolic, Diffusion, and Perfusion Properties in GBM: Contrast-Enhancing versus Non-Enhancing Tumor.

    Science.gov (United States)

    Autry, Adam; Phillips, Joanna J; Maleschlijski, Stojan; Roy, Ritu; Molinaro, Annette M; Chang, Susan M; Cha, Soonmee; Lupo, Janine M; Nelson, Sarah J

    2017-12-01

    Although the contrast-enhancing (CE) lesion on T 1 -weighted MR images is widely used as a surrogate for glioblastoma (GBM), there are also non-enhancing regions of infiltrative tumor within the T 2 -weighted lesion, which elude radiologic detection. Because non-enhancing GBM (Enh-) challenges clinical patient management as latent disease, this study sought to characterize ex vivo metabolic profiles from Enh- and CE GBM (Enh+) samples, alongside histological and in vivo MR parameters, to assist in defining criteria for estimating total tumor burden. Fifty-six patients with newly diagnosed GBM received a multi-parametric pre-surgical MR examination. Targets for obtaining image-guided tissue samples were defined based on in vivo parameters that were suspicious for tumor. The actual location from where tissue samples were obtained was recorded, and half of each sample was analyzed for histopathology while the other half was scanned using HR-MAS spectroscopy. The Enh+ and Enh- tumor samples demonstrated comparable mitotic activity, but also significant heterogeneity in microvascular morphology. Ex vivo spectroscopic parameters indicated similar levels of total choline and N-acetylaspartate between these contrast-based radiographic subtypes of GBM, and characteristic differences in the levels of myo-inositol, creatine/phosphocreatine, and phosphoethanolamine. Analysis of in vivo parameters at the sample locations were consistent with histological and ex vivo metabolic data. The similarity between ex vivo levels of choline and NAA, and between in vivo levels of choline, NAA and nADC in Enh+ and Enh- tumor, indicate that these parameters can be used in defining non-invasive metrics of total tumor burden for patients with GBM. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  16. Characterization of Metabolic, Diffusion, and Perfusion Properties in GBM: Contrast-Enhancing versus Non-Enhancing Tumor

    Directory of Open Access Journals (Sweden)

    Adam Autry

    2017-12-01

    Full Text Available BACKGROUND: Although the contrast-enhancing (CE lesion on T1-weighted MR images is widely used as a surrogate for glioblastoma (GBM, there are also non-enhancing regions of infiltrative tumor within the T2-weighted lesion, which elude radiologic detection. Because non-enhancing GBM (Enh− challenges clinical patient management as latent disease, this study sought to characterize ex vivo metabolic profiles from Enh− and CE GBM (Enh+ samples, alongside histological and in vivo MR parameters, to assist in defining criteria for estimating total tumor burden. Methods: Fifty-six patients with newly diagnosed GBM received a multi-parametric pre-surgical MR examination. Targets for obtaining image-guided tissue samples were defined based on in vivo parameters that were suspicious for tumor. The actual location from where tissue samples were obtained was recorded, and half of each sample was analyzed for histopathology while the other half was scanned using HR-MAS spectroscopy. Results: The Enh+ and Enh− tumor samples demonstrated comparable mitotic activity, but also significant heterogeneity in microvascular morphology. Ex vivo spectroscopic parameters indicated similar levels of total choline and N-acetylaspartate between these contrast-based radiographic subtypes of GBM, and characteristic differences in the levels of myo-inositol, creatine/phosphocreatine, and phosphoethanolamine. Analysis of in vivo parameters at the sample locations were consistent with histological and ex vivo metabolic data. CONCLUSIONS: The similarity between ex vivo levels of choline and NAA, and between in vivo levels of choline, NAA and nADC in Enh+ and Enh− tumor, indicate that these parameters can be used in defining non-invasive metrics of total tumor burden for patients with GBM.

  17. First clinical results of a personalized immunotherapeutic vaccine against recurrent, incompletely resected, treatment-resistant glioblastoma multiforme (GBM) tumors, based on combined allo- and auto-immune tumor reactivity.

    Science.gov (United States)

    Schijns, Virgil E J C; Pretto, Chrystel; Devillers, Laurent; Pierre, Denis; Hofman, Florence M; Chen, Thomas C; Mespouille, Pascal; Hantos, Peter; Glorieux, Philippe; Bota, Daniela A; Stathopoulos, Apostolos

    2015-05-28

    Glioblastoma multiforme (GBM) patients have a poor prognosis. After tumor recurrence statistics suggest an imminent death within 1-4.5 months. Supportive preclinical data, from a rat model, provided the rational for a prototype clinical vaccine preparation, named Gliovac (or ERC 1671) composed of autologous antigens, derived from the patient's surgically removed tumor tissue, which is administered together with allogeneic antigens from glioma tissue resected from other GBM patients. We now report the first results of the Gliovac treatment for treatment-resistant GBM patients. Nine (9) recurrent GBM patients, after standard of care treatment, including surgery radio- and chemotherapy temozolomide, and for US patients, also bevacizumab (Avastin™), were treated under a compassionate use/hospital exemption protocol. Gliovac was given intradermally, together with human GM-CSF (Leukine(®)), and preceded by a regimen of regulatory T cell-depleting, low-dose cyclophosphamide. Gliovac administration in patients that have failed standard of care therapies showed minimal toxicity and enhanced overall survival (OS). Six-month (26 weeks) survival for the nine Gliovac patients was 100% versus 33% in control group. At week 40, the published overall survival was 10% if recurrent, reoperated patients were not treated. In the Gliovac treated group, the survival at 40 weeks was 77%. Our data suggest that Gliovac has low toxicity and a promising efficacy. A phase II trial has recently been initiated in recurrent, bevacizumab naïve GBM patients (NCT01903330). Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  18. Tight regulation between cell survival and programmed cell death in GBM stem-like cells by EGFR/GSK3b/PP2A signaling.

    Science.gov (United States)

    Gürsel, Demirkan B; Banu, Matei A; Berry, Nicholas; Marongiu, Roberta; Burkhardt, Jan-Karl; Kobylarz, Keith; Kaplitt, Michael G; Rafii, Shahin; Boockvar, John A

    2015-01-01

    Malignant gliomas represent one of the most aggressive forms of cancer, displaying high mortality rates and limited treatment options. Specific subpopulations of cells residing in the tumor niche with stem-like characteristics have been postulated to initiate and maintain neoplasticity while resisting conventional therapies. The study presented here aims to define the role of glycogen synthase kinase 3 beta (GSK3b) in patient-derived glioblastoma (GBM) stem-like cell (GSC) proliferation, apoptosis and invasion. To evaluate the potential role of GSK3b in GBM, protein profiles from 68 GBM patients and 20 normal brain samples were analyzed for EGFR-mediated PI3kinase/Akt and GSK3b signaling molecules including protein phosphatase 2A (PP2A). To better understand the function of GSK3b in GBM, GSCs were isolated from GBM patient samples. Blocking GSK3b phosphorylation at Serine 9 attenuated cell proliferation while concomitantly stimulating apoptosis through activation of Caspase-3 in patient-derived GSCs. Increasing GSK3b protein content resulted in the inhibition of cell proliferation, colony formation and stimulated programmed cell death. Depleting GSK3b in GSCs down regulated PP2A. Furthermore, knocking down PP2A or blocking its activity by okadaic acid inactivated GSK3b by increasing GSK3b phosphorylation at Serine 9. Our data suggests that GSK3b may function as a regulator of apoptosis and tumorigenesis in GSCs. Therapeutic approaches targeting GSK3b in glioblastoma stem-like cells may be a useful addition to our current therapeutic armamentarium.

  19. Investigating tumor perfusion by hyperpolarized (13) C MRI with comparison to conventional gadolinium contrast-enhanced MRI and pathology in orthotopic human GBM xenografts

    DEFF Research Database (Denmark)

    Park, Ilwoo; von Morze, Cornelius; Lupo, Janine M

    2016-01-01

    glioblastoma (GBM) model for the characterization of tumor perfusion and compared with standard Gd-based dynamic susceptibility contrast (DSC) MRI data and immunohistochemical analysis from resected brains. Distinct HMCP perfusion characteristics were observed within the GBM tumors compared with contralateral...... for tumor that exhibited high levels of hyperpolarized HMCP signal. The results from this study have demonstrated that hyperpolarized HMCP data can be used as an indicator of tumor perfusion in an orthotopic xenograft model for GBM. Magn Reson Med, 2016. © 2016 Wiley Periodicals, Inc....

  20. Cell of Origin and Cancer Stem Cells in Tumor Suppressor Mouse Models of Glioblastoma.

    Science.gov (United States)

    Alcantara Llaguno, Sheila R; Xie, Xuanhua; Parada, Luis F

    2016-01-01

    The cellular origins and the mechanisms of progression, maintenance of tumorigenicity, and therapeutic resistance are central questions in the glioblastoma multiforme (GBM) field. Using tumor suppressor mouse models, our group recently reported two independent populations of adult GBM-initiating central nervous system progenitors. We found different functional and molecular subtypes depending on the tumor-initiating cell lineage, indicating that the cell of origin is a driver of GBM subtype diversity. Using an in vivo model, we also showed that GBM cancer stem cells (CSCs) or glioma stem cells (GSCs) contribute to resistance to chemotherapeutic agents and that genetic ablation of GSCs leads to a delay in tumor progression. These studies are consistent with the cell of origin and CSCs as critical regulators of the pathogenesis of GBM. © 2016 Alcantara Llaguno et al; Published by Cold Spring Harbor Laboratory Press.

  1. Decreased miR-106a inhibits glioma cell glucose uptake and proliferation by targeting SLC2A3 in GBM.

    Science.gov (United States)

    Dai, Dong-Wei; Lu, Qiong; Wang, Lai-Xing; Zhao, Wen-Yuan; Cao, Yi-Qun; Li, Ya-Nan; Han, Guo-Sheng; Liu, Jian-Min; Yue, Zhi-Jian

    2013-10-14

    MiR-106a is frequently down-regulated in various types of human cancer. However the underlying mechanism of miR-106a involved in glioma remains elusive. The association of miR-106a with glioma grade and patient survival was analyzed. The biological function and target of miR-106a were determined by bioinformatic analysis and cell experiments (Western blot, luciferase reporter, cell cycle, ntracellular ATP production and glucose uptake assay). Finally, rescue expression of its target SLC2A3 was used to test the role of SLC2A3 in miR-106a-mediated cell glycolysis and proliferation. Here we showed that miR-106a was a tumor suppressor miRNA was involved in GBM cell glucose uptake and proliferation. Decreased miR-106a in GBM tissues and conferred a poor survival of GBM patients. SLC2A3 was identified as a core target of miR-106a in GBM cells. Inhibition of SLC2A3 by miR-106a attenuated cell proliferation and inhibited glucose uptake. In addition, for each biological process we identified ontology-associated transcripts that significantly correlated with SLC2A3 expression. Finally, the expression of SLC2A3 largely abrogated miR-106a-mediated cell proliferation and glucose uptake in GBM cells. Taken together, miR-106a and SLC2A3 could be potential therapeutic approaches for GBM.

  2. Combined VEGF and CXCR4 antagonism targets the GBM stem cell population and synergistically improves survival in an intracranial mouse model of glioblastoma.

    Science.gov (United States)

    Barone, Amy; Sengupta, Rajarshi; Warrington, Nicole M; Smith, Erin; Wen, Patrick Y; Brekken, Rolf A; Romagnoli, Barbara; Douglas, Garry; Chevalier, Eric; Bauer, Michael P; Dembowsky, Klaus; Piwnica-Worms, David; Rubin, Joshua B

    2014-10-30

    Glioblastoma recurrence involves the persistence of a subpopulation of cells with enhanced tumor-initiating capacity (TIC) that reside within the perivascular space, or niche (PVN). Anti-angiogenic therapies may prevent the formation of new PVN but have not prevented recurrence in clinical trials, suggesting they cannot abrogate TIC activity. We hypothesized that combining anti-angiogenic therapy with blockade of PVN function would have superior anti-tumor activity. We tested this hypothesis in an established intracranial xenograft model of GBM using a monoclonal antibody specific for murine and human VEGF (mcr84) and a Protein Epitope Mimetic (PEM) CXCR4 antagonist, POL5551. When doses of POL5551 were increased to overcome an mcr84-induced improvement in vascular barrier function, combinatorial therapy significantly inhibited intracranial tumor growth and improved survival. Anti-tumor activity was associated with significant changes in tumor cell proliferation and apoptosis, and a reduction in the numbers of perivascular cells expressing the TIC marker nestin. A direct effect on TICs was demonstrated for POL5551, but not mcr84, in three primary patient-derived GBM isolates. These findings indicate that targeting the structure and function of the PVN has superior anti-tumor effect and provide a strong rationale for clinical evaluation of POL5551 and Avastin in patients with GBM.

  3. Tumour cell dormancy as a contributor to the reduced survival of GBM patients who received standard therapy.

    Science.gov (United States)

    Tong, Luqing; Yi, Li; Liu, Peidong; Abeysekera, Iruni Roshanie; Hai, Long; Li, Tao; Tao, Zhennan; Ma, Haiwen; Xie, Yang; Huang, Yubao; Yu, Shengping; Li, Jiabo; Yuan, Feng; Yang, Xuejun

    2018-07-01

    Glioblastoma multiforme (GBM) is a fatal cancer with varying life expectancy, even for patients undergoing the same standard therapy. Identification of differentially expressed genes in GBM patients with different survival rates may benefit the development of effective therapeutic strategies. In the present study, key pathways and genes correlated with survival in GBM patients were screened with bioinformatic analysis. Included in the study were 136 eligible patients who had undertaken surgical resection of GBM followed by temozolomide (TMZ) chemoradiation and long-term therapy with TMZ. A total of 383 differentially expressed genes (DEGs) related to GBM survival were identified. Gene Ontology and pathway enrichment analysis as well as hub gene screening and module analysis were performed. As expected, angiogenesis and migration of GBM cells were closely correlated with a poor prognosis. Importantly, the results also indicated that cell dormancy was an essential contributor to the reduced survival of GBM patients. Given the lack of specific targeted genes and pathways known to be involved in tumour cell dormancy, we proposed enriched candidate genes related to the negative regulation of cell proliferation, signalling pathways regulating pluripotency of stem cells and neuroactive ligand-receptor interaction, and 3 hub genes (FTH1, GRM1 and DDIT3). Maintaining persistent cell dormancy or preventing tumour cells from entering dormancy during chemoradiation should be a promising therapeutic strategy.

  4. Standardized orthotopic xenografts in zebrafish reveal glioma cell-line-specific characteristics and tumor cell heterogeneity

    Directory of Open Access Journals (Sweden)

    Alessandra M. Welker

    2016-02-01

    Full Text Available Glioblastoma (GBM is a deadly brain cancer, for which few effective drug treatments are available. Several studies have used zebrafish models to study GBM, but a standardized approach to modeling GBM in zebrafish was lacking to date, preventing comparison of data across studies. Here, we describe a new, standardized orthotopic xenotransplant model of GBM in zebrafish. Dose-response survival assays were used to define the optimal number of cells for tumor formation. Techniques to measure tumor burden and cell spread within the brain over real time were optimized using mouse neural stem cells as control transplants. Applying this standardized approach, we transplanted two patient-derived GBM cell lines, serum-grown adherent cells and neurospheres, into the midbrain region of embryonic zebrafish and analyzed transplanted larvae over time. Progressive brain tumor growth and premature larval death were observed using both cell lines; however, fewer transplanted neurosphere cells were needed for tumor growth and lethality. Tumors were heterogeneous, containing both cells expressing stem cell markers and cells expressing markers of differentiation. A small proportion of transplanted neurosphere cells expressed glial fibrillary acidic protein (GFAP or vimentin, markers of more differentiated cells, but this number increased significantly during tumor growth, indicating that these cells undergo differentiation in vivo. By contrast, most serum-grown adherent cells expressed GFAP and vimentin at the earliest times examined post-transplant. Both cell types produced brain tumors that contained Sox2+ cells, indicative of tumor stem cells. Transplanted larvae were treated with currently used GBM therapeutics, temozolomide or bortezomib, and this resulted in a reduction in tumor volume in vivo and an increase in survival. The standardized model reported here facilitates robust and reproducible analysis of glioblastoma tumor cells in real time and provides a

  5. Migrating glioma cells express stem cell markers and give rise to new tumors upon xenografting

    DEFF Research Database (Denmark)

    Munthe, Sune; Sørensen, Mia D; Thomassen, Mads

    2016-01-01

    Glioblastoma (GBM) is the most frequent and malignant brain tumor with an overall survival of only 14.6 months. Although these tumors are treated with surgery, radiation and chemotherapy, recurrence is inevitable. A critical population of tumor cells in terms of therapy, the so-called cancer stem......-like phenotype is currently lacking. In the present study, the aim was to characterize the phenotype of migrating tumor cells using a novel migration assay based on serum-free stem cell medium and patient-derived spheroid cultures. The results showed pronounced migration of five different GBM spheroid cultures......-related genes and the HOX-gene list in migrating cells compared to spheroids. Determination of GBM molecular subtypes revealed that subtypes of spheroids and migrating cells were identical. In conclusion, migrating tumor cells preserve expression of stem cell markers and functional CSC characteristics. Since...

  6. Pancreatic islet cell tumor

    Science.gov (United States)

    ... cell tumors; Islet of Langerhans tumor; Neuroendocrine tumors; Peptic ulcer - islet cell tumor; Hypoglycemia - islet cell tumor ... stomach acid. Symptoms may include: Abdominal pain Diarrhea ... and small bowel Vomiting blood (occasionally) Glucagonomas make ...

  7. Circulating gamma delta T cells are activated and depleted during progression of high-grade gliomas: Implications for gamma delta T cell therapy of GBM

    Science.gov (United States)

    Glioblastoma multiforme (GBM) remains frustratingly impervious to any existing therapy. We have previously shown that GBM is sensitive to recognition and lysis by ex vivo activated gamma delta T cells, a minor subset of lymphocytes that innately recognize autologous stress-associated target antigens...

  8. Tamoxifen in combination with temozolomide induce a synergistic inhibition of PKC-pan in GBM cell lines.

    Science.gov (United States)

    Balça-Silva, Joana; Matias, Diana; do Carmo, Anália; Girão, Henrique; Moura-Neto, Vivaldo; Sarmento-Ribeiro, Ana Bela; Lopes, Maria Celeste

    2015-04-01

    Glioblastoma (GBM) is a highly proliferative, angiogenic grade IV astrocytoma that develops resistance to the alkylating agents used in chemotherapy, such as temozolomide (TMZ), which is considered the gold standard. The mean survival time for GBM patients is approximately 12 months, increasing to 14.6 months after TMZ treatment. The resistance of GBM to chemotherapy seems to be associated to genetic alterations and to the constitutive activation of several signaling pathways. Therefore, the combination of different drugs with different mechanisms of action may contribute to circumvent the chemoresistance of glioma cells. Here we describe the potential synergistic behavior of the therapeutic combination of tamoxifen (TMX), a known inhibitor of PKC, and TMZ in GBM. We used two GBM cell lines incubated in absence and presence of TMX and/or TMZ and measured cell viability, proliferation, apoptosis, cell cycle, migration ability, cytoskeletal organization and the phosphorylated amount of the p-PKC-pan. The combination of low doses of TMX with increasing doses of TMZ shows an increased antiproliferative and apoptotic effect compared to the effect with TMX alone. The combination of TMX and TMZ seems to potentiate the effect of each other. These alterations seem to be associated to a decrease in the phosphorylation status of PKC. We emphasize that TMX is an inhibitor of the p-PKC-pan and that these combination is more effective in the reduction of proliferation and in the increase of apoptosis than each drug alone, which presents a new therapeutic strategy in GBM treatment. Copyright © 2014 Elsevier B.V. All rights reserved.

  9. Inhibition of Notch signaling alters the phenotype of orthotopic tumors formed from glioblastoma multiforme neurosphere cells but does not hamper intracranial tumor growth regardless of endogene Notch pathway signature

    DEFF Research Database (Denmark)

    Kristoffersen, Karina; Nedergaard, Mette Kjølhede; Villingshøj, Mette

    2014-01-01

    BACKGROUND: Brain cancer stem-like cells (bCSC) are cancer cells with neural stem cell (NSC)-like properties found in the devastating brain tumor glioblastoma multiforme (GBM). bCSC are proposed a central role in tumor initiation, progression, treatment resistance and relapse and as such present...... a promising target in GBM research. The Notch signaling pathway is often deregulated in GBM and we have previously characterized GBM-derived bCSC cultures based on their expression of the Notch-1 receptor and found that it could be used as predictive marker for the effect of Notch inhibition. The aim...... of the present project was therefore to further elucidate the significance of Notch pathway activity for the tumorigenic properties of GBM-derived bCSC. METHODS: Human-derived GBM xenograft cells previously established as NSC-like neurosphere cultures were used. Notch inhibition was accomplished by exposing...

  10. Survey of the effect of doxorubicin and flavonoid extract of white Morus alba leaf on apoptosis induction in a-172 GBM cell line.

    Science.gov (United States)

    Dabili, Sheyda; Fallah, Soudabeh; Aein, Mojdeh; Vatannejad, Akram; Panahi, Ghodratollah; Fadaei, Reza; Moradi, Nariman; Shojaii, Asie

    2018-02-20

    In this study, the effect of doxorubicin, flavonoid extract of white Morus alba leaf (MFE) and a combination of doxorubicin and flavonoid extract on Bax and Bcl2 levels and caspase 3 activity of cancer A-172 GBM cell line was investigated. Bax/Bcl2 levels of treated A-172 GBM cell line with flavonoid extract of white mulberry leaf were estimated by ELISA methods. Caspase 3 activity of treated A-172 GBM cells was determined by calorimetric assay. The flow cytometry assessment was used to estimate the apoptosis percent of treated A-172 GBM cells. Treatment of A-172 GBM cells with MFE, doxorubicin and a combination of MFE and doxorubicin caused a significant decrease in Bcl2 level and an increase in Bax level. The apoptosis percent of treated cells were also elevated significantly. Present results suggest that concomitant use of herbal medicine and chemotherapy may be an effective alternative method for the treatment of cancers.

  11. Glioblastoma progression is assisted by induction of immunosuppressive function of pericytes through interaction with tumor cells

    Science.gov (United States)

    Valdor, Rut; García-Bernal, David; Bueno, Carlos; Ródenas, Mónica; Moraleda, José M.; Macian, Fernando; Martínez, Salvador

    2017-01-01

    The establishment of immune tolerance during Glioblastoma Multiforme (GBM) progression, is characterized by high levels expression of anti-inflammatory cytokines, which suppress the function of tumor assocciated myeloid cells, and the activation and expansion of tumor antigen specific T cells. However, the mechanisms underlying the failed anti-tumor immune response around the blood vessels during GBM, are poorly understood. The consequences of possible interactions between cancer cells and the perivascular compartment might affect the tumor growth. In this work we show for the first time that GBM cells induce immunomodulatory changes in pericytes in a cell interaction-dependent manner, acquiring an immunosuppresive function that possibly assists the evasion of the anti-tumor immune response and consequently participates in tumor growth promotion. Expression of high levels of anti-inflammatory cytokines was detected in vitro and in vivo in brain pericytes that interacted with GBM cells (GBC-PC). Furthermore, reduction of surface expression of co-stimulatory molecules and major histocompatibility complex molecules in GBC-PC correlated with a failure of antigen presentation to T cells and the acquisition of the ability to supress T cell responses. In vivo, orthotopic xenotransplant of human glioblastoma in an immunocompetent mouse model showed significant GBM cell proliferation and tumor growth after the establishment of interspecific immunotolerance that followed GMB interaction with pericytes. PMID:28978142

  12. Suppression of Peroxiredoxin 4 in Glioblastoma Cells Increases Apoptosis and Reduces Tumor Growth

    Science.gov (United States)

    Kim, Tae Hyong; Song, Jieun; Alcantara Llaguno, Sheila R.; Murnan, Eric; Liyanarachchi, Sandya; Palanichamy, Kamalakannan; Yi, Ji-Yeun; Viapiano, Mariano Sebastian; Nakano, Ichiro; Yoon, Sung Ok; Wu, Hong; Parada, Luis F.; Kwon, Chang-Hyuk

    2012-01-01

    Glioblastoma multiforme (GBM), the most common and aggressive primary brain malignancy, is incurable despite the best combination of current cancer therapies. For the development of more effective therapies, discovery of novel candidate tumor drivers is urgently needed. Here, we report that peroxiredoxin 4 (PRDX4) is a putative tumor driver. PRDX4 levels were highly increased in a majority of human GBMs as well as in a mouse model of GBM. Reducing PRDX4 expression significantly decreased GBM cell growth and radiation resistance in vitro with increased levels of ROS, DNA damage, and apoptosis. In a syngenic orthotopic transplantation model, Prdx4 knockdown limited GBM infiltration and significantly prolonged mouse survival. These data suggest that PRDX4 can be a novel target for GBM therapies in the future. PMID:22916164

  13. Suppression of peroxiredoxin 4 in glioblastoma cells increases apoptosis and reduces tumor growth.

    Directory of Open Access Journals (Sweden)

    Tae Hyong Kim

    Full Text Available Glioblastoma multiforme (GBM, the most common and aggressive primary brain malignancy, is incurable despite the best combination of current cancer therapies. For the development of more effective therapies, discovery of novel candidate tumor drivers is urgently needed. Here, we report that peroxiredoxin 4 (PRDX4 is a putative tumor driver. PRDX4 levels were highly increased in a majority of human GBMs as well as in a mouse model of GBM. Reducing PRDX4 expression significantly decreased GBM cell growth and radiation resistance in vitro with increased levels of ROS, DNA damage, and apoptosis. In a syngenic orthotopic transplantation model, Prdx4 knockdown limited GBM infiltration and significantly prolonged mouse survival. These data suggest that PRDX4 can be a novel target for GBM therapies in the future.

  14. DNER, an epigenetically modulated gene, regulates glioblastoma-derived neurosphere cell differentiation and tumor propagation.

    Science.gov (United States)

    Sun, Peng; Xia, Shuli; Lal, Bachchu; Eberhart, Charles G; Quinones-Hinojosa, Alfredo; Maciaczyk, Jarek; Matsui, William; Dimeco, Francesco; Piccirillo, Sara M; Vescovi, Angelo L; Laterra, John

    2009-07-01

    Neurospheres derived from glioblastoma (GBM) and other solid malignancies contain neoplastic stem-like cells that efficiently propagate tumor growth and resist cytotoxic therapeutics. The primary objective of this study was to use histone-modifying agents to elucidate mechanisms by which the phenotype and tumor-promoting capacity of GBM-derived neoplastic stem-like cells are regulated. Using established GBM-derived neurosphere lines and low passage primary GBM-derived neurospheres, we show that histone deacetylase (HDAC) inhibitors inhibit growth, induce differentiation, and induce apoptosis of neoplastic neurosphere cells. A specific gene product induced by HDAC inhibition, Delta/Notch-like epidermal growth factor-related receptor (DNER), inhibited the growth of GBM-derived neurospheres, induced their differentiation in vivo and in vitro, and inhibited their engraftment and growth as tumor xenografts. The differentiating and tumor suppressive effects of DNER, a noncanonical Notch ligand, contrast with the previously established tumor-promoting effects of canonical Notch signaling in brain cancer stem-like cells. Our findings are the first to implicate noncanonical Notch signaling in the regulation of neoplastic stem-like cells and suggest novel neoplastic stem cell targeting treatment strategies for GBM and potentially other solid malignancies.

  15. A small noncoding RNA signature found in exosomes of GBM patient serum as a diagnostic tool.

    Science.gov (United States)

    Manterola, Lorea; Guruceaga, Elizabeth; Gállego Pérez-Larraya, Jaime; González-Huarriz, Marisol; Jauregui, Patricia; Tejada, Sonia; Diez-Valle, Ricardo; Segura, Victor; Samprón, Nicolás; Barrena, Cristina; Ruiz, Irune; Agirre, Amaia; Ayuso, Angel; Rodríguez, Javier; González, Alvaro; Xipell, Enric; Matheu, Ander; López de Munain, Adolfo; Tuñón, Teresa; Zazpe, Idoya; García-Foncillas, Jesús; Paris, Sophie; Delattre, Jean Yves; Alonso, Marta M

    2014-04-01

    Glioblastoma multiforme (GBM) is the most frequent malignant brain tumor in adults, and its prognosis remains dismal despite intensive research and therapeutic advances. Diagnostic biomarkers would be clinically meaningful to allow for early detection of the tumor and for those cases in which surgery is contraindicated or biopsy results are inconclusive. Recent findings show that GBM cells release microvesicles that contain a select subset of cellular proteins and RNA. The aim of this hypothesis-generating study was to assess the diagnostic potential of miRNAs found in microvesicles isolated from the serum of GBM patients. To control disease heterogeneity, we used patients with newly diagnosed GBM. In the discovery stage, PCR-based TaqMan Low Density Arrays followed by individual quantitative reverse transcriptase polymerase chain reaction were used to test the differences in the miRNA expression levels of serum microvesicles among 25 GBM patients and healthy controls paired by age and sex. The detected noncoding RNAs were then validated in another 50 GBM patients. We found that the expression levels of 1 small noncoding RNA (RNU6-1) and 2 microRNAs (miR-320 and miR-574-3p) were significantly associated with a GBM diagnosis. In addition, RNU6-1 was consistently an independent predictor of a GBM diagnosis. Altogether our results uncovered a small noncoding RNA signature in microvesicles isolated from GBM patient serum that could be used as a fast and reliable differential diagnostic biomarker.

  16. Pim1 kinase is upregulated in glioblastoma multiforme and mediates tumor cell survival

    Science.gov (United States)

    Herzog, Susann; Fink, Matthias Alexander; Weitmann, Kerstin; Friedel, Claudius; Hadlich, Stefan; Langner, Sönke; Kindermann, Katharina; Holm, Tobias; Böhm, Andreas; Eskilsson, Eskil; Miletic, Hrvoje; Hildner, Markus; Fritsch, Michael; Vogelgesang, Silke; Havemann, Christoph; Ritter, Christoph Alexander; Meyer zu Schwabedissen, Henriette Elisabeth; Rauch, Bernhard; Hoffmann, Wolfgang; Kroemer, Heyo Klaus; Schroeder, Henry; Bien-Möller, Sandra

    2015-01-01

    Background The current therapy for glioblastoma multiforme (GBM), the most aggressive and common primary brain tumor of adults, involves surgery and a combined radiochemotherapy that controls tumor progression only for a limited time window. Therefore, the identification of new molecular targets is highly necessary. Inhibition of kinases has become a standard of clinical oncology, and thus the oncogenic kinase Pim1 might represent a promising target for improvement of GBM therapy. Methods Expression of Pim1 and associated signaling molecules was analyzed in human GBM samples, and the potential role of this kinase in patients' prognosis was evaluated. Furthermore, we analyzed the in vivo role of Pim1 in GBM cell growth in an orthotopic mouse model and examined the consequences of Pim1 inhibition in vitro to clarify underlying pathways. Results In comparison with normal brain, a strong upregulation of Pim1 was demonstrated in human GBM samples. Notably, patients with short overall survival showed a significantly higher Pim1 expression compared with GBM patients who lived longer than the median. In vitro experiments with GBM cells and analysis of patients' GBM samples suggest that Pim1 regulation is dependent on epidermal growth factor receptor. Furthermore, inhibition of Pim1 resulted in reduced cell viability accompanied by decreased cell numbers and increased apoptotic cells, as seen by elevated subG1 cell contents and caspase-3 and -9 activation, as well as modulation of several cell cycle or apoptosis regulatory proteins. Conclusions Altogether, Pim1 could be a novel therapeutic target, which should be further analyzed to improve the outcome of patients with aggressive GBM. PMID:25155357

  17. Senescence from glioma stem cell differentiation promotes tumor growth

    International Nuclear Information System (INIS)

    Ouchi, Rie; Okabe, Sachiko; Migita, Toshiro; Nakano, Ichiro; Seimiya, Hiroyuki

    2016-01-01

    Glioblastoma (GBM) is a lethal brain tumor composed of heterogeneous cellular populations including glioma stem cells (GSCs) and differentiated non-stem glioma cells (NSGCs). While GSCs are involved in tumor initiation and propagation, NSGCs' role remains elusive. Here, we demonstrate that NSGCs undergo senescence and secrete pro-angiogenic proteins, boosting the GSC-derived tumor formation in vivo. We used a GSC model that maintains stemness in neurospheres, but loses the stemness and differentiates into NSGCs upon serum stimulation. These NSGCs downregulated telomerase, shortened telomeres, and eventually became senescent. The senescent NSGCs released pro-angiogenic proteins, including vascular endothelial growth factors and senescence-associated interleukins, such as IL-6 and IL-8. Conditioned medium from senescent NSGCs promoted proliferation of brain microvascular endothelial cells, and mixed implantation of GSCs and senescent NSGCs into mice enhanced the tumorigenic potential of GSCs. The senescent NSGCs seem to be clinically relevant, because both clinical samples and xenografts of GBM contained tumor cells that expressed the senescence markers. Our data suggest that senescent NSGCs promote malignant progression of GBM in part via paracrine effects of the secreted proteins. - Highlights: • Non-stem glioma cells (NSGCs) lose telomerase and eventually become senescent. • Senescent NSGCs secrete pro-angiogenic proteins, such as VEGFs, IL-6, and IL-8. • Senescent NSGCs enhance the growth of brain microvascular endothelial cells. • Senescent NSGCs enhance the tumorigenic potential of glioma stem cells in vivo.

  18. Senescence from glioma stem cell differentiation promotes tumor growth

    Energy Technology Data Exchange (ETDEWEB)

    Ouchi, Rie [Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550 (Japan); Laboratory of Molecular Target Therapy of Cancer, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550 (Japan); Okabe, Sachiko; Migita, Toshiro [Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550 (Japan); Nakano, Ichiro [Department of Neurosurgery, Comprehensive Cancer Center, University of Alabama at Birmingham, 1824 6th Avenue South, Birmingham, AL 35233 (United States); Seimiya, Hiroyuki, E-mail: hseimiya@jfcr.or.jp [Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550 (Japan); Laboratory of Molecular Target Therapy of Cancer, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550 (Japan)

    2016-02-05

    Glioblastoma (GBM) is a lethal brain tumor composed of heterogeneous cellular populations including glioma stem cells (GSCs) and differentiated non-stem glioma cells (NSGCs). While GSCs are involved in tumor initiation and propagation, NSGCs' role remains elusive. Here, we demonstrate that NSGCs undergo senescence and secrete pro-angiogenic proteins, boosting the GSC-derived tumor formation in vivo. We used a GSC model that maintains stemness in neurospheres, but loses the stemness and differentiates into NSGCs upon serum stimulation. These NSGCs downregulated telomerase, shortened telomeres, and eventually became senescent. The senescent NSGCs released pro-angiogenic proteins, including vascular endothelial growth factors and senescence-associated interleukins, such as IL-6 and IL-8. Conditioned medium from senescent NSGCs promoted proliferation of brain microvascular endothelial cells, and mixed implantation of GSCs and senescent NSGCs into mice enhanced the tumorigenic potential of GSCs. The senescent NSGCs seem to be clinically relevant, because both clinical samples and xenografts of GBM contained tumor cells that expressed the senescence markers. Our data suggest that senescent NSGCs promote malignant progression of GBM in part via paracrine effects of the secreted proteins. - Highlights: • Non-stem glioma cells (NSGCs) lose telomerase and eventually become senescent. • Senescent NSGCs secrete pro-angiogenic proteins, such as VEGFs, IL-6, and IL-8. • Senescent NSGCs enhance the growth of brain microvascular endothelial cells. • Senescent NSGCs enhance the tumorigenic potential of glioma stem cells in vivo.

  19. CXCL12 MODULATION OF CXCR4 AND CXCR7 ACTIVITY IN HUMAN GLIOBLASTOMA STEM-LIKE CELLS AND REGULATION OF THE TUMOR MICROENVIRONMENT

    Directory of Open Access Journals (Sweden)

    Roberto eWurth

    2014-05-01

    Full Text Available Chemokines are crucial autocrine and paracrine players in tumor development. In particular, CXCL12, through its receptors CXCR4 and CXCR7, affects tumor progression by controlling cancer cell survival, proliferation and migration, and, indirectly, via angiogenesis or recruiting immune cells.Glioblastoma (GBM is the most prevalent primary malignant brain tumor in adults and despite current multimodal therapies it remains almost incurable. The aggressive and recurrent phenotype of GBM is ascribed to high growth rate, invasiveness to normal brain, marked angiogenesis, ability to escape the immune system and resistance to standard of care therapies. Tumor molecular and cellular heterogeneity severely hinders GBM therapeutic improvement. In particular, a subpopulation of chemo- and radio-therapy resistant tumorigenic cancer stem–like cells (CSCs is believed to be the main responsible for tumor cell dissemination to the brain.GBM cells display heterogeneous expression levels of CXCR4 and CXCR7 that are overexpressed in CSCs, representing a molecular correlate for the invasive potential of GBM. The microenvironment contribution in GBM development is increasingly emphasized. An interplay exists between CSCs, differentiated GBM cells, and the microenvironment, mainly through secreted chemokines (e.g. CXCL12 causing recruitment of fibroblasts, endothelial, mesenchymal and inflammatory cells to the tumor, via specific receptors such as CXCR4.This review covers recent developments on the role of CXCL12/CXCR4-CXCR7 networks in GBM progression and the potential translational impact of their targeting. The biological and molecular understanding of the heterogeneous GBM cell behavior, phenotype and signaling is still limited. Progress in the identification of chemokine-dependent mechanisms that affect GBM cell survival, trafficking and chemo-attractive functions, opens new perspectives for development of more specific therapeutic approaches that include

  20. Biomimetic brain tumor niche regulates glioblastoma cells towards a cancer stem cell phenotype.

    Science.gov (United States)

    Liu, Yung-Chiang; Lee, I-Chi; Chen, Pin-Yuan

    2018-05-01

    Glioblastoma (GBM) is the most malignant primary brain tumor and contains tumorigenic cancer stem cells (CSCs), which support the progression of tumor growth. The selection of CSCs and facilitation of the brain tumor niches may assist the development of novel therapeutics for GBM. Herein, hydrogel materials composed of agarose and hydroxypropyl methyl cellulose (HMC) in different concentrations were established and compared to emulate brain tumor niches and CSC microenvironments within a label-free system. Human GBM cell line, U-87 MG, was cultured on a series of HMC-agarose based culture system. Cell aggregation and spheroids formation were investigated after 4 days of culture, and 2.5% HMC-agarose based culture system demonstrated the largest spheroids number and size. Moreover, CD133 marker expression of GBM cells after 6 days of culture in 2.5% HMC-agarose based culture system was 60%, relatively higher than the control group at only 15%. Additionally, cells on 2.5% HMC-agarose based culture system show the highest chemoresistance, even at the high dose of 500 µM temozolomide for 72 h, the live cell ratio was still > 80%. Furthermore, the results also indicate that the expression of ABCG2 gene was up-regulated after culture in 2.5% HMC-agarose based culture system. Therefore, our results demonstrated that biomimetic brain tumor microenvironment may regulate GBM cells towards the CSC phenotype and expression of CSC characteristics. The microenvironment selection and spheroids formation in HMC-agarose based culture system may provide a label-free CSC selection strategy and drug testing model for future biomedical applications.

  1. Combination of systemic chemotherapy with local stem cell delivered S-TRAIL in resected brain tumors.

    Science.gov (United States)

    Redjal, Navid; Zhu, Yanni; Shah, Khalid

    2015-01-01

    Despite advances in standard therapies, the survival of glioblastoma multiforme (GBM) patients has not improved. Limitations to successful translation of new therapies include poor delivery of systemic therapies and use of simplified preclinical models which fail to reflect the clinical complexity of GBMs. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis specifically in tumor cells and we have tested its efficacy by on-site delivery via engineered stem cells (SC) in mouse models of GBM that mimic the clinical scenario of tumor aggressiveness and resection. However, about half of tumor lines are resistant to TRAIL and overcoming TRAIL-resistance in GBM by combining therapeutic agents that are currently in clinical trials with SC-TRAIL and understanding the molecular dynamics of these combination therapies are critical to the broad use of TRAIL as a therapeutic agent in clinics. In this study, we screened clinically relevant chemotherapeutic agents for their ability to sensitize resistant GBM cell lines to TRAIL induced apoptosis. We show that low dose cisplatin increases surface receptor expression of death receptor 4/5 post G2 cycle arrest and sensitizes GBM cells to TRAIL induced apoptosis. In vivo, using an intracranial resection model of resistant primary human-derived GBM and real-time optical imaging, we show that a low dose of cisplatin in combination with synthetic extracellular matrix encapsulated SC-TRAIL significantly decreases tumor regrowth and increases survival in mice bearing GBM. This study has the potential to help expedite effective translation of local stem cell-based delivery of TRAIL into the clinical setting to target a broad spectrum of GBMs. © 2014 AlphaMed Press.

  2. SU-D-BRB-06: Treating Glioblastoma Multiforme (GBM) as a Chronic Disease: Implication of Temporal-Spatial Dose Fractionation Optimization Including Cancer Stem Cell Dynamics

    Energy Technology Data Exchange (ETDEWEB)

    Yu, V; Nguyen, D; Pajonk, F; Kaprealian, T; Kupelian, P; Steinberg, M; Low, D; Sheng, K [Department of Radiation Oncology, UCLA, Los Angeles, CA (United States)

    2015-06-15

    Purpose: To explore the feasibility of improving GBM treatment outcome with temporal-spatial dose optimization of an ordinary differential equation (ODE) that models the differentiation and distinct radiosensitivity between cancer stem cells (CSC) and differentiated cancer cells (DCC). Methods: The ODE was formulated into a non-convex optimization problem with the objective to minimize remaining total cancer cells 500 days from the onset of radiotherapy when the total cancer cell number was 3.5×10{sup 7}, while maintaining normal tissue biological effective dose (BED) of 100Gy resulted from standard prescription of 2Gyx30. Assuming spatially separated CSC and DCC, optimization was also performed to explore the potential benefit from dose-painting the two compartments. Dose escalation to a sub-cell-population in the GTV was also examined assuming that a 2 cm margin around the GTV allows sufficient dose drop-off to 100Gy BED. The recurrence time was determined as the time at which the total cancer cell number regrows to 10{sup 9} cells. Results: The recurrence time with variable fractional doses administered once per week, bi-week and month for one year were found to be 615, 593 and 570 days, superior to the standard-prescription recurrence time of 418 days. The optimal dose-fraction size progression for both uniform and dose-painting to the tumor is low and relatively constant in the beginning and gradually increases to more aggressive fractions at end of the treatment course. Dose escalation to BED of 200Gy to the whole tumor alongside with protracted weekly treatment was found to further delay recurrence to 733 days. Dose-painting of 200 and 500Gy BED to CSC on a year-long weekly schedule further extended recurrence to 736 and 1076 days, respectively. Conclusion: GBM treatment outcome can possibly be improved with a chronic treatment approach. Further dose escalation to the entire tumor or CSC targeted killing is needed to achieve total tumor control. This work

  3. Sulforaphane suppresses the growth of glioblastoma cells, glioblastoma stem cell-like spheroids, and tumor xenografts through multiple cell signaling pathways.

    Science.gov (United States)

    Bijangi-Vishehsaraei, Khadijeh; Reza Saadatzadeh, M; Wang, Haiyan; Nguyen, Angie; Kamocka, Malgorzata M; Cai, Wenjing; Cohen-Gadol, Aaron A; Halum, Stacey L; Sarkaria, Jann N; Pollok, Karen E; Safa, Ahmad R

    2017-12-01

    OBJECTIVE Defects in the apoptotic machinery and augmented survival signals contribute to drug resistance in glioblastoma (GBM). Moreover, another complexity related to GBM treatment is the concept that GBM development and recurrence may arise from the expression of GBM stem cells (GSCs). Therefore, the use of a multifaceted approach or multitargeted agents that affect specific tumor cell characteristics will likely be necessary to successfully eradicate GBM. The objective of this study was to investigate the usefulness of sulforaphane (SFN)-a constituent of cruciferous vegetables with a multitargeted effect-as a therapeutic agent for GBM. METHODS The inhibitory effects of SFN on established cell lines, early primary cultures, CD133-positive GSCs, GSC-derived spheroids, and GBM xenografts were evaluated using various methods, including GSC isolation and the sphere-forming assay, analysis of reactive oxygen species (ROS) and apoptosis, cell growth inhibition assay, comet assays for assessing SFN-triggered DNA damage, confocal microscopy, Western blot analysis, and the determination of in vivo efficacy as assessed in human GBM xenograft models. RESULTS SFN triggered the significant inhibition of cell survival and induced apoptotic cell death, which was associated with caspase 3 and caspase 7 activation. Moreover, SFN triggered the formation of mitochondrial ROS, and SFN-triggered cell death was ROS dependent. Comet assays revealed that SFN increased single- and double-strand DNA breaks in GBM. Compared with the vehicle control cells, a significantly higher amount of γ-H2AX foci correlated with an increase in DNA double-strand breaks in the SFN-treated samples. Furthermore, SFN robustly inhibited the growth of GBM cell-induced cell death in established cell cultures and early-passage primary cultures and, most importantly, was effective in eliminating GSCs, which play a major role in drug resistance and disease recurrence. In vivo studies revealed that SFN

  4. Pre-clinical analysis of changes in intra-cellular biochemistry of glioblastoma multiforme (GBM) cells due to c-Myc silencing.

    Science.gov (United States)

    Rajagopalan, Vishal; Vaidyanathan, Muthukumar; Janardhanam, Vanisree Arambakkam; Bradner, James E

    2014-10-01

    Glioblastoma Multiforme (GBM) is an aggressive form of brain Tumor that has few cures. In this study, we analyze the anti-proliferative effects of a new molecule JQ1 against GBMs induced in Wistar Rats. JQ1 is essentially a Myc inhibitor. c-Myc is also known for altering the biochemistry of a tumor cell. Therefore, the study is intended to analyze certain other oncogenes associated with c-Myc and also the change in cellular biochemistry upon c-Myc inhibition. The quantitative analysis of gene expression gave a co-expressive pattern for all the three genes involved namely; c-Myc, Bcl-2, and Akt. The cellular biochemistry analysis by transmission electron microscopy revealed high glycogen and lipid aggregation in Myc inhibited cells and excessive autophagy. The study demonstrates the role of c-Myc as a central metabolic regulator and Bcl-2 and Akt assisting in extending c-Myc half-life as well as in regulation of autophagy, so as to regulate cell survival on the whole. The study also demonstrates that transient treatment by JQ1 leads to aggressive development of tumor and therefore, accelerating death, emphasizing the importance of dosage fixation, and duration for clinical use in future.

  5. Metaphyseal giant cell tumor

    International Nuclear Information System (INIS)

    Pereira, L.F.; Hemais, P.M.P.G.; Aymore, I.L.; Carmo, M.C.R. do; Cunha, M.E.P.R. da; Resende, C.M.C.

    1986-01-01

    Three cases of metaphyseal giant cell tumor are presented. A review of the literature is done, demostrating the lesion is rare and that there are few articles about it. Age incidence and characteristics of the tumor are discussed. (Author) [pt

  6. CD44v6 regulates growth of brain tumor stem cells partially through the AKT-mediated pathway.

    Directory of Open Access Journals (Sweden)

    Mayumi Jijiwa

    Full Text Available Identification of stem cell-like brain tumor cells (brain tumor stem-like cells; BTSC has gained substantial attention by scientists and physicians. However, the mechanism of tumor initiation and proliferation is still poorly understood. CD44 is a cell surface protein linked to tumorigenesis in various cancers. In particular, one of its variant isoforms, CD44v6, is associated with several cancer types. To date its expression and function in BTSC is yet to be identified. Here, we demonstrate the presence and function of the variant form 6 of CD44 (CD44v6 in BTSC of a subset of glioblastoma multiforme (GBM. Patients with CD44(high GBM exhibited significantly poorer prognoses. Among various variant forms, CD44v6 was the only isoform that was detected in BTSC and its knockdown inhibited in vitro growth of BTSC from CD44(high GBM but not from CD44(low GBM. In contrast, this siRNA-mediated growth inhibition was not apparent in the matched GBM sample that does not possess stem-like properties. Stimulation with a CD44v6 ligand, osteopontin (OPN, increased expression of phosphorylated AKT in CD44(high GBM, but not in CD44(low GBM. Lastly, in a mouse spontaneous intracranial tumor model, CD44v6 was abundantly expressed by tumor precursors, in contrast to no detectable CD44v6 expression in normal neural precursors. Furthermore, overexpression of mouse CD44v6 or OPN, but not its dominant negative form, resulted in enhanced growth of the mouse tumor stem-like cells in vitro. Collectively, these data indicate that a subset of GBM expresses high CD44 in BTSC, and its growth may depend on CD44v6/AKT pathway.

  7. Non-tumor cell IDO1 predominantly contributes to enzyme activity and response to CTLA-4/PD-L1 inhibition in mouse glioblastoma.

    Science.gov (United States)

    Zhai, Lijie; Ladomersky, Erik; Dostal, Carlos R; Lauing, Kristen L; Swoap, Kathleen; Billingham, Leah K; Gritsina, Galina; Wu, Meijing; McCusker, Robert H; Binder, David C; Wainwright, Derek A

    2017-05-01

    Glioblastoma (GBM) is the most common malignant brain tumor in adults with a median survival of 14.6months. A contributing factor to GBM aggressiveness is the intratumoral expression of the potently immunosuppressive enzyme, indoleamine 2,3 dioxygenase 1 (IDO1). The enzymatic activity of IDO1 is associated with the conversion of tryptophan into downstream kynurenine (Kyn), which has previously been hypothesized to contribute toward the suppression of tumor immunity. Utilizing the syngeneic, immunocompetent, intracranial GL261 cell GBM model, we previously demonstrated that tumor cell, but not non-tumor cell IDO1, suppresses T cell-mediated brain tumor regression in mice. Paradoxically, we also showed that the survival advantage mediated by immune checkpoint blockade is abrogated by non-tumor cell IDO1 deficiency. Here, we have built on our past observations and confirm the maladaptive role of tumor cell IDO1 in a novel mouse GBM model. We also demonstrate that, non-tumor cells, rather than mouse GBM cells, are the dominant contributor to IDO1-mediated enzyme activity. Finally, we show the novel associations between maximally-effective immune-checkpoint blockade-mediated survival, non-tumor cell IDO1 and intra-GBM Kyn levels. These data suggest for the first time that, GBM cell-mediated immunosuppression is IDO1 enzyme independent, while the survival benefits of immune checkpoint blockade require non-tumor cell IDO1 enzyme activity. Given that current clinical inhibitors vary in their mechanism of action, in terms of targeting IDO1 enzyme activity versus enzyme-independent effects, this work suggests that choosing an appropriate IDO1 pharmacologic will maximize the effectiveness of future immune checkpoint blockade approaches. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. Quantitative imaging of magnesium distribution at single-cell resolution in brain tumors and infiltrating tumor cells with secondary ion mass spectrometry (SIMS)

    Science.gov (United States)

    Chandra, Subhash; Parker, Dylan J.; Barth, Rolf F.; Pannullo, Susan C.

    2016-01-01

    Glioblastoma multiforme (GBM) is one of the deadliest forms of human brain tumors. The infiltrative pattern of growth of these tumors includes the spread of individual and/or clusters of tumor cells at some distance from the main tumor mass in parts of the brain protected by an intact blood-brain-barrier. Pathophysiological studies of GBM could be greatly enhanced by analytical techniques capable of in situ single-cell resolution measurements of infiltrating tumor cells. Magnesium homeostasis is an area of active investigation in high grade gliomas. In the present study, we have used the F98 rat glioma as a model of human GBM and an elemental/isotopic imaging technique of secondary ion mass spectrometry (SIMS), a CAMECA IMS-3f ion microscope, for studying Mg distributions with single-cell resolution in freeze-dried brain tissue cryosections. Quantitative observations were made on tumor cells in the main tumor mass, contiguous brain tissue, and infiltrating tumor cells in adjacent normal brain. The brain tissue contained a significantly lower total Mg concentration of 4.70 ± 0.93 mmol/Kg wet weight (mean ± SD) in comparison to 11.64 ± 1.96 mmol/Kg wet weight in tumor cells of the main tumor mass and 10.72 ± 1.76 mmol/Kg wet weight in infiltrating tumor cells (p<0.05). The nucleus of individual tumor cells contained elevated levels of bound Mg. These observations demonstrate enhanced Mg-influx and increased binding of Mg in tumor cells and provide strong support for further investigation of GBMs for altered Mg homeostasis and activation of Mg-transporting channels as possible therapeutic targets. PMID:26703785

  9. Tumor cell surface proteins

    International Nuclear Information System (INIS)

    Kennel, S.J.; Braslawsky, G.R.; Flynn, K.; Foote, L.J.; Friedman, E.; Hotchkiss, J.A.; Huang, A.H.L.; Lankford, P.K.

    1982-01-01

    Cell surface proteins mediate interaction between cells and their environment. Unique tumor cell surface proteins are being identified and quantified in several tumor systems to address the following questions: (i) how do tumor-specific proteins arise during cell transformation; (ii) can these proteins be used as markers of tumor cell distribution in vivo; (iii) can cytotoxic drugs be targeted specifically to tumor cells using antibody; and (iv) can solid state radioimmunoassay of these proteins provide a means to quantify transformation frequencies. A tumor surface protein of 180,000 M/sub r/ (TSP-180) has been identified on cells of several lung carcinomas of BALB/c mice. TSP-180 was not detected on normal lung tissue, embryonic tissue, or other epithelial or sarcoma tumors, but it was found on lung carcinomas of other strains of mice. Considerable amino acid sequence homology exists among TSP-180's from several cell sources, indicating that TSP-180 synthesis is directed by normal cellular genes although it is not expressed in normal cells. The regulation of synthesis of TSP-180 and its relationship to normal cell surface proteins are being studied. Monoclonal antibodies (MoAb) to TSP-180 have been developed. The antibodies have been used in immunoaffinity chromatography to isolate TSP-180 from tumor cell sources. This purified tumor antigen was used to immunize rats. Antibody produced by these animals reacted at different sites (epitopes) on the TSP-180 molecule than did the original MoAb. These sera and MoAb from these animals are being used to identify normal cell components related to the TSP-180 molecule

  10. DW-MRI as a Predictive Biomarker of Radiosensitization of GBM through Targeted Inhibition of Checkpoint Kinases.

    Science.gov (United States)

    Williams, Terence M; Galbán, Stefanie; Li, Fei; Heist, Kevin A; Galbán, Craig J; Lawrence, Theodore S; Holland, Eric C; Thomae, Tami L; Chenevert, Thomas L; Rehemtulla, Alnawaz; Ross, Brian D

    2013-04-01

    The inherent treatment resistance of glioblastoma (GBM) can involve multiple mechanisms including checkpoint kinase (Chk1/2)-mediated increased DNA repair capability, which can attenuate the effects of genotoxic chemotherapies and radiation. The goal of this study was to evaluate diffusion-weighted magnetic resonance imaging (DW-MRI) as a biomarker for Chk1/2 inhibitors in combination with radiation for enhancement of treatment efficacy in GBM. We evaluated a specific small molecule inhibitor of Chk1/2, AZD7762, in combination with radiation using in vitro human cell lines and in vivo using a genetically engineered GBM mouse model. DW-MRI and T1-contrast MRI were used to follow treatment effects on intracranial tumor cellularity and growth rates, respectively. AZD7762 inhibited clonal proliferation in a panel of GBM cell lines and increased radiosensitivity in p53-mutated GBM cell lines to a greater extent compared to p53 wild-type cells. In vivo efficacy of AZD7762 demonstrated a dose-dependent inhibitory effect on GBM tumor growth rate and a reduction in tumor cellularity based on DW-MRI scans along with enhancement of radiation efficacy. DW-MRI was found to be a useful imaging biomarker for the detection of radiosensitization through inhibition of checkpoint kinases. Chk1/2 inhibition resulted in antiproliferative activity, prevention of DNA damage-induced repair, and radiosensitization in preclinical GBM tumor models, both in vitro and in vivo. The effects were found to be maximal in p53-mutated GBM cells. These results provide the rationale for integration of DW-MRI in clinical translation of Chk1/2 inhibition with radiation for the treatment of GBM.

  11. Temozolomide, sirolimus and chloroquine is a new therapeutic combination that synergizes to disrupt lysosomal function and cholesterol homeostasis in GBM cells.

    Science.gov (United States)

    Hsu, Sanford P C; Kuo, John S; Chiang, Hsin-Chien; Wang, Hsin-Ell; Wang, Yu-Shan; Huang, Cheng-Chung; Huang, Yi-Chun; Chi, Mau-Shin; Mehta, Minesh P; Chi, Kwan-Hwa

    2018-01-23

    Glioblastoma (GBM) cells are characterized by high phagocytosis, lipogenesis, exocytosis activities, low autophagy capacity and high lysosomal demand are necessary for survival and invasion. The lysosome stands at the cross roads of lipid biosynthesis, transporting, sorting between exogenous and endogenous cholesterol. We hypothesized that three already approved drugs, the autophagy inducer, sirolimus (rapamycin, Rapa), the autophagy inhibitor, chloroquine (CQ), and DNA alkylating chemotherapy, temozolomide (TMZ) could synergize against GBM. This repurposed triple therapy combination induced GBM apoptosis in vitro and inhibited GBM xenograft growth in vivo . Cytotoxicity is caused by induction of lysosomal membrane permeabilization and release of hydrolases, and may be rescued by cholesterol supplementation. Triple treatment inhibits lysosomal function, prevents cholesterol extraction from low density lipoprotein (LDL), and causes clumping of lysosome associated membrane protein-1 (LAMP-1) and lipid droplets (LD) accumulation. Co-treatment of the cell lines with inhibitor of caspases and cathepsin B only partially reverse of cytotoxicities, while N-acetyl cysteine (NAC) can be more effective. A combination of reactive oxygen species (ROS) generation from cholesterol depletion are the early event of underling mechanism. Cholesterol repletion abolished the ROS production and reversed the cytotoxicity from QRT treatment. The shortage of free cholesterol destabilizes lysosomal membranes converting aborted autophagy to apoptosis through either direct mitochondria damage or cathepsin B release. This promising anti-GBM triple therapy combination severely decreases mitochondrial function, induces lysosome-dependent apoptotic cell death, and is now poised for further clinical testing and validation.

  12. Opposing roles of PGD2 in GBM.

    Science.gov (United States)

    Ferreira, Matthew Thomas; Gomes, Renata Nascimento; Panagopoulos, Alexandros Theodoros; de Almeida, Fernando Gonçalves; Veiga, José Carlos Esteves; Colquhoun, Alison

    2018-01-01

    The World Health Organization classifies glioblastoma (GBM) as a grade IV astrocytoma. Despite the advances in chemotherapy, surgery, and radiation treatments that improve a patient's length of survival, the overall trajectory of the disease remains unchanged. GBM cells produce significant levels of various types of bioactive lipids. Prostaglandin D 2 (PGD 2 ) influences both pro- and anti-tumorigenic activities in the cell; however, its role in GBM is unclear. Therefore, this study aimed to identify the impact of PGD 2 on GBM cell activities in vitro. First we looked to identify the presence of the PGD 2 synthesis pathway through RT-PCR, immunohistochemistry, and HPLC-MS/MS in three GBM cell lines. Then, to observe PGD 2 's effects on cell count and apoptosis/mitosis (Hoechst 33342 stain), and migration (Transwell Assay), the cells were treated in vitro with physiological (1μM) concentrations of PGD 2 over 72h. HPLC-MS/MS was used to identify the lipid composition of patients with either Grade II/III gliomas or GBM. We identified the presence of endogenous PGD 2 with its corresponding enzymes and receptors. Exogenous PGD 2 both increased cell count (GBM. Our study demonstrates that prostaglandin D 2 possesses a dynamic, concentration-dependent effect in GBM cell activities. The increase of PGD 2 production in GBM patients suggests a pro-tumorigenic role of PGD 2 in glioma growth and invasion. Therefore, prostaglandin signaling in GBM requires further investigation to identify new targets for more effective therapies. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. Neutrophil degranulation and immunosuppression in patients with GBM: restoration of cellular immune function by targeting arginase I.

    Science.gov (United States)

    Sippel, Trisha R; White, Jason; Nag, Kamalika; Tsvankin, Vadim; Klaassen, Marci; Kleinschmidt-DeMasters, B K; Waziri, Allen

    2011-11-15

    The source of glioblastoma (GBM)-associated immunosuppression remains multifactorial. We sought to clarify and therapeutically target myeloid cell-derived peripheral immunosuppression in patients with GBM. Direct ex vivo T-cell function, serum Arginase I (ArgI) levels, and circulating myeloid lineage populations were compared between patients with GBM and normal donors or patients with other intracranial tumors. Immunofunctional assays were conducted using bulk and sorted cell populations to explore the potential transfer of myeloid cell-mediated immunosuppression and to identify a potential mechanism for these effects. ArgI-mediated immunosuppression was therapeutically targeted in vitro through pharmacologic inhibition or arginine supplementation. We identified a significantly expanded population of circulating, degranulated neutrophils associated with elevated levels of serum ArgI and decreased T-cell CD3ζ expression within peripheral blood from patients with GBM. Sorted CD11b(+) cells from patients with GBM were found to markedly suppress normal donor T-cell function in coculture, and media harvested from mitogen-stimulated GBM peripheral blood mononuclear cell (PBMC) or GBM-associated mixed lymphoid reactions showed ArgI levels that were significantly higher than controls. Critically, T-cell suppression in both settings could be completely reversed through pharmacologic ArgI inhibition or with arginine supplementation. These data indicate that peripheral cellular immunosuppression in patients with GBM is associated with neutrophil degranulation and elevated levels of circulating ArgI, and that T-cell function can be restored in these individuals by targeting ArgI. These data identify a novel pathway of GBM-mediated suppression of cellular immunity and offer a potential therapeutic window for improving antitumor immunity in affected patients.

  14. EGFRvIII-specific chimeric antigen receptor T cells migrate to and kill tumor deposits infiltrating the brain parenchyma in an invasive xenograft model of glioblastoma.

    Science.gov (United States)

    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.

  15. EGFRvIII-specific chimeric antigen receptor T cells migrate to and kill tumor deposits infiltrating the brain parenchyma in an invasive xenograft model of glioblastoma.

    Directory of Open Access Journals (Sweden)

    Hongsheng Miao

    Full Text Available 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.

  16. Virus vector-mediated genetic modification of brain tumor stromal cells after intravenous delivery.

    Science.gov (United States)

    Volak, Adrienn; LeRoy, Stanley G; Natasan, Jeya Shree; Park, David J; Cheah, Pike See; Maus, Andreas; Fitzpatrick, Zachary; Hudry, Eloise; Pinkham, Kelsey; Gandhi, Sheetal; Hyman, Bradley T; Mu, Dakai; GuhaSarkar, Dwijit; Stemmer-Rachamimov, Anat O; Sena-Esteves, Miguel; Badr, Christian E; Maguire, Casey A

    2018-05-16

    The malignant primary brain tumor, glioblastoma (GBM) is generally incurable. New approaches are desperately needed. Adeno-associated virus (AAV) vector-mediated delivery of anti-tumor transgenes is a promising strategy, however direct injection leads to focal transgene spread in tumor and rapid tumor division dilutes out the extra-chromosomal AAV genome, limiting duration of transgene expression. Intravenous (IV) injection gives widespread distribution of AAV in normal brain, however poor transgene expression in tumor, and high expression in non-target cells which may lead to ineffective therapy and high toxicity, respectively. Delivery of transgenes encoding secreted, anti-tumor proteins to tumor stromal cells may provide a more stable and localized reservoir of therapy as they are more differentiated than fast-dividing tumor cells. Reactive astrocytes and tumor-associated macrophage/microglia (TAMs) are stromal cells that comprise a large portion of the tumor mass and are associated with tumorigenesis. In mouse models of GBM, we used IV delivery of exosome-associated AAV vectors driving green fluorescent protein expression by specific promoters (NF-κB-responsive promoter and a truncated glial fibrillary acidic protein promoter), to obtain targeted transduction of TAMs and reactive astrocytes, respectively, while avoiding transgene expression in the periphery. We used our approach to express the potent, yet toxic anti-tumor cytokine, interferon beta, in tumor stroma of a mouse model of GBM, and achieved a modest, yet significant enhancement in survival compared to controls. Noninvasive genetic modification of tumor microenvironment represents a promising approach for therapy against cancers. Additionally, the vectors described here may facilitate basic research in the study of tumor stromal cells in situ.

  17. Tumors of germinal cells

    International Nuclear Information System (INIS)

    Plazas, Ricardo; Avila, Andres

    2002-01-01

    The tumors of germinal cells (TGC) are derived neoplasia of the primordial germinal cells that in the life embryonic migrant from the primitive central nervous system until being located in the gonads. Their cause is even unknown and they represent 95% of the testicular tumors. In them, the intention of the treatment is always healing and the diagnostic has improved thanks to the results of the handling multidisciplinary. The paper includes topics like their incidence and prevalence, epidemiology and pathology, clinic and diagnoses among other topics

  18. Differential role of EGF and BFGF in human GBM-TIC proliferation: relationship to EGFR-tyrosine kinase inhibitor sensibility.

    Science.gov (United States)

    Bajetto, A; Porcile, C; Pattarozzi, A; Scotti, L; Aceto, A; Daga, A; Barbieri, F; Florio, T

    2013-01-01

    Glioblastoma multiforme (GBM) is among the most devastating human tumors being rapidly fatal despite aggressive surgery, radiation and chemotherapies. It is characterized by extensive dissemination of tumor cells within the brain that hinders complete surgical resection. GBM tumor initiating-cells (TICs) are a rare subpopulation of cells responsible for tumor development, growth, invasiveness and recurrence after chemotherapy. TICs from human GBM can be selected in vitro using the same conditions permissive for the growth of normal neural cells, of which share some features including marker expression, self-renewal capacity, long-term proliferation, and ability to differentiate into neuronal and glial cells. EGFR overexpression and its constitutive activation is one of the most important signaling alteration identified in GBM, and its pharmacological targeting represents an attractive therapeutic goal. We previously demonstrated that human GBM TICs have different sensitivity to the EGFR kinase inhibitors erlotinib and gefitinib, depending on the differential modulation of downstream signaling cascades. In this work we investigated the mechanisms of resistance to erlotinib in two human GBM TIC cultures, analyzing EGF and bFGF individual contribution to proliferation, clonogenicity, and migration. We demonstrated the presence of a small cell subpopulation whose proliferation is supported by EGF and a larger one mainly dependent on bFGF. Thus, insensitivity to EGFR kinase inhibitors as far as TIC proliferation results from a predominant FGFR activation that hides the inhibitory effects induced on EGFR signaling. Conversely, EGF and bFGF induced cell migration with similar efficacy. In addition, unlike neural stem/progenitors cells, the removal of chondroitin sulphate proteoglycans from cell surface was unable to discern EGF- and bFGF-dependent subpopulations in GBM TICs.

  19. Autocrine VEGF-VEGFR2-Neuropilin-1 signaling promotes glioma stem-like cell viability and tumor growth

    DEFF Research Database (Denmark)

    Hamerlik, Petra; Lathia, Justin D; Rasmussen, Rikke

    2012-01-01

    Although vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) is traditionally regarded as an endothelial cell protein, evidence suggests that VEGFRs may be expressed by cancer cells. Glioblastoma multiforme (GBM) is a lethal cancer characterized by florid vascularization and aberrantly...... elevated VEGF. Antiangiogenic therapy with the humanized VEGF antibody bevacizumab reduces GBM tumor growth; however, the clinical benefits are transient and invariably followed by tumor recurrence. In this study, we show that VEGFR2 is preferentially expressed on the cell surface of the CD133(+) human......, which is associated with VEGFR2-NRP1 recycling and a pool of active VEGFR2 within a cytosolic compartment of a subset of human GBM cells. Whereas bevacizumab failed to inhibit prosurvival effects of VEGFR2-mediated signaling, GSC viability under unperturbed or radiation-evoked stress conditions...

  20. Allogeneic tumor cell vaccines

    Science.gov (United States)

    Srivatsan, Sanjay; Patel, Jaina M; Bozeman, Erica N; Imasuen, Imade E; He, Sara; Daniels, Danielle; Selvaraj, Periasamy

    2014-01-01

    The high mortality rate associated with cancer and its resistance to conventional treatments such as radiation and chemotherapy has led to the investigation of a variety of anti-cancer immunotherapies. The development of novel immunotherapies has been bolstered by the discovery of tumor-associated antigens (TAAs), through gene sequencing and proteomics. One such immunotherapy employs established allogeneic human cancer cell lines to induce antitumor immunity in patients through TAA presentation. Allogeneic cancer immunotherapies are desirable in a clinical setting due to their ease of production and availability. This review aims to summarize clinical trials of allogeneic tumor immunotherapies in various cancer types. To date, clinical trials have shown limited success due potentially to extensive degrees of inter- and intra-tumoral heterogeneity found among cancer patients. However, these clinical results provide guidance for the rational design and creation of more effective allogeneic tumor immunotherapies for use as monotherapies or in combination with other therapies. PMID:24064957

  1. CD155/PVR plays a key role in cell motility during tumor cell invasion and migration

    International Nuclear Information System (INIS)

    Sloan, Kevin E; Ilag, Leodevico L; Jay, Daniel G; Eustace, Brenda K; Stewart, Jean K; Zehetmeier, Carol; Torella, Claudia; Simeone, Marina; Roy, Jennifer E; Unger, Christine; Louis, David N

    2004-01-01

    Invasion is an important early step of cancer metastasis that is not well understood. Developing therapeutics to limit metastasis requires the identification and validation of candidate proteins necessary for invasion and migration. We developed a functional proteomic screen to identify mediators of tumor cell invasion. This screen couples Fluorophore Assisted Light Inactivation (FALI) to a scFv antibody library to systematically inactivate surface proteins expressed by human fibrosarcoma cells followed by a high-throughput assessment of transwell invasion. Using this screen, we have identified CD155 (the poliovirus receptor) as a mediator of tumor cell invasion through its role in migration. Knockdown of CD155 by FALI or by RNAi resulted in a significant decrease in transwell migration of HT1080 fibrosarcoma cells towards a serum chemoattractant. CD155 was found to be highly expressed in multiple cancer cell lines and primary tumors including glioblastoma (GBM). Knockdown of CD155 also decreased migration of U87MG GBM cells. CD155 is recruited to the leading edge of migrating cells where it colocalizes with actin and αv-integrin, known mediators of motility and adhesion. Knockdown of CD155 also altered cellular morphology, resulting in cells that were larger and more elongated than controls when plated on a Matrigel substrate. These results implicate a role for CD155 in mediating tumor cell invasion and migration and suggest that CD155 may contribute to tumorigenesis

  2. CD4+ and Perivascular Foxp3+ T Cells in Glioma Correlate with Angiogenesis and Tumor Progression

    Directory of Open Access Journals (Sweden)

    Luyan Mu

    2017-11-01

    Full Text Available BackgroundAngiogenesis and immune cell infiltration are key features of gliomas and their manipulation of the microenvironment, but their prognostic significance remains indeterminate. We evaluate the interconnection between tumor-infiltrating lymphocyte (TIL and tumor blood-vasculatures in the context of glioma progression.MethodsPaired tumor tissues of 44 patients from three tumor-recurrent groups: diffuse astrocytomas (DA recurred as DA, DA recurred as glioblastomas (GBM, and GBM recurred as GBM were evaluated by genetic analysis, immunohistochemistry for tumor blood vessel density, TIL subsets, and clinical outcomes. These cells were geographically divided into perivascular and intratumoral TILs. Associations were examined between these TILs, CD34+ tumor blood vessels, and clinical outcomes. To determine key changes in TIL subsets, microarray data of 15-paired tumors from patients who failed antiangiogenic therapy- bevacizumab, and 16-paired tumors from chemo-naïve recurrent GBM were also evaluated and compared.ResultsUpon recurrence in primary gliomas, similar kinetic changes were found between tumor blood vessels and each TIL subset in all groups, but only CD4+ including Foxp3+ TILs, positively correlated with the density of tumor blood vessels. CD4 was the predominant T cell population based on the expression of gene-transcripts in primary GBMs, and increased activated CD4+ T cells were revealed in Bevacizumab-resistant recurrent tumors (not in chemo-naïve recurrent tumors. Among these TILs, 2/3 of them were found in the perivascular niche; Foxp3+ T cells in these niches not only correlated with the tumor vessels but were also an independent predictor of shortened recurrence-free survival (RFS (HR = 4.199, 95% CI 1.522–11.584, p = 0.006.ConclusionThe minimal intratumoral T cell infiltration and low detection of CD8 transcripts expression in primary GBMs can potentially limit antitumor response. CD4+ and perivascular Foxp3

  3. Pericytes limit tumor cell metastasis

    DEFF Research Database (Denmark)

    Xian, Xiaojie; Håkansson, Joakim; Ståhlberg, Anders

    2006-01-01

    Previously we observed that neural cell adhesion molecule (NCAM) deficiency in beta tumor cells facilitates metastasis into distant organs and local lymph nodes. Here, we show that NCAM-deficient beta cell tumors grew leaky blood vessels with perturbed pericyte-endothelial cell-cell interactions...... the microvessel wall. To directly address whether pericyte dysfunction increases the metastatic potential of solid tumors, we studied beta cell tumorigenesis in primary pericyte-deficient Pdgfb(ret/ret) mice. This resulted in beta tumor cell metastases in distant organs and local lymph nodes, demonstrating a role...... and deficient perivascular deposition of ECM components. Conversely, tumor cell expression of NCAM in a fibrosarcoma model (T241) improved pericyte recruitment and increased perivascular deposition of ECM molecules. Together, these findings suggest that NCAM may limit tumor cell metastasis by stabilizing...

  4. Tumor Mesenchymal Stem-Like Cell as a Prognostic Marker in Primary Glioblastoma

    Directory of Open Access Journals (Sweden)

    Seon-Jin Yoon

    2016-01-01

    Full Text Available The isolation from brain tumors of tumor mesenchymal stem-like cells (tMSLCs suggests that these cells play a role in creating a microenvironment for tumor initiation and progression. The clinical characteristics of patients with primary glioblastoma (pGBM positive for tMSLCs have not been determined. This study analyzed samples from 82 patients with pGBM who had undergone tumor removal, pathological diagnosis, and isolation of tMSLC from April 2009 to October 2014. Survival, extent of resection, molecular markers, and tMSLC culture results were statistically evaluated. Median overall survival was 18.6 months, 15.0 months in tMSLC-positive patients and 29.5 months in tMSLC-negative patients (P=0.014. Multivariate cox regression model showed isolation of tMSLC (OR = 2.5, 95% CI = 1.1~5.6, P=0.021 showed poor outcome while larger extent of resection (OR = 0.5, 95% CI = 0.2~0.8, P=0.011 has association with better outcome. The presence of tMSLCs isolated from the specimen of pGBM is associated with the survival of patient.

  5. Radiotherapy effect on the release of tumor micro-vesicles by glioblastoma cells

    International Nuclear Information System (INIS)

    Ding, Haixia

    2014-01-01

    Radiation therapy is a major therapeutic tool for glioblastoma (GBM). However, the post-radiation recurrence is almost inevitable, due to the emergence of a subpopulation of radioresistant cancer cells with greater proliferative, invasive, and pro-angiogenic capacities. The objective of this study was to investigate in vitro how irradiated cancer cells affect the function of untreated neighboring tumor cells and endothelial cells, focusing on signals exchange initiated by irradiation, such as soluble factors and tumor micro-vesicles (TMVs). Radiotherapy has slowed down the proliferation of GBM cells (T98G, U87) and induced mitotic death of 50-60%, without significant apoptosis. Through long-term monitoring of cell growth (xCELLigence) and wound-healing assay, we have confirmed that surviving GBM cells after irradiation release signals that can change the functions of endothelial cells HUVEC and non-irradiated tumor cells. In addition to the secretion of known soluble factors (VEGF, uPA), we were able to show using scanning electron microscopy and the Nanoparticle Tracking Analysis (NTA), the release of tumor micro-vesicles (TMVS), whose size was generally less than 500 nm. By NTA and flow cytometry, we have shown that the release of TMVs (exosome + 'shedding vesicles') can be significantly stimulated by irradiation in two lines, in a time-dependent manner. According to the proteomics analysis, soluble factors such as VEGF or IL-8, well known as pro-angiogenic factors, rather contribute to promote the survival or proliferation of HUVEC, while the released TMVs after irradiation, significantly altered the migration abilities of non-irradiated HUVEC and tumor cells. The pro-migratory properties of TMVs could thus contribute to glioblastoma recurrence after irradiation. (author) [fr

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

    Science.gov (United States)

    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.

  7. Saponin 1 Induces Apoptosis and Suppresses NF-κB-Mediated Survival Signaling in Glioblastoma Multiforme (GBM)

    Science.gov (United States)

    Tang, Chi; Li, Bo; Wang, Yuangang; Gao, Zhenhui; Luo, Peng; Yin, Anan; Wang, Xiaoyang; Cheng, Guang; Fei, Zhou

    2013-01-01

    Saponin 1 is a triterpeniod saponin extracted from Anemone taipaiensis, a traditional Chinese medicine against rheumatism and phlebitis. It has also been shown to exhibit significant anti-tumor activity against human leukemia (HL-60 cells) and human hepatocellular carcinoma (Hep-G2 cells). Herein we investigated the effect of saponin 1 in human glioblastoma multiforme (GBM) U251MG and U87MG cells. Saponin 1 induced significant growth inhibition in both glioblastoma cell lines, with a 50% inhibitory concentration at 24 h of 7.4 µg/ml in U251MG cells and 8.6 µg/ml in U87MG cells, respectively. Nuclear fluorescent staining and electron microscopy showed that saponin 1 caused characteristic apoptotic morphological changes in the GBM cell lines. Saponin 1-induced apoptosis was also verified by DNA ladder electrophoresis and flow cytometry. Additionally, immunocytochemistry and western blotting analyses revealed a time-dependent decrease in the expression and nuclear location of NF-κB following saponin 1 treatment. Western blotting data indicated a significant decreased expression of inhibitors of apoptosis (IAP) family members,(e.g., survivin and XIAP) by saponin 1. Moreover, saponin 1 caused a decrease in the Bcl-2/Bax ratio and initiated apoptosis by activating caspase-9 and caspase-3 in the GBM cell lines. These findings indicate that saponin 1 inhibits cell growth of GBM cells at least partially by inducing apoptosis and inhibiting survival signaling mediated by NF-κB. In addition, in vivo study also demonstrated an obvious inhibition of saponin 1 treatment on the tumor growth of U251MG and U87MG cells-produced xenograft tumors in nude mice. Given the minimal toxicities of saponin 1 in non-neoplastic astrocytes, our results suggest that saponin 1 exhibits significant in vitro and in vivo anti-tumor efficacy and merits further investigation as a potential therapeutic agent for GBM. PMID:24278406

  8. Saponin 1 induces apoptosis and suppresses NF-κB-mediated survival signaling in glioblastoma multiforme (GBM.

    Directory of Open Access Journals (Sweden)

    Juan Li

    Full Text Available Saponin 1 is a triterpeniod saponin extracted from Anemone taipaiensis, a traditional Chinese medicine against rheumatism and phlebitis. It has also been shown to exhibit significant anti-tumor activity against human leukemia (HL-60 cells and human hepatocellular carcinoma (Hep-G2 cells. Herein we investigated the effect of saponin 1 in human glioblastoma multiforme (GBM U251MG and U87MG cells. Saponin 1 induced significant growth inhibition in both glioblastoma cell lines, with a 50% inhibitory concentration at 24 h of 7.4 µg/ml in U251MG cells and 8.6 µg/ml in U87MG cells, respectively. Nuclear fluorescent staining and electron microscopy showed that saponin 1 caused characteristic apoptotic morphological changes in the GBM cell lines. Saponin 1-induced apoptosis was also verified by DNA ladder electrophoresis and flow cytometry. Additionally, immunocytochemistry and western blotting analyses revealed a time-dependent decrease in the expression and nuclear location of NF-κB following saponin 1 treatment. Western blotting data indicated a significant decreased expression of inhibitors of apoptosis (IAP family members,(e.g., survivin and XIAP by saponin 1. Moreover, saponin 1 caused a decrease in the Bcl-2/Bax ratio and initiated apoptosis by activating caspase-9 and caspase-3 in the GBM cell lines. These findings indicate that saponin 1 inhibits cell growth of GBM cells at least partially by inducing apoptosis and inhibiting survival signaling mediated by NF-κB. In addition, in vivo study also demonstrated an obvious inhibition of saponin 1 treatment on the tumor growth of U251MG and U87MG cells-produced xenograft tumors in nude mice. Given the minimal toxicities of saponin 1 in non-neoplastic astrocytes, our results suggest that saponin 1 exhibits significant in vitro and in vivo anti-tumor efficacy and merits further investigation as a potential therapeutic agent for GBM.

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

    NARCIS (Netherlands)

    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

    2010-01-01

    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

  10. PD-L1 expression by neurons nearby tumors indicates better prognosis in glioblastoma patients

    DEFF Research Database (Denmark)

    Liu, Yawei; Carlsson, Robert; Ambjørn, Malene

    2013-01-01

    Glioblastoma multiforme (GBM) is the most aggressive form of brain tumor. In general, tumor growth requires disruption of the tissue microenvironment, yet how this affects glioma progression is unknown. We studied program death-ligand (PD-L)1 in neurons and gliomas in tumors from GBM patients...... and associated the findings with clinical outcome. Remarkably, we found that upregulation of PD-L1 by neurons in tumor-adjacent brain tissue (TABT) associated positively with GBM patient survival, whereas lack of neuronal PD-L1 expression was associated with high PD-L1 in tumors and unfavorable prognosis...... in GBM patients, better survival in wild-type mice was associated with high neuronal PD-L1 in TABT and downregulation of PD-L1 in tumors, which was defective in Ifnb-/- mice. Our data indicated that neuronal PD-L1 signaling in brain cells was important for GBM patient survival. Reciprocal PD-L1...

  11. Molecular analysis of ex-vivo CD133+ GBM cells revealed a common invasive and angiogenic profile but different proliferative signatures among high grade gliomas

    Directory of Open Access Journals (Sweden)

    Garcia Juan L

    2010-08-01

    Full Text Available Abstract Background Gliomas are the most common type of primary brain tumours, and in this group glioblastomas (GBMs are the higher-grade gliomas with fast progression and unfortunate prognosis. Two major aspects of glioma biology that contributes to its awful prognosis are the formation of new blood vessels through the process of angiogenesis and the invasion of glioma cells. Despite of advances, two-year survival for GBM patients with optimal therapy is less than 30%. Even in those patients with low-grade gliomas, that imply a moderately good prognosis, treatment is almost never curative. Recent studies have demonstrated the existence of a small fraction of glioma cells with characteristics of neural stem cells which are able to grow in vitro forming neurospheres and that can be isolated in vivo using surface markers such as CD133. The aim of this study was to define the molecular signature of GBM cells expressing CD133 in comparison with non expressing CD133 cells. This molecular classification could lead to the finding of new potential therapeutic targets for the rationale treatment of high grade GBM. Methods Eight fresh, primary and non cultured GBMs were used in order to study the gene expression signatures from its CD133 positive and negative populations isolated by FACS-sorting. Dataset was generated with Affymetrix U133 Plus 2 arrays and analysed using the software of the Affymetrix Expression Console. In addition, genomic analysis of these tumours was carried out by CGH arrays, FISH studies and MLPA; Results Gene expression analysis of CD133+ vs. CD133- cell population from each tumour showed that CD133+ cells presented common characteristics in all glioblastoma samples (up-regulation of genes involved in angiogenesis, permeability and down-regulation of genes implicated in cell assembly, neural cell organization and neurological disorders. Furthermore, unsupervised clustering of gene expression led us to distinguish between two groups

  12. Precursor States of Brain Tumor Initiating Cell Lines Are Predictive of Survival in Xenografts and Associated with Glioblastoma Subtypes

    Directory of Open Access Journals (Sweden)

    Carlo Cusulin

    2015-07-01

    Full Text Available In glioblastoma multiforme (GBM, brain-tumor-initiating cells (BTICs with cancer stem cell characteristics have been identified and proposed as primordial cells responsible for disease initiation, recurrence, and therapeutic resistance. However, the extent to which individual, patient-derived BTIC lines reflect the heterogeneity of GBM remains poorly understood. Here we applied a stem cell biology approach and compared self-renewal, marker expression, label retention, and asymmetric cell division in 20 BTIC lines. Through cluster analysis, we identified two subgroups of BTIC lines with distinct precursor states, stem- or progenitor-like, predictive of survival after xenograft. Moreover, stem and progenitor transcriptomic signatures were identified, which showed a strong association with the proneural and mesenchymal subtypes, respectively, in the TCGA cohort. This study proposes a different framework for the study and use of BTIC lines and provides precursor biology insights into GBM.

  13. Sertoli-Leydig cell tumor

    Science.gov (United States)

    Sertoli-Leydig cell tumor (SLCT) is a rare cancer of the ovaries. The cancer cells produce and release a male sex hormone ... lead to cancer. SLCT starts in the female ovaries. The cancer cells release a male sex hormone. As a ...

  14. The Effect of Sodium Valproate on the Glioblastoma U87 Cell Line Tumor Development on the Chicken Embryo Chorioallantoic Membrane and on EZH2 and p53 Expression

    Directory of Open Access Journals (Sweden)

    Dovilė Kavaliauskaitė

    2017-01-01

    Full Text Available Literature data support evidences that glioblastoma (GBM patients experience prolonged survival due to sodium valproate (NaVP treatment. The study assessed the human GBM cell U87 xenograft studied in the chicken embryo chorioallantoic membrane (CAM model evaluating NaVP effect on tumor. Three groups of tumors (each n = 10 were studied: nontreated, treated with 4 mM, and treated with 8 mM of NaVP. The majority of tumors without NaVP treatment during tumor growth destroyed the chorionic epithelium, invaded the mesenchyme, and induced angiogenesis. Incidence of tumor formation on CAM without invasion into the mesenchyme was higher when U87 cells were treated with NaVP; the effect significantly increased with NaVP concentration. Treatment with 8 mM of NaVP did not show clear dynamics of tumor growth during 5 days; at the same time, the angiogenesis failed. With a strong staining of EZH2, p53 in tumors without NaVP treatment was found, and NaVP significantly decreased the expression of EZH2- and p53-positive cells; the effect was significantly higher at its 8 mM concentration. NaVP has a function in blocking the growth, invasion, and angiogenesis of tumor in the CAM model; tumor growth interferes with EZH2 and p53 molecular pathways, supporting the NaVP potential in GBM therapy.

  15. The Clinical and Immunologic Features of Patients With Combined Anti-GBM Disease and Castleman Disease.

    Science.gov (United States)

    Gu, Qiu-Hua; Jia, Xiao-Yu; Hu, Shui-Yi; Wang, Su-Xia; Zou, Wan-Zhong; Cui, Zhao; Zhao, Ming-Hui

    2018-06-01

    Patients with both anti-glomerular basement membrane (anti-GBM) disease and Castleman disease have been rarely reported. In this study, we report 3 patients with this combination. They had immunologic features similar to patients with classic anti-GBM disease. Sera from the 3 patients recognized the noncollagenous (NC) domain of the α3 chain of type IV collagen (α3(IV)NC1) and its 2 major epitopes, EA and EB. All 4 immunogloblin G (IgG) subclasses against α3(IV)NC1 were detectable, with predominance of IgG1. In one patient with lymph node biopsy specimens available, sporadic plasma cells producing α3(IV)NC1-IgG were found, suggesting a causal relationship between the 2 diseases. One patient, who achieved remission with antibody clearance and normalization of serum creatinine and interleukin 6 concentrations after plasma exchange and 3 cycles of chemotherapy, experienced recurrence of anti-GBM antibodies and an increase in interleukin 6 concentration after chemotherapy discontinuation because of adverse effects, but both returned to normal after another cycle of chemotherapy. This clinical course and the pathologic findings support the hypothesis that the Castleman disease-associated tumor cells are the source of the anti-GBM autoantibodies. Copyright © 2018 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

  16. Granular Cell Tumor

    African Journals Online (AJOL)

    1). Her packed cell volume was 40%, she was system, gastro-intestinal tract, brain, heart, and negative to human immunodeficiency virus. 2 female reproductive . ... histocytes and neurons at various times. They granules. The granules are probably of lysosmal were consequently termed granular cell origin and contain ...

  17. Large Intergenic Non-coding RNA-RoR Inhibits Aerobic Glycolysis of Glioblastoma Cells via Akt Pathway

    Science.gov (United States)

    Li, Yong; He, Zhi-Cheng; Liu, Qing; Zhou, Kai; Shi, Yu; Yao, Xiao-Hong; Zhang, Xia; Kung, Hsiang-Fu; Ping, Yi-Fang; Bian, Xiu-Wu

    2018-01-01

    Reprogramming energy metabolism is a hallmark of malignant tumors, including glioblastoma (GBM). Aerobic glycolysis is often utilized by tumor cells to maintain survival and proliferation. However, the underlying mechanisms of aerobic glycolysis in GBM remain elusive. Herein, we demonstrated that large intergenic non-coding RNA-RoR (LincRNA-RoR) functioned as a critical suppressor to inhibit the aerobic glycolysis and viability of GBM cells. We found that LincRNA-RoR was markedly reduced in GBM tissues compared with adjacent non-tumor tissues from 10 cases of GBM patients. Consistently, LincRNA-RoR expression in GBM cells was significantly lower than that in normal glial cells. The aerobic glycolysis of GBM cells, as determined by the measurement of glucose uptake and lactate production, was impaired by LincRNA-RoR overexpression. Mechanistically, LincRNA-RoR inhibited the expression of Rictor, the key component of mTORC2 (mammalian target of rapamycin complex 2), to suppress the activity of Akt pathway and impair the expression of glycolytic effectors, including Glut1, HK2, PKM2 and LDHA. Finally, enforced expression of LincRNA-RoR reduced the proliferation of GBM cells in vitro, restrained tumor growth in vivo, and repressed the expression of glycolytic molecules in GBM xenografts. Collectively, our results underscore LincRNA-RoR as a new suppressor of GBM aerobic glycolysis with therapeutic potential. PMID:29581766

  18. A Chimeric Antibody against ACKR3/CXCR7 in Combination with TMZ Activates Immune Responses and Extends Survival in Mouse GBM Models.

    Science.gov (United States)

    Salazar, Nicole; Carlson, Jeffrey C; Huang, Kexin; Zheng, Yayue; Oderup, Cecilia; Gross, Julia; Jang, Andrew D; Burke, Thomas M; Lewén, Susanna; Scholz, Alexander; Huang, Serina; Nease, Leona; Kosek, Jon; Mittelbronn, Michel; Butcher, Eugene C; Tu, Hua; Zabel, Brian A

    2018-05-02

    Glioblastoma (GBM) is the least treatable type of brain tumor, afflicting over 15,000 people per year in the United States. Patients have a median survival of 16 months, and over 95% die within 5 years. The chemokine receptor ACKR3 is selectively expressed on both GBM cells and tumor-associated blood vessels. High tumor expression of ACKR3 correlates with poor prognosis and potential treatment resistance, making it an attractive therapeutic target. We engineered a single chain FV-human FC-immunoglobulin G1 (IgG 1 ) antibody, X7Ab, to target ACKR3 in human and mouse GBM cells. We used hydrodynamic gene transfer to overexpress the antibody, with efficacy in vivo. X7Ab kills GBM tumor cells and ACKR3-expressing vascular endothelial cells by engaging the cytotoxic activity of natural killer (NK) cells and complement and the phagocytic activity of macrophages. Combining X7Ab with TMZ allows the TMZ dosage to be lowered, without compromising therapeutic efficacy. Mice treated with X7Ab and in combination with TMZ showed significant tumor reduction by MRI and longer survival overall. Brain-tumor-infiltrating leukocyte analysis revealed that X7Ab enhances the activation of M1 macrophages to support anti-tumor immune response in vivo. Targeting ACKR3 with immunotherapeutic monoclonal antibodies (mAbs) in combination with standard of care therapies may prove effective in treating GBM. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

  19. Osthole Suppresses the Migratory Ability of Human Glioblastoma Multiforme Cells via Inhibition of Focal Adhesion Kinase-Mediated Matrix Metalloproteinase-13 Expression

    Directory of Open Access Journals (Sweden)

    Cheng-Fang Tsai

    2014-03-01

    Full Text Available Glioblastoma multiforme (GBM is the most common type of primary and malignant tumor occurring in the adult central nervous system. GBM often invades surrounding regions of the brain during its early stages, making successful treatment difficult. Osthole, an active constituent isolated from the dried C. monnieri fruit, has been shown to suppress tumor migration and invasion. However, the effects of osthole in human GBM are largely unknown. Focal adhesion kinase (FAK is important for the metastasis of cancer cells. Results from this study show that osthole can not only induce cell death but also inhibit phosphorylation of FAK in human GBM cells. Results from this study show that incubating GBM cells with osthole reduces matrix metalloproteinase (MMP-13 expression and cell motility, as assessed by cell transwell and wound healing assays. This study also provides evidence supporting the potential of osthole in reducing FAK activation, MMP-13 expression, and cell motility in human GBM cells.

  20. ZFHX4 interacts with the NuRD core member CHD4 and regulates the glioblastoma tumor initiating cell state

    Science.gov (United States)

    Chudnovsky, Yakov; Kim, Dohoon; Zheng, Siyuan; Whyte, Warren A.; Bansal, Mukesh; Bray, Mark-Anthony; Gopal, Shuba; Theisen, Matthew A.; Bilodeau, Steve; Thiru, Prathapan; Muffat, Julien; Yilmaz, Omer H.; Mitalipova, Maya; Woolard, Kevin; Lee, Jeongwu; Nishimura, Riko; Sakata, Nobuo; Fine, Howard A.; Carpenter, Anne E.; Silver, Serena J.; Verhaak, Roel G. W.; Califano, Andrea; Young, Richard A.; Ligon, Keith L.; Mellinghoff, Ingo K.; Root, David E.; Sabatini, David M.; Hahn, William C.; Chheda, Milan G.

    2014-01-01

    Summary Glioblastomas (GBM) harbor subpopulations of therapy-resistant tumor initiating cells (TICs) that are self-renewing and multipotent. To understand the regulation of the TIC state, we performed an image-based screen for genes regulating GBM TIC maintenance and identified ZFHX4, a 397-kDa transcription factor. ZFHX4 is required to maintain TIC-associated and normal human neural precursor cell phenotypes in vitro, suggesting that ZFHX4 regulates differentiation, and its suppression increases glioma-free survival in intracranial xenografts. ZFHX4 interacts with CHD4, a core member of the NuRD (nucleosome remodeling and deacetylase) complex. ZFHX4 and CHD4 bind to overlapping sets of genomic loci and control similar gene expression programs. Using expression data derived from GBM patients, we found that ZFHX4 significantly affects CHD4-mediated gene expression perturbations, which defines ZFHX4 as a master regulator of CHD4. These observations define ZFHX4 as a regulatory factor that links the chromatin remodeling NuRD complex and the GBM TIC state. PMID:24440720

  1. The Methanol Extract of Angelica sinensis Induces Cell Apoptosis and Suppresses Tumor Growth in Human Malignant Brain Tumors

    Directory of Open Access Journals (Sweden)

    Yu-Ling Lin

    2013-01-01

    Full Text Available Glioblastoma multiforme (GBM is a highly vascularized and invasive neoplasm. The methanol extract of Angelica sinensis (AS-M is commonly used in traditional Chinese medicine to treat several diseases, such as gastric mucosal damage, hepatic injury, menopausal symptoms, and chronic glomerulonephritis. AS-M also displays potency in suppressing the growth of malignant brain tumor cells. The growth suppression of malignant brain tumor cells by AS-M results from cell cycle arrest and apoptosis. AS-M upregulates expression of cyclin kinase inhibitors, including p16, to decrease the phosphorylation of Rb proteins, resulting in arrest at the G0-G1 phase. The expression of the p53 protein is increased by AS-M and correlates with activation of apoptosis-associated proteins. Therefore, the apoptosis of cancer cells induced by AS-M may be triggered through the p53 pathway. In in vivo studies, AS-M not only suppresses the growth of human malignant brain tumors but also significantly prolongs patient survival. In addition, AS-M has potent anticancer effects involving cell cycle arrest, apoptosis, and antiangiogenesis. The in vitro and in vivo anticancer effects of AS-M indicate that this extract warrants further investigation and potential development as a new antibrain tumor agent, providing new hope for the chemotherapy of malignant brain cancer.

  2. The Human Glioblastoma Cell Culture Resource: Validated Cell Models Representing All Molecular Subtypes

    Directory of Open Access Journals (Sweden)

    Yuan Xie

    2015-10-01

    Full Text Available Glioblastoma (GBM is the most frequent and malignant form of primary brain tumor. GBM is essentially incurable and its resistance to therapy is attributed to a subpopulation of cells called glioma stem cells (GSCs. To meet the present shortage of relevant GBM cell (GC lines we developed a library of annotated and validated cell lines derived from surgical samples of GBM patients, maintained under conditions to preserve GSC characteristics. This collection, which we call the Human Glioblastoma Cell Culture (HGCC resource, consists of a biobank of 48 GC lines and an associated database containing high-resolution molecular data. We demonstrate that the HGCC lines are tumorigenic, harbor genomic lesions characteristic of GBMs, and represent all four transcriptional subtypes. The HGCC panel provides an open resource for in vitro and in vivo modeling of a large part of GBM diversity useful to both basic and translational GBM research.

  3. Tumor cell proliferation kinetics and tumor growth rate

    Energy Technology Data Exchange (ETDEWEB)

    Tubiana, M

    1989-01-01

    The present knowledge on the growth rate and the proliferation kinetics of human tumor is based on the measurement of the tumor doubling times (DT) in several hundred patients and on the determination of the proportion of proliferating cells with radioactive thymidine or by flow cytometry in large numbers of patients. The results show that the DT of human tumor varies widely, from less than one week to over one year with a median value of approximately 2 months. The DTs are significantly correlated with the histological type. They depend upon (1) the duration of the cell cycle whose mean duration is 2 days with small variations from tumor to tumor, (2) the proportion of proliferating cells and consequently the cell birth rate which varies widely among tumors and which is significantly correlated to the DT, (3) the cell loss factors which also vary widely and which are the greatest when proliferation is most intensive. These studies have several clinical implications: (a) they have further increased our understanding of the natural history of human tumor, (b) they have therapeutic implications since tumor responsiveness and curability by radiation and drugs are strongly influenced by the cell kinetic parameters of the tumor, (c) the proportion of proliferating cells is of great prognostic value in several types of human cancers. The investigation of the molecular defects, which are correlated with the perturbation of control of cell proliferation, should lead to significant fundamental and therapeutic advances. (orig.).

  4. Multiparametric classification links tumor microenvironments with tumor cell phenotype.

    Directory of Open Access Journals (Sweden)

    Bojana Gligorijevic

    2014-11-01

    Full Text Available While it has been established that a number of microenvironment components can affect the likelihood of metastasis, the link between microenvironment and tumor cell phenotypes is poorly understood. Here we have examined microenvironment control over two different tumor cell motility phenotypes required for metastasis. By high-resolution multiphoton microscopy of mammary carcinoma in mice, we detected two phenotypes of motile tumor cells, different in locomotion speed. Only slower tumor cells exhibited protrusions with molecular, morphological, and functional characteristics associated with invadopodia. Each region in the primary tumor exhibited either fast- or slow-locomotion. To understand how the tumor microenvironment controls invadopodium formation and tumor cell locomotion, we systematically analyzed components of the microenvironment previously associated with cell invasion and migration. No single microenvironmental property was able to predict the locations of tumor cell phenotypes in the tumor if used in isolation or combined linearly. To solve this, we utilized the support vector machine (SVM algorithm to classify phenotypes in a nonlinear fashion. This approach identified conditions that promoted either motility phenotype. We then demonstrated that varying one of the conditions may change tumor cell behavior only in a context-dependent manner. In addition, to establish the link between phenotypes and cell fates, we photoconverted and monitored the fate of tumor cells in different microenvironments, finding that only tumor cells in the invadopodium-rich microenvironments degraded extracellular matrix (ECM and disseminated. The number of invadopodia positively correlated with degradation, while the inhibiting metalloproteases eliminated degradation and lung metastasis, consistent with a direct link among invadopodia, ECM degradation, and metastasis. We have detected and characterized two phenotypes of motile tumor cells in vivo, which

  5. Patient-Derived Antibody Targets Tumor Cells

    Science.gov (United States)

    An NCI Cancer Currents blog on an antibody derived from patients that killed tumor cells in cell lines of several cancer types and slowed tumor growth in mouse models of brain and lung cancer without evidence of side effects.

  6. EG-07CELL CYCLE SIGNATURE AND TUMOR PHYLOGENY ARE ENCODED IN THE EVOLUTIONARY DYNAMICS OF DNA METHYLATION IN GLIOMA

    Science.gov (United States)

    Mazor, Tali; Pankov, Aleksandr; Johnson, Brett E.; Hong, Chibo; Bell, Robert J.A.; Smirnov, Ivan V.; Reis, Gerald F.; Phillips, Joanna J.; Barnes, Michael; Bollen, Andrew W.; Taylor, Barry S.; Molinaro, Annette M.; Olshen, Adam B.; Song, Jun S.; Berger, Mitchel S.; Chang, Susan M.; Costello, Joseph F.

    2014-01-01

    The clonal evolution of tumor cell populations can be reconstructed from patterns of genetic alterations. In contrast, tumor epigenetic states, including DNA methylation, are reversible and sensitive to the tumor microenvironment, presumably precluding the use of epigenetics to discover tumor phylogeny. Here we examined the spatial and temporal dynamics of DNA methylation in a clinically and genetically characterized cohort of IDH1-mutant low-grade gliomas and their patient-matched recurrences. WHO grade II gliomas are diffuse, infiltrative tumors that frequently recur and may undergo malignant progression to a higher grade with a worse prognosis. The extent to which epigenetic alterations contribute to the evolution of low-grade gliomas, including malignant progression, is unknown. While all gliomas in the cohort exhibited the hypermethylation signature associated with IDH1 mutation, low-grade gliomas that underwent malignant progression to high-grade glioblastoma (GBM) had a unique signature of DNA hypomethylation enriched for active enhancers, as well as sites of age-related hypermethylation in the brain. Genes with promoter hypomethylation and concordant transcriptional upregulation during evolution to GBM were enriched in cell cycle function, evolving in concert with genetic alterations that deregulate the G1/S cell cycle checkpoint. Despite the plasticity of tumor epigenetic states, phyloepigenetic trees robustly recapitulated phylogenetic trees derived from somatic mutations in the same patients. These findings highlight widespread co-dependency of genetic and epigenetic events throughout the clonal evolution of initial and recurrent glioma.

  7. Peripheral dentinogenic ghost cell tumor

    Directory of Open Access Journals (Sweden)

    Sushant S Kamat

    2013-01-01

    Full Text Available Dentinogenic ghost cell tumors (DGCT are uncommon lesions mainly with rare peripheral types. This report presents a case of peripheral DGCT on the left side of the mandibular alveolar ridge of a heavy smoker, a 68-year-old man, with main presenting feature as a mild pain. Submandibular lymphadenopathy and radiological "saucerization" were evident. Differential diagnosis included fibroma, neurofibroma, peripheral ameloblastoma, peripheral odontogenic fibroma, and peripheral giant cell granuloma. Histologically, ameloblastoma-like epithelial elements were seen in association with grouped ghost cells. Proliferating polyhedral cells and stellate reticulum-like cells with various densities were spread over a wide range of the field. The lesion was curetted and after 2 years of follow up, it did not recur.

  8. Human neutrophils facilitate tumor cell transendothelial migration.

    LENUS (Irish Health Repository)

    Wu, Q D

    2012-02-03

    Tumor cell extravasation plays a key role in tumor metastasis. However, the precise mechanisms by which tumor cells migrate through normal vascular endothelium remain unclear. In this study, using an in vitro transendothelial migration model, we show that human polymorphonuclear neutrophils (PMN) assist the human breast tumor cell line MDA-MB-231 to cross the endothelial barrier. We found that tumor-conditioned medium (TCM) downregulated PMN cytocidal function, delayed PMN apoptosis, and concomitantly upregulated PMN adhesion molecule expression. These PMN treated with TCM attached to tumor cells and facilitated tumor cell migration through different endothelial monolayers. In contrast, MDA-MB-231 cells alone did not transmigrate. FACScan analysis revealed that these tumor cells expressed high levels of intercellular adhesion molecule-1 (ICAM-1) but did not express CD11a, CD11b, or CD18. Blockage of CD11b and CD18 on PMN and of ICAM-1 on MDA-MB-231 cells significantly attenuated TCM-treated, PMN-mediated tumor cell migration. These tumor cells still possessed the ability to proliferate after PMN-assisted transmigration. These results indicate that TCM-treated PMN may serve as a carrier to assist tumor cell transendothelial migration and suggest that tumor cells can exploit PMN and alter their function to facilitate their extravasation.

  9. Tumor stem cells: A new approach for tumor therapy (Review)

    Science.gov (United States)

    MENG, MIN; ZHAO, XIN-HAN; NING, QIAN; HOU, LEI; XIN, GUO-HONG; LIU, LI-FENG

    2012-01-01

    Recent studies have demonstrated the existence of a minority of tumor cells possessing the stem cell properties of self-renewal and differentiation in leukemia and several solid tumors. However, these cells do not possess the normal regulatory mechanisms of stem cells. Following transplantation, they are capable of initiating tumorigenesis and are therefore known as ‘tumor stem cells’. Cellular origin analysis of tumor stem cells has resulted in three hypotheses: Embryonal rest hypothesis, anaplasia and maturation arrest. Several signaling pathways which are involved in carcinogenesis, including Wnt/β-catenin, Notch and Oct-4 signaling pathways are crucial in normal stem cell self-renewal decisions, suggesting that breakdown in the regulation of self-renewal may be a key event in the development of tumors. Thus, tumors can be regarded as an abnormal organ in which stem cells have escaped from the normal constraints on self-renewal, thus, leading to abnormally differentiated tumor cells that lose the ability to form tumors. This new model for maligancies has significance for clinical research and treatment. PMID:22844351

  10. Metformin inhibits TGF-β1-induced epithelial-to-mesenchymal transition-like process and stem-like properties in GBM via AKT/mTOR/ZEB1 pathway.

    Science.gov (United States)

    Song, Yang; Chen, Yong; Li, Yunqian; Lyu, Xiaoyan; Cui, Jiayue; Cheng, Ye; Zhao, Liyan; Zhao, Gang

    2018-01-23

    Glioblastoma (GBM) is the most frequent and aggressive brain tumor in adults. In spite of advances in diagnosis and therapy, the prognosis is still relatively poor. The invasive property of GBM is the major cause of death in patients. Epithelial-to-mesenchymal transition-like process (EMT-like process) is considered to play an important role in the invasive property. Metformin has been reported as a regulator of EMT-like process. In this study, we confirmed that metformin inhibited TGF-β1-induced EMT-like process and EMT-associated migration and invasion in LN18 and U87 GBM cells. Our results also showed that metformin significantly suppressed self-renewal capacity of glioblastoma stem cells (GSCs), and expression of stem cell markers Bmi1, Sox2 and Musashi1, indicating that metformin can inhibit cancer stem-like properties of GBM cells. We further clarified that metformin specifically inhibited TGF-β1 activated AKT, the downstream molecular mTOR and the leading transcription factor ZEB1. Taken together, our data demonstrate that metformin inhibits TGF-β1-induced EMT-like process and cancer stem-like properties in GBM cells via AKT/mTOR/ZEB1 pathway and provide evidence of metformin for further clinical investigation targeted GBM.

  11. Glioblastoma-Initiating Cells: Relationship with Neural Stem Cells and the Micro-Environment

    OpenAIRE

    Goffart, Nicolas; KROONEN, Jérôme

    2013-01-01

    Glioblastoma multiforme (GBM, WHO grade IV) is the most common and lethal subtype of primary brain tumor with a median overall survival of 15 months from the time of diagnosis. The presence in GBM of a cancer population displaying neural stem cell (NSC) properties as well as tumor-initiating abilities and resistance to current therapies suggests that these glioblastoma-initiating cells (GICs) play a central role in tumor development and are closely related to NSCs. However, it is nowadays sti...

  12. Imp2 regulates GBM progression by activating IGF2/PI3K/Akt pathway.

    Science.gov (United States)

    Mu, Qingchun; Wang, Lijun; Yu, Fengbo; Gao, Haijun; Lei, Ting; Li, Peiwen; Liu, Pengfei; Zheng, Xu; Hu, Xitong; Chen, Yong; Jiang, Zhenfeng; Sayari, Arash J; Shen, Jia; Huang, Haiyan

    2015-01-01

    Glioblastomas multiforme (GBM) are the most frequently occurring malignant brain cancers. Treatment for GBM consists of surgical resection and subsequent adjuvant radiation therapy and chemotherapy. Despite this, GBM patient survival is limited to 12-15 months, and researchers are continually trying to develop improved therapy options. Insulin-like growth factor 2 mRNA-binding protein 2 (Imp2) is known to be upregulated in many cancers and is known to regulate the signaling activity of insulin-like growth factor 2 (IGF2). However, relatively little is known about its role in malignant development of GBM. In this study, we first found Imp2 is upregulated in GBM tissues by using clinical samples and public database search. Studies with loss and gain of Imp2 expression in in vitro GBM cell culture system demonstrated the role of Imp2 in promoting GBM cell proliferation, migration, invasion and epithelial-to-mesenchymal transition (EMT). Additionally, our results show that Imp2 regulates the activity of IGF2, which further activates PI3K/Akt signaling, thereby to promote GBM malignancy. Inhibition of Imp2 was also found to sensitize GBM to temozolomide treatment. These observations add to the current knowledge of GBM biology, and may prove useful in development of more effective GBM therapy.

  13. Imaging of human glioblastoma cells and their interactions with mesenchymal stem cells in the zebrafish (Danio rerio) embryonic brain

    International Nuclear Information System (INIS)

    Vittori, Milos; Breznik, Barbara; Gredar, Tajda; Hrovat, Katja; Bizjak Mali, Lilijana; Lah, Tamara T

    2016-01-01

    An attractive approach in the study of human cancers is the use of transparent zebrafish (Danio rerio) embryos, which enable the visualization of cancer progression in a living animal. We implanted mixtures of fluorescently labeled glioblastoma (GBM) cells and bonemarrow-derived mesenchymal stem cells (MSCs) into zebrafish embryos to study the cellular pathways of their invasion and the interactions between these cells in vivo. By developing and applying a carbocyanine-dye-compatible clearing protocol for observation of cells in deep tissues, we showed that U87 and U373 GBM cells rapidly aggregated into tumor masses in the ventricles and midbrain hemispheres of the zebrafish embryo brain, and invaded the central nervous system, often using the ventricular system and the central canal of the spinal cord. However, the GBM cells did not leave the central nervous system. With co-injection of differentially labeled cultured GBM cells and MSCs, the implanted cells formed mixed tumor masses in the brain. We observed tight associations between GBM cells and MSCs, and possible cell-fusion events. GBM cells and MSCs used similar invasion routes in the central nervous system. This simple model can be used to study the molecular pathways of cellular processes in GBM cell invasion, and their interactions with various types of stromal cells in double or triple cell co-cultures, to design anti-GBM cell therapies that use MSCs as vectors

  14. Experimental rat lung tumor model with intrabronchial tumor cell implantation.

    Science.gov (United States)

    Gomes Neto, Antero; Simão, Antônio Felipe Leite; Miranda, Samuel de Paula; Mourão, Lívia Talita Cajaseiras; Bezerra, Nilfácio Prado; Almeida, Paulo Roberto Carvalho de; Ribeiro, Ronaldo de Albuquerque

    2008-01-01

    The objective of this study was to develop a rat lung tumor model for anticancer drug testing. Sixty-two female Wistar rats weighing 208 +/- 20 g were anesthetized intraperitoneally with 2.5% tribromoethanol (1 ml/100 g live weight), tracheotomized and intubated with an ultrafine catheter for inoculation with Walker's tumor cells. In the first step of the experiment, a technique was established for intrabronchial implantation of 10(5) to 5 x 10(5) tumor cells, and the tumor take rate was determined. The second stage consisted of determining tumor volume, correlating findings from high-resolution computed tomography (HRCT) with findings from necropsia and determining time of survival. The tumor take rate was 94.7% for implants with 4 x 10(5) tumor cells, HRCT and necropsia findings matched closely (r=0.953; p<0.0001), the median time of survival was 11 days, and surgical mortality was 4.8%. The present rat lung tumor model was shown to be feasible: the take rate was high, surgical mortality was negligible and the procedure was simple to perform and easily reproduced. HRCT was found to be a highly accurate tool for tumor diagnosis, localization and measurement and may be recommended for monitoring tumor growth in this model.

  15. Determinates of tumor response to radiation: Tumor cells, tumor stroma and permanent local control

    International Nuclear Information System (INIS)

    Li, Wende; Huang, Peigen; Chen, David J.; Gerweck, Leo E.

    2014-01-01

    Background and purpose: The causes of tumor response variation to radiation remain obscure, thus hampering the development of predictive assays and strategies to decrease resistance. The present study evaluates the impact of host tumor stromal elements and the in vivo environment on tumor cell kill, and relationship between tumor cell radiosensitivity and the tumor control dose. Material and methods: Five endpoints were evaluated and compared in a radiosensitive DNA double-strand break repair-defective (DNA-PKcs −/− ) tumor line, and its DNA-PKcs repair competent transfected counterpart. In vitro colony formation assays were performed on in vitro cultured cells, on cells obtained directly from tumors, and on cells irradiated in situ. Permanent local control was assessed by the TCD 50 assay. Vascular effects were evaluated by functional vascular density assays. Results: The fraction of repair competent and repair deficient tumor cells surviving radiation did not substantially differ whether irradiated in vitro, i.e., in the absence of host stromal elements and factors, from the fraction of cells killed following in vivo irradiation. Additionally, the altered tumor cell sensitivity resulted in a proportional change in the dose required to achieve permanent local control. The estimated number of tumor cells per tumor, their cloning efficiency and radiosensitivity, all assessed by in vitro assays, were used to predict successfully, the measured tumor control doses. Conclusion: The number of clonogens per tumor and their radiosensitivity govern the permanent local control dose

  16. Glioblastoma with oligodendroglioma component (GBM-O): molecular genetic and clinical characteristics.

    Science.gov (United States)

    Appin, Christina L; Gao, Jingjing; Chisolm, Candace; Torian, Mike; Alexis, Dianne; Vincentelli, Cristina; Schniederjan, Matthew J; Hadjipanayis, Costas; Olson, Jeffrey J; Hunter, Stephen; Hao, Chunhai; Brat, Daniel J

    2013-07-01

    Glioblastoma (GBM) is an aggressive primary brain tumor with an average survival of approximately 1 year. A recently recognized subtype, glioblastoma with oligodendroglioma component (GBM-O), was designated by the World Health Organization (WHO) in 2007. We investigated GBM-Os for their clinical and molecular characteristics as compared to other forms of GBM. Tissue samples were used to determine EGFR, PTEN, and 1p and 19q status by fluorescence in situ hybridization (FISH); p53 and mutant IDH1 protein expression by immunohistochemistry (IHC); and MGMT promoter status by methylation-specific polymerase chain reaction (PCR). GBM-Os accounted for 11.9% of all GBMs. GBM-Os arose in younger patients compared to other forms of GBMs (50.7 years vs. 58.7 years, respectively), were more frequently secondary neoplasms, had a higher frequency of IDH1 mutations and had a lower frequency of PTEN deletions. Survival was longer in patients with GBM-Os compared to those with other GBMs, with median survivals of 16.2 and 8.1 months, respectively. Most of the survival advantage for GBM-O appeared to be associated with a younger age at presentation. Among patients with GBM-O, younger age at presentation and 1p deletion were most significant in conferring prolonged survival. Thus, GBM-O represents a subset of GBMs with distinctive morphologic, clinical and molecular characteristics. © 2013 The Authors; Brain Pathology © 2013 International Society of Neuropathology.

  17. Periurethral granular cell tumor: a case report

    International Nuclear Information System (INIS)

    Kim, Jeong Kon; Choi, Hyo Gyeong; Cho, Kyoung Sik

    1998-01-01

    Granular cell tumors are uncommon soft tissue tumors which arise as solitary or multiple masses. Lesions commonly arise in the head, neck, and chest wall, but can occur in any part of the body. To our knowledge, periurethral granular cell tumor has not been previously reported. We report one such case

  18. MicroRNA-145 is downregulated in glial tumors and regulates glioma cell migration by targeting connective tissue growth factor.

    Science.gov (United States)

    Lee, Hae Kyung; Bier, Ariel; Cazacu, Simona; Finniss, Susan; Xiang, Cunli; Twito, Hodaya; Poisson, Laila M; Mikkelsen, Tom; Slavin, Shimon; Jacoby, Elad; Yalon, Michal; Toren, Amos; Rempel, Sandra A; Brodie, Chaya

    2013-01-01

    Glioblastomas (GBM), the most common and aggressive type of malignant glioma, are characterized by increased invasion into the surrounding brain tissues. Despite intensive therapeutic strategies, the median survival of GBM patients has remained dismal over the last decades. In this study we examined the expression of miR-145 in glial tumors and its function in glioma cells. Using TCGA analysis and real-time PCR we found that the expression of miR-145/143 cluster was downregulated in astrocytic tumors compared to normal brain specimens and in glioma cells and glioma stem cells (GSCs) compared to normal astrocytes and neural stem cells. Moreover, the low expression of both miR-145 and miR-143 in GBM was correlated with poor patient prognosis. Transfection of glioma cells with miR-145 mimic or transduction with a lentivirus vector expressing pre-miR 145 significantly decreased the migration and invasion of glioma cells. We identified connective tissue growth factor (CTGF) as a novel target of miR-145 in glioma cells; transfection of the cells with this miRNA decreased the expression of CTGF as determined by Western blot analysis and the expression of its 3'-UTR fused to luciferase. Overexpression of a CTGF plasmid lacking the 3'-UTR and administration of recombinant CTGF protein abrogated the inhibitory effect of miR-145 on glioma cell migration. Similarly, we found that silencing of CTGF decreased the migration of glioma cells. CTGF silencing also decreased the expression of SPARC, phospho-FAK and FAK and overexpression of SPARC abrogated the inhibitory effect of CTGF silencing on cell migration. These results demonstrate that miR-145 is downregulated in glial tumors and its low expression in GBM predicts poor patient prognosis. In addition miR-145 regulates glioma cell migration by targeting CTGF which downregulates SPARC expression. Therefore, miR-145 is an attractive therapeutic target for anti-invasive treatment of astrocytic tumors.

  19. MicroRNA-145 is downregulated in glial tumors and regulates glioma cell migration by targeting connective tissue growth factor.

    Directory of Open Access Journals (Sweden)

    Hae Kyung Lee

    Full Text Available Glioblastomas (GBM, the most common and aggressive type of malignant glioma, are characterized by increased invasion into the surrounding brain tissues. Despite intensive therapeutic strategies, the median survival of GBM patients has remained dismal over the last decades. In this study we examined the expression of miR-145 in glial tumors and its function in glioma cells. Using TCGA analysis and real-time PCR we found that the expression of miR-145/143 cluster was downregulated in astrocytic tumors compared to normal brain specimens and in glioma cells and glioma stem cells (GSCs compared to normal astrocytes and neural stem cells. Moreover, the low expression of both miR-145 and miR-143 in GBM was correlated with poor patient prognosis. Transfection of glioma cells with miR-145 mimic or transduction with a lentivirus vector expressing pre-miR 145 significantly decreased the migration and invasion of glioma cells. We identified connective tissue growth factor (CTGF as a novel target of miR-145 in glioma cells; transfection of the cells with this miRNA decreased the expression of CTGF as determined by Western blot analysis and the expression of its 3'-UTR fused to luciferase. Overexpression of a CTGF plasmid lacking the 3'-UTR and administration of recombinant CTGF protein abrogated the inhibitory effect of miR-145 on glioma cell migration. Similarly, we found that silencing of CTGF decreased the migration of glioma cells. CTGF silencing also decreased the expression of SPARC, phospho-FAK and FAK and overexpression of SPARC abrogated the inhibitory effect of CTGF silencing on cell migration. These results demonstrate that miR-145 is downregulated in glial tumors and its low expression in GBM predicts poor patient prognosis. In addition miR-145 regulates glioma cell migration by targeting CTGF which downregulates SPARC expression. Therefore, miR-145 is an attractive therapeutic target for anti-invasive treatment of astrocytic tumors.

  20. Combinatorial Drug Testing in 3D Microtumors Derived from GBM Patient-Derived Xenografts Reveals Cytotoxic Synergy in Pharmacokinomics-informed Pathway Interactions.

    Science.gov (United States)

    Gilbert, Ashley N; Anderson, Joshua C; Duarte, Christine W; Shevin, Rachael S; Langford, Catherine P; Singh, Raj; Gillespie, G Yancey; Willey, Christopher D

    2018-05-30

    Glioblastoma multiforme (GBM), the most common form of primary malignant brain cancer in adults, is a devastating disease for which effective treatment has remained elusive for over 75 years. One reason for the minimal progress during this time is the lack of accurate preclinical models to represent the patient's tumor's in vivo environment, causing a disconnect in drug therapy effectiveness between the laboratory and clinic. While patient-derived xenografts (PDX's or xenolines) are excellent human tumor representations, they are not amenable to high throughput testing. Therefore, we developed a miniaturized xenoline system (microtumors) for drug testing. Nineteen GBM xenolines were profiled for global kinase (kinomic) activity revealing actionable kinase targets associated with intracranial tumor growth rate. Kinase inhibitors for these targets (WP1066, selumetinib, crizotinib, and cediranib) were selected for single and combination therapy using a fully human-derived three-dimensional (3D) microtumor model of GBM xenoline cells embedded in HuBiogel for subsequent molecular and phenotype assays. GBM microtumors closely resembled orthotopically-implanted tumors based on immunohistochemical analysis and displayed kinomic and morphological diversity. Drug response testing could be reproducibly performed in a 96-well format identifying several synergistic combinations. Our findings indicate that 3D microtumors can provide a suitable high-throughput model for combination drug testing.

  1. Interaction of tumor cells with the microenvironment

    Directory of Open Access Journals (Sweden)

    Lehnert Hendrik

    2011-09-01

    Full Text Available Abstract Recent advances in tumor biology have revealed that a detailed analysis of the complex interactions of tumor cells with their adjacent microenvironment (tumor stroma is mandatory in order to understand the various mechanisms involved in tumor growth and the development of metastasis. The mutual interactions between tumor cells and cellular and non-cellular components (extracellular matrix = ECM of the tumor microenvironment will eventually lead to a loss of tissue homeostasis and promote tumor development and progression. Thus, interactions of genetically altered tumor cells and the ECM on the one hand and reactive non-neoplastic cells on the other hand essentially control most aspects of tumorigenesis such as epithelial-mesenchymal-transition (EMT, migration, invasion (i.e. migration through connective tissue, metastasis formation, neovascularisation, apoptosis and chemotherapeutic drug resistance. In this mini-review we will focus on these issues that were recently raised by two review articles in CCS.

  2. Granular cell tumor: An uncommon benign neoplasm

    Directory of Open Access Journals (Sweden)

    Tirthankar Gayen

    2015-01-01

    Full Text Available Granular cell tumor is a distinctly rare neoplasm of neural sheath origin. It mainly presents as a solitary asymptomatic swelling in the oral cavity, skin, and rarely internal organs in the middle age. Histopathology is characteristic, showing polyhedral cells containing numerous fine eosinophilic granules with indistinct cell margins. We present a case of granular cell tumor on the back of a 48-year-old woman which was painful, mimicking an adnexal tumor.

  3. Reciprocal Supportive Interplay between Glioblastoma and Tumor-Associated Macrophages

    International Nuclear Information System (INIS)

    Zhou, Wenchao; Bao, Shideng

    2014-01-01

    Glioblastoma multiforme (GBM) is the most lethal and aggressive type of primary brain malignancy. Failures of the traditional therapies in treating GBMs raise the urgent requirement to develop new approaches with more responsive targets. The phenomenon of the high infiltration of tumor-associated macrophages (TAMs) into GBMs has been observed for a long time. Regardless of the limited knowledge about TAMs, the high percentage of supportive TAM in GBM tumor mass makes it possible to be a good target for GBM treatment. In this review, we discussed the unique features of TAMs in GBMs, including their origin, the tumor-supportive properties, the secreted cytokines, and the relevant mechanisms. In addition, we tried to interpret the current understandings about the interplay between GBM cancer cells and TAMs. Finally, the translational studies of targeting TAMs were also described

  4. Reciprocal Supportive Interplay between Glioblastoma and Tumor-Associated Macrophages

    Energy Technology Data Exchange (ETDEWEB)

    Zhou, Wenchao; Bao, Shideng, E-mail: baos@ccf.org [Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195 (United States)

    2014-03-26

    Glioblastoma multiforme (GBM) is the most lethal and aggressive type of primary brain malignancy. Failures of the traditional therapies in treating GBMs raise the urgent requirement to develop new approaches with more responsive targets. The phenomenon of the high infiltration of tumor-associated macrophages (TAMs) into GBMs has been observed for a long time. Regardless of the limited knowledge about TAMs, the high percentage of supportive TAM in GBM tumor mass makes it possible to be a good target for GBM treatment. In this review, we discussed the unique features of TAMs in GBMs, including their origin, the tumor-supportive properties, the secreted cytokines, and the relevant mechanisms. In addition, we tried to interpret the current understandings about the interplay between GBM cancer cells and TAMs. Finally, the translational studies of targeting TAMs were also described.

  5. [Circulating tumor cells: cornerstone of personalized medicine].

    Science.gov (United States)

    Rafii, A; Vidal, F; Rathat, G; Alix-Panabières, C

    2014-11-01

    Cancer treatment has evolved toward personalized medicine. It is mandatory for clinicians to ascertain tumor biological features in order to optimize patients' treatment. Identification and characterization of circulating tumor cells demonstrated a prognostic value in many solid tumors. Here, we describe the main technologies for identification and characterization of circulating tumor cells and their clinical application in gynecologic and breast cancers. Copyright © 2014. Published by Elsevier Masson SAS.

  6. Vindesine in plasma cell tumors.

    Science.gov (United States)

    Salvagno, L; Paccagnella, A; Chiarion Sileni, V; De Besi, P; Frizzarin, M; Casara, D; Fiorentino, M V

    1985-12-31

    Twenty-one patients with plasma cell tumors received vindesine (VDS) at the dose of 3 mg/m2 i.v. on day 1 plus prednisone at the dose of 100 mg p.o. from day 1 to 5, recycling every 8 days 3 times and then every 10-12 days. In 3 patients with gastric or duodenal ulcer prednisone was not administered. All but one patient were heavily pretreated and resistant to M-2 regimen. Overall there were 4 objective responses (19%): 2 among 15 patients (13%) with multiple myeloma and 2 among 6 patients (33%) with extramedullary plasmacytoma (EMP). The responses lasted for 2, 12, 15 and 48+ months. One previously untreated EMP patient received VDS without prednisone and obtained a complete long-lasting remission. The association of VDS with high-dose prednisone seems to have some activity in plasma cell tumors; probably in multiple myeloma the objective responses are due to the high dose of cortisone rather than to VDS. On the contrary, in EMP patients, VDS may be an active agent, even if administered without cortisone.

  7. Glucocorticoids promote a glioma stem cell-like phenotype and resistance to chemotherapy in human glioblastoma primary cells

    DEFF Research Database (Denmark)

    Kostopoulou, Ourania N; Mohammad, Abdul-Aleem; Bartek, Jiri

    2018-01-01

    Glioma stem cells (GSCs) are glioblastoma (GBM) cells that are resistant to therapy and can give rise to recurrent tumors. The identification of patient-related factors that support GSCs is thus necessary to design effective therapies for GBM patients. Glucocorticoids (GCs) are used to treat GBM......-associated edema. However, glucocorticoids participate in the physiological response to psychosocial stress, which has been linked to poor cancer prognosis. This raises concern that glucocorticoids affect the tumor and GSCs. Here, we treated primary human GBM cells with dexamethasone and evaluated GC......-driven changes in cell morphology, proliferation, migration, gene expression, secretory activity and growth as neurospheres. Dexamethasone treatment of GBM cells appeared to promote the development of a GSC-like phenotype and conferred resistance to physiological stress and chemotherapy. We also analyzed...

  8. Tumor-reactive immune cells protect against metastatic tumor and induce immunoediting of indolent but not quiescent tumor cells.

    Science.gov (United States)

    Payne, Kyle K; Keim, Rebecca C; Graham, Laura; Idowu, Michael O; Wan, Wen; Wang, Xiang-Yang; Toor, Amir A; Bear, Harry D; Manjili, Masoud H

    2016-09-01

    Two major barriers to cancer immunotherapy include tumor-induced immune suppression mediated by myeloid-derived suppressor cells and poor immunogenicity of the tumor-expressing self-antigens. To overcome these barriers, we reprogrammed tumor-immune cell cross-talk by combined use of decitabine and adoptive immunotherapy, containing tumor-sensitized T cells and CD25(+) NKT cells. Decitabine functioned to induce the expression of highly immunogenic cancer testis antigens in the tumor, while also reducing the frequency of myeloid-derived suppressor cells and the presence of CD25(+) NKT cells rendered T cells, resistant to remaining myeloid-derived suppressor cells. This combinatorial therapy significantly prolonged survival of animals bearing metastatic tumor cells. Adoptive immunotherapy also induced tumor immunoediting, resulting in tumor escape and associated disease-related mortality. To identify a tumor target that is incapable of escape from the immune response, we used dormant tumor cells. We used Adriamycin chemotherapy or radiation therapy, which simultaneously induce tumor cell death and tumor dormancy. Resultant dormant cells became refractory to additional doses of Adriamycin or radiation therapy, but they remained sensitive to tumor-reactive immune cells. Importantly, we discovered that dormant tumor cells contained indolent cells that expressed low levels of Ki67 and quiescent cells that were Ki67 negative. Whereas the former were prone to tumor immunoediting and escape, the latter did not demonstrate immunoediting. Our results suggest that immunotherapy could be highly effective against quiescent dormant tumor cells. The challenge is to develop combinatorial therapies that could establish a quiescent type of tumor dormancy, which would be the best target for immunotherapy. © The Author(s).

  9. Role of Axumin PET Scan in Germ Cell Tumor

    Science.gov (United States)

    2018-05-01

    Testis Cancer; Germ Cell Tumor; Testicular Cancer; Germ Cell Tumor of Testis; Germ Cell Tumor, Testicular, Childhood; Testicular Neoplasms; Testicular Germ Cell Tumor; Testicular Yolk Sac Tumor; Testicular Choriocarcinoma; Testicular Diseases; Germ Cell Cancer Metastatic; Germ Cell Neoplasm of Retroperitoneum; Germ Cell Cancer, Nos

  10. Blockade of the SNARE protein syntaxin 1 inhibits glioblastoma tumor growth.

    Directory of Open Access Journals (Sweden)

    Fausto Ulloa

    Full Text Available Glioblastoma (GBM is the most prevalent adult brain tumor, with virtually no cure, and with a median overall survival of 15 months from diagnosis despite of the treatment. SNARE proteins mediate membrane fusion events in cells and are essential for many cellular processes including exocytosis and neurotransmission, intracellular trafficking and cell migration. Here we show that the blockade of the SNARE protein Syntaxin 1 (Stx1 function impairs GBM cell proliferation. We show that Stx1 loss-of-function in GBM cells, through ShRNA lentiviral transduction, a Stx1 dominant negative and botulinum toxins, dramatically reduces the growth of GBM after grafting U373 cells into the brain of immune compromised mice. Interestingly, Stx1 role on GBM progression may not be restricted just to cell proliferation since the blockade of Stx1 also reduces in vitro GBM cell invasiveness suggesting a role in several processes relevant for tumor progression. Altogether, our findings indicate that the blockade of SNARE proteins may represent a novel therapeutic tool against GBM.

  11. Stages of Childhood Extracranial Germ Cell Tumors

    Science.gov (United States)

    ... tumors: Yolk sac tumors make a hormone called alpha-fetoprotein (AFP). They can form in the ovary, testicle, ... are used to detect extracranial germ cell tumors: Alpha-fetoprotein (AFP). Beta-human chorionic gonadotropin (β-hCG). For ...

  12. IL22/IL-22R pathway induces cell survival in human glioblastoma cells.

    Directory of Open Access Journals (Sweden)

    Hussein Akil

    Full Text Available Interleukin-22 (IL-22 is a member of the IL-10 cytokine family that binds to a heterodimeric receptor consisting of IL-22 receptor 1 (IL-22R1 and IL-10R2. IL-22R expression was initially characterized on epithelial cells, and plays an essential role in a number of inflammatory diseases. Recently, a functional receptor was detected on cancer cells such as hepatocarcinoma and lung carcinoma, but its presence was not reported in glioblastoma (GBM. Two GBM cell lines and 10 primary cell lines established from patients undergoing surgery for malignant GBM were used to investigate the expression of IL-22 and IL-22R by using quantitative RT-PCR, western blotting and confocal microscopy studies. The role of IL-22 in proliferation and survival of GBM cell lines was investigated in vitro by BrdU and ELISA cell death assays. We report herein that the two subunits of the IL-22R complex are expressed on human GBM cells. Their activation, depending on exogenous IL-22, induced antiapoptotic effect and cell proliferation. IL-22 treatment of GBM cells resulted in increased levels of phosphorylated Akt, STAT3 signaling protein and its downstream antiapoptotic protein Bcl-xL and decreased level of phosphorylated ERK1/2. In addition, IL-22R subunits were expressed in all the 10 tested primary cell lines established from GBM tumors. Our results showed that IL-22R is expressed on GBM established and primary cell lines. Depending on STAT3, ERK1/2 and PI3K/Akt pathways, IL-22 induced GBM cell survival. These data are consistent with a potential role of IL-22R in tumorigenesis of GBM. Since endogenous IL-22 was not detected in all studied GBM cells, we hypothesize that IL-22R could be activated by immune microenvironmental IL-22 producing cells.

  13. Monitoring of regulatory T cell frequencies and expression of CTLA-4 on T cells, before and after DC vaccination, can predict survival in GBM patients.

    Directory of Open Access Journals (Sweden)

    Brendan Fong

    Full Text Available PURPOSE: Dendritic cell (DC vaccines have recently emerged as an innovative therapeutic option for glioblastoma patients. To identify novel surrogates of anti-tumor immune responsiveness, we studied the dynamic expression of activation and inhibitory markers on peripheral blood lymphocyte (PBL subsets in glioblastoma patients treated with DC vaccination at UCLA. EXPERIMENTAL DESIGN: Pre-treatment and post-treatment PBL from 24 patients enrolled in two Phase I clinical trials of dendritic cell immunotherapy were stained and analyzed using flow cytometry. A univariate Cox proportional hazards model was utilized to investigate the association between continuous immune monitoring variables and survival. Finally, the immune monitoring variables were dichotomized and a recursive partitioning survival tree was built to obtain cut-off values predictive of survival. RESULTS: The change in regulatory T cell (CD3(+CD4(+CD25(+CD127(low frequency in PBL was significantly associated with survival (p = 0.0228; hazard ratio = 3.623 after DC vaccination. Furthermore, the dynamic expression of the negative co-stimulatory molecule, CTLA-4, was also significantly associated with survival on CD3(+CD4(+ T cells (p = 0.0191; hazard ratio = 2.840 and CD3(+CD8(+ T cells (p = 0.0273; hazard ratio = 2.690, while that of activation markers (CD25, CD69 was not. Finally, a recursive partitioning tree algorithm was utilized to dichotomize the post/pre fold change immune monitoring variables. The resultant cut-off values from these immune monitoring variables could effectively segregate these patients into groups with significantly different overall survival curves. CONCLUSIONS: Our results suggest that monitoring the change in regulatory T cell frequencies and dynamic expression of the negative co-stimulatory molecules on peripheral blood T cells, before and after DC vaccination, may predict survival. The cut-off point generated from these data can be utilized in future

  14. Intracranial germ-cell tumors

    International Nuclear Information System (INIS)

    Baker, L.L.; Kollias, S.S.; Cogen, P.H.; Barkovich, A.J.

    1991-01-01

    This paper reports on the MR characteristics together with the clinical and histologic features of cerebral germ-cell tumors were investigated to augment data regarding this rare, diverse class of neoplasms. Germinomas were homogeneous or heterogeneous masses, predominantly isointense to normal brain on T1-weighted images, and hyperintense and heterogeneous on T2-weighted images; three showed adjacent brain edema. Enhancement was prominent, either homogeneous or heterogeneous. One had spinal drop metastases. Teratomas, more common in young patients, were more heterogeneous than germinomas on T1-weighted and T2-weighted images. Five showed hyper- and hypointense foci on T1-weighted images that corresponded to fat and calcium, respectively, at CT. Teratomas did not enhance or enhanced heterogeneously. Two had intratumoral hemorrhage; there were no metastases. Both patients with choriocarcinoma had hemorrhagic masses

  15. The lifetime of hypoxic human tumor cells

    International Nuclear Information System (INIS)

    Durand, Ralph E.; Sham, Edward

    1998-01-01

    Purpose: For hypoxic and anoxic cells in solid tumors to be a therapeutic problem, they must live long enough to be therapeutically relevant, or else be rapidly recruited into the proliferating compartment during therapy. We have, therefore, estimated lifetime and recruitment rate of hypoxic human tumor cells in multicell spheroids in vitro, or in xenografted tumors in SCID mice. Materials and Methods: Cell turnover was followed by flow cytometry techniques, using antibodies directed at incorporated halogenated pyrimidines. The disappearance of labeled cells was quantified, and verified to be cell loss rather than label dilution. Repopulation was studied in SiHa tumor xenografts during twice-daily 2.5-Gy radiation exposures. Results: The longevity of hypoxic human tumor cells in spheroids or xenografts exceeded that of rodent cell lines, and cell turnover was slower in xenografts than under static growth as spheroids. Human tumor cells remained viable in the hypoxic regions of xenografts for 4-10 days, compared to 3-5 days in spheroids, and 1-3 days for most rodent cells in spheroids. Repopulation was observed within the first few radiation treatments for the SiHa xenografts and, with accumulated doses of more than 10 Gy, virtually all recovered cells had progressed through at least one S-phase. Conclusion: Our results suggest an important difference in the ability of human vs. rodent tumor cells to withstand hypoxia, and raise questions concerning the increased longevity seen in vivo relative to the steady-state spheroid system

  16. Quantitative Magnetization Transfer in Monitoring Glioblastoma (GBM) Response to Therapy.

    Science.gov (United States)

    Mehrabian, Hatef; Myrehaug, Sten; Soliman, Hany; Sahgal, Arjun; Stanisz, Greg J

    2018-02-06

    Quantitative magnetization transfer (qMT) was used as a biomarker to monitor glioblastoma (GBM) response to chemo-radiation and identify the earliest time-point qMT could differentiate progressors from non-progressors. Nineteen GBM patients were recruited and MRI-scanned before (Day 0 ), two weeks (Day 14 ), and four weeks (Day 28 ) into the treatment, and one month after the end of the treatment (Day 70 ). Comprehensive qMT data was acquired, and a two-pool MT model was fit to the data. Response was determined at 3-8 months following the end of chemo-radiation. The amount of magnetization transfer ([Formula: see text]) was significantly lower in GBM compared to normal appearing white matter (p GBM are more sensitive to treatment effects compared to clinically used metrics. qMT could assess tumor aggressiveness and identify early progressors even before the treatment. Changes in qMT parameters within the first 14 days of the treatment were capable of separating early progressors from non-progressors, making qMT a promising biomarker to guide adaptive radiotherapy for GBM.

  17. Treatment Option Overview (Ovarian Germ Cell Tumors)

    Science.gov (United States)

    ... Germ Cell Tumors Treatment (PDQ®)–Patient Version Treatment Option Overview Go to Health Professional Version Key Points ... and restore) the body’s blood cells. New treatment options Combination chemotherapy (the use of more than one ...

  18. Treatment Option Overview (Extragonadal Germ Cell Tumors)

    Science.gov (United States)

    ... Cell Tumors Treatment Testicular Cancer Treatment Age and gender can affect the risk of extragonadal germ cell ... Headache. Change in bowel habits. Feeling very tired. Trouble walking. Trouble in seeing or moving the eyes. ...

  19. General Information about Extragonadal Germ Cell Tumors

    Science.gov (United States)

    ... Cell Tumors Treatment Testicular Cancer Treatment Age and gender can affect the risk of extragonadal germ cell ... Headache. Change in bowel habits. Feeling very tired. Trouble walking. Trouble in seeing or moving the eyes. ...

  20. Immune Cells in Blood Recognize Tumors

    Science.gov (United States)

    NCI scientists have developed a novel strategy for identifying immune cells circulating in the blood that recognize specific proteins on tumor cells, a finding they believe may have potential implications for immune-based therapies.

  1. ZFHX4 interacts with the NuRD core member CHD4 and regulates the glioblastoma tumor-initiating cell state.

    Science.gov (United States)

    Chudnovsky, Yakov; Kim, Dohoon; Zheng, Siyuan; Whyte, Warren A; Bansal, Mukesh; Bray, Mark-Anthony; Gopal, Shuba; Theisen, Matthew A; Bilodeau, Steve; Thiru, Prathapan; Muffat, Julien; Yilmaz, Omer H; Mitalipova, Maya; Woolard, Kevin; Lee, Jeongwu; Nishimura, Riko; Sakata, Nobuo; Fine, Howard A; Carpenter, Anne E; Silver, Serena J; Verhaak, Roel G W; Califano, Andrea; Young, Richard A; Ligon, Keith L; Mellinghoff, Ingo K; Root, David E; Sabatini, David M; Hahn, William C; Chheda, Milan G

    2014-01-30

    Glioblastoma (GBM) harbors subpopulations of therapy-resistant tumor-initiating cells (TICs) that are self-renewing and multipotent. To understand the regulation of the TIC state, we performed an image-based screen for genes regulating GBM TIC maintenance and identified ZFHX4, a 397 kDa transcription factor. ZFHX4 is required to maintain TIC-associated and normal human neural precursor cell phenotypes in vitro, suggesting that ZFHX4 regulates differentiation, and its suppression increases glioma-free survival in intracranial xenografts. ZFHX4 interacts with CHD4, a core member of the nucleosome remodeling and deacetylase (NuRD) complex. ZFHX4 and CHD4 bind to overlapping sets of genomic loci and control similar gene expression programs. Using expression data derived from GBM patients, we found that ZFHX4 significantly affects CHD4-mediated gene expression perturbations, which defines ZFHX4 as a master regulator of CHD4. These observations define ZFHX4 as a regulatory factor that links the chromatin-remodeling NuRD complex and the GBM TIC state. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

  2. ZFHX4 Interacts with the NuRD Core Member CHD4 and Regulates the Glioblastoma Tumor-Initiating Cell State

    Directory of Open Access Journals (Sweden)

    Yakov Chudnovsky

    2014-01-01

    Full Text Available Glioblastoma (GBM harbors subpopulations of therapy-resistant tumor-initiating cells (TICs that are self-renewing and multipotent. To understand the regulation of the TIC state, we performed an image-based screen for genes regulating GBM TIC maintenance and identified ZFHX4, a 397 kDa transcription factor. ZFHX4 is required to maintain TIC-associated and normal human neural precursor cell phenotypes in vitro, suggesting that ZFHX4 regulates differentiation, and its suppression increases glioma-free survival in intracranial xenografts. ZFHX4 interacts with CHD4, a core member of the nucleosome remodeling and deacetylase (NuRD complex. ZFHX4 and CHD4 bind to overlapping sets of genomic loci and control similar gene expression programs. Using expression data derived from GBM patients, we found that ZFHX4 significantly affects CHD4-mediated gene expression perturbations, which defines ZFHX4 as a master regulator of CHD4. These observations define ZFHX4 as a regulatory factor that links the chromatin-remodeling NuRD complex and the GBM TIC state.

  3. A PTEN-COL17A1 fusion gene and its novel regulatory role in Collagen XVII expression and GBM malignance.

    Science.gov (United States)

    Yan, Xiaoyan; Zhang, Chuanbao; Liang, Tingyu; Yang, Fan; Wang, Haoyuan; Wu, Fan; Wang, Wen; Wang, Zheng; Cheng, Wen; Xu, Jiangnan; Jiang, Tao; Chen, Jing; Ding, Yaozhong

    2017-10-17

    Collagen XVII expression has recently been demonstrated to be correlated with the tumor malignance. While Collagen XVII is known to be widely distributed in neurons of the human brain, its precise role in pathogenesis of glioblastoma multiforme (GBM) is unknown. In this study, we identified and characterized a new PTEN-COL17A1 fusion gene in GMB using transcriptome sequencing. Although fusion gene did not result in measurable fusion protein production, its presence is accompanied with high levels of COL17A1 expression, revealed a novel regulatory mechanism of Collagen XVII expression by PTEN-COL17A1 gene fusion. Knocked down Collagen XVII expression in glioma cell lines resulted in decreased tumor invasiveness, along with significant reduction of MMP9 expression, while increased Collagen XVII expression promotes invasive activities of glioma cells and associated with GBM recurrences. Together, our results uncovered a new PTEN-COL17A1 fusion gene and its novel regulatory role in Collagen XVII expression and GBM malignance, and demonstrated that COL17A1 could serve as a useful prognostic biomarker and therapeutic targets for GBM.

  4. Pathway-specific differences between tumor cell lines and normal and tumor tissue cells

    Directory of Open Access Journals (Sweden)

    Tozeren Aydin

    2006-11-01

    Full Text Available Abstract Background Cell lines are used in experimental investigation of cancer but their capacity to represent tumor cells has yet to be quantified. The aim of the study was to identify significant alterations in pathway usage in cell lines in comparison with normal and tumor tissue. Methods This study utilized a pathway-specific enrichment analysis of publicly accessible microarray data and quantified the gene expression differences between cell lines, tumor, and normal tissue cells for six different tissue types. KEGG pathways that are significantly different between cell lines and tumors, cell lines and normal tissues and tumor and normal tissue were identified through enrichment tests on gene lists obtained using Significance Analysis of Microarrays (SAM. Results Cellular pathways that were significantly upregulated in cell lines compared to tumor cells and normal cells of the same tissue type included ATP synthesis, cell communication, cell cycle, oxidative phosphorylation, purine, pyrimidine and pyruvate metabolism, and proteasome. Results on metabolic pathways suggested an increase in the velocity nucleotide metabolism and RNA production. Pathways that were downregulated in cell lines compared to tumor and normal tissue included cell communication, cell adhesion molecules (CAMs, and ECM-receptor interaction. Only a fraction of the significantly altered genes in tumor-to-normal comparison had similar expressions in cancer cell lines and tumor cells. These genes were tissue-specific and were distributed sparsely among multiple pathways. Conclusion Significantly altered genes in tumors compared to normal tissue were largely tissue specific. Among these genes downregulation was a major trend. In contrast, cell lines contained large sets of significantly upregulated genes that were common to multiple tissue types. Pathway upregulation in cell lines was most pronounced over metabolic pathways including cell nucleotide metabolism and oxidative

  5. Targeting Hypoxia-Inducible Factor 1α in a New Orthotopic Model of Glioblastoma Recapitulating the Hypoxic Tumor Microenvironment.

    Science.gov (United States)

    Nigim, Fares; Cavanaugh, Jill; Patel, Anoop P; Curry, William T; Esaki, Shin-ichi; Kasper, Ekkehard M; Chi, Andrew S; Louis, David N; Martuza, Robert L; Rabkin, Samuel D; Wakimoto, Hiroaki

    2015-07-01

    Tissue hypoxia and necrosis represent pathophysiologic and histologic hallmarks of glioblastoma (GBM). Although hypoxia inducible factor 1α (HIF-1α) plays crucial roles in the malignant phenotypes of GBM, developing HIF-1α-targeted agents has been hampered by the lack of a suitable preclinical model that recapitulates the complex biology of clinical GBM. We present a new GBM model, MGG123, which was established from a recurrent human GBM. Orthotopic xenografting of stem-like MGG123 cells reproducibly generated lethal tumors that were characterized by foci of palisading necrosis, hypervascularity, and robust stem cell marker expression. Perinecrotic neoplastic cells distinctively express HIF-1α and are proliferative in both xenografts and the patient tissue. The xenografts contain scattered hypoxic foci that were consistently greater than 50 μm distant from blood vessels, indicating intratumoral heterogeneity of oxygenation. Hypoxia enhanced HIF-1α expression in cultured MGG123 cells, which was abrogated by the HIF-1α inhibitors digoxin or ouabain. In vivo, treatment of orthotopic MGG123 xenografts with digoxin decreased HIF-1α expression, vascular endothelial growth factor mRNA levels, and CD34-positive vasculature within the tumors, and extended survival of mice bearing the aggressive MGG123 GBM. This preclinical tumor model faithfully recapitulates the GBM-relevant hypoxic microenvironment and stemness and is a suitable platform for studying disease biology and developing hypoxia-targeted agents.

  6. Enrichment of tumor cells for cell kinetic analysis in human tumor biopsies using cytokeratin gating

    International Nuclear Information System (INIS)

    Haustermans, K.; Hofland, I.; Ramaekers, M.; Ivanyi, D.; Balm, A.J.M.; Geboes, K.; Lerut, T.; Schueren, E. van der; Begg, A.C.

    1996-01-01

    Purpose: To determine the feasibility of using cytokeratin antibodies to distinguish normal and malignant cells in human tumors using flow cytometry. The goal was ultimately to increase the accuracy of cell kinetic measurements on human tumor biopsies. Material and methods: A panel of four antibodies was screened on a series of 48 tumors from two centres; 22 head and neck tumors (Amsterdam) and 26 esophagus carcinomas (Leuven). First, screening was carried out by immunohistochemistry on frozen sections to test intensity of staining and the fraction of cytokeratin-positive tumor cells. The antibody showing the most positive staining was then used for flow cytometry on the same tumor. Results: The two broadest spectrum antibodies (AE1/AE3, E3/C4) showed overall the best results with immunohistochemical staining, being positive in over 95% of tumors. Good cell suspensions for DNA flow cytometry could be made from frozen material by a mechanical method, whereas enzymatic methods with trypsin or collagenase were judged failures in almost all cases. >From fresh material, both collagenase and trypsin produced good suspensions for flow cytometry, although the fraction of tumor cells, judged by proportion aneuploid cells, was markedly higher for trypsin. Using the best cytokeratin antibody for each tumor, two parameter flow cytometry was done (cytokeratin versus DNA content). Enrichment of tumor cells was then tested by measuring the fraction of aneuploid cells (the presumed malignant population) of cytokeratin-positive cells versus all cells. An enrichment factor ranging between 0 (no enrichment) and 1 (perfect enrichment, tumor cells only) was then calculated. The average enrichment was 0.60 for head and neck tumors and 0.59 for esophagus tumors. Conclusions: We conclude that this method can substantially enrich the proportion of tumor cells in biopsies from carcinomas. Application of this method could significantly enhance accuracy of tumor cell kinetic measurements

  7. Andrographolide suppresses the migratory ability of human glioblastoma multiforme cells by targeting ERK1/2-mediated matrix metalloproteinase-2 expression

    OpenAIRE

    Yang, Shih-Liang; Kuo, Fu-Hsuan; Chen, Pei-Ni; Hsieh, Yi-Hsien; Yu, Nuo-Yi; Yang, Wei-En; Hsieh, Ming-Ju; Yang, Shun-Fa

    2017-01-01

    Glioblastoma multiforme (GBM) can be a fatal tumor because of difficulties in treating the related metastasis. Andrographolide is the bioactive component of the Andrographis paniculata. Andrographolide possesses the anti-inflammatory activity and inhibits the growth of various cancers; however, its effect on GBM cancer motility remains largely unknown. In this study, we examined the antimetastatic properties of andrographolide in human GBM cells. Our results revealed that andrographolide inhi...

  8. Retrotransposon Targeting of Tumor Cells

    National Research Council Canada - National Science Library

    Wu, Dongdong; DeVaux, George

    2005-01-01

    .... Cancer gene therapy techniques include oncogene inactivation, tumor suppressor gene replacement, inhibition of angiogenesis, immunopotentiation, molecular chemotherapy, and transfer of drug resistance genes...

  9. miR-124 and miR-137 inhibit proliferation of glioblastoma multiforme cells and induce differentiation of brain tumor stem cells

    Directory of Open Access Journals (Sweden)

    Costello Joseph F

    2008-06-01

    Full Text Available Abstract Background Glioblastoma multiforme (GBM is an invariably fatal central nervous system tumor despite treatment with surgery, radiation, and chemotherapy. Further insights into the molecular and cellular mechanisms that drive GBM formation are required to improve patient outcome. MicroRNAs are emerging as important regulators of cellular differentiation and proliferation, and have been implicated in the etiology of a variety of cancers, yet the role of microRNAs in GBM remains poorly understood. In this study, we investigated the role of microRNAs in regulating the differentiation and proliferation of neural stem cells and glioblastoma-multiforme tumor cells. Methods We used quantitative RT-PCR to assess microRNA expression in high-grade astrocytomas and adult mouse neural stem cells. To assess the function of candidate microRNAs in high-grade astrocytomas, we transfected miR mimics to cultured-mouse neural stem cells, -mouse oligodendroglioma-derived stem cells, -human glioblastoma multiforme-derived stem cells and -glioblastoma multiforme cell lines. Cellular differentiation was assessed by immunostaining, and cellular proliferation was determined using fluorescence-activated cell sorting. Results Our studies revealed that expression levels of microRNA-124 and microRNA-137 were significantly decreased in anaplastic astrocytomas (World Health Organization grade III and glioblastoma multiforme (World Health Organization grade IV relative to non-neoplastic brain tissue (P erbB tumors and cluster of differentiation 133+ human glioblastoma multiforme-derived stem cells (SF6969. Transfection of microRNA-124 or microRNA-137 also induced G1 cell cycle arrest in U251 and SF6969 glioblastoma multiforme cells, which was associated with decreased expression of cyclin-dependent kinase 6 and phosphorylated retinoblastoma (pSer 807/811 proteins. Conclusion microRNA-124 and microRNA-137 induce differentiation of adult mouse neural stem cells, mouse

  10. Apparent diffusion coefficient in glioblastoma with PNET-like components, a GBM variant.

    Science.gov (United States)

    Ali, Saad; Joseph, Nancy M; Perry, Arie; Barajas, Ramon F; Cha, Soonmee

    2014-09-01

    Glioblastoma (GBM) with primitive neuroectodermal tumor (PNET)-like (GBM-PNET) components is a rare variant of GBM. Recent studies describe PNET-like clinical behavior in these patients-with significantly increased propensity for CSF dissemination and a benefit of "PNET-like" chemotherapy. The imaging appearance of GBM-PNET is not well-described and given areas of marked cellularity in the PNET components one might expect significantly reduced diffusion on MRI. The purpose of this study is to quantitatively evaluate the diffusion characteristics in GBM-PNET and compare them with conventional GBMs. Nine patients with surgical specimens yielding GBM-PNET were identified from the UCSF Pathology files. MR images of these patients were reviewed retrospectively. DWI (diffusion-weighted imaging) sequences were analyzed with multiple regions of interests placed within the tumor, and ADC (apparent diffusion coefficient) values were measured. Results were compared to previously published ADC values in pathology-proven conventional GBM cases from our institution. Reduced ADC was seen in GBM-PNET (mean 581 × 10(-6) mm(2)/s, range 338-817) compared to previously published mean of 1,030 × 10(-6) mm(2)/s in the enhancing components of conventional GBMs. We report substantially reduced ADC values in GBM-PNETs compared to conventional GBMs. If demonstrated in a larger sample, when areas of marked reduced diffusion are seen in a suspected GBM, MRI may appropriately direct tissue sampling and can advocate a thorough search for PNET-like components on histopathology. These patients may have a higher chance of developing CSF dissemination and may benefit from "PNET-like" platinum-based chemotherapy.

  11. Fully automatic GBM segmentation in the TCGA-GBM dataset: Prognosis and correlation with VASARI features.

    Science.gov (United States)

    Rios Velazquez, Emmanuel; Meier, Raphael; Dunn, William D; Alexander, Brian; Wiest, Roland; Bauer, Stefan; Gutman, David A; Reyes, Mauricio; Aerts, Hugo J W L

    2015-11-18

    Reproducible definition and quantification of imaging biomarkers is essential. We evaluated a fully automatic MR-based segmentation method by comparing it to manually defined sub-volumes by experienced radiologists in the TCGA-GBM dataset, in terms of sub-volume prognosis and association with VASARI features. MRI sets of 109 GBM patients were downloaded from the Cancer Imaging archive. GBM sub-compartments were defined manually and automatically using the Brain Tumor Image Analysis (BraTumIA). Spearman's correlation was used to evaluate the agreement with VASARI features. Prognostic significance was assessed using the C-index. Auto-segmented sub-volumes showed moderate to high agreement with manually delineated volumes (range (r): 0.4 - 0.86). Also, the auto and manual volumes showed similar correlation with VASARI features (auto r = 0.35, 0.43 and 0.36; manual r = 0.17, 0.67, 0.41, for contrast-enhancing, necrosis and edema, respectively). The auto-segmented contrast-enhancing volume and post-contrast abnormal volume showed the highest AUC (0.66, CI: 0.55-0.77 and 0.65, CI: 0.54-0.76), comparable to manually defined volumes (0.64, CI: 0.53-0.75 and 0.63, CI: 0.52-0.74, respectively). BraTumIA and manual tumor sub-compartments showed comparable performance in terms of prognosis and correlation with VASARI features. This method can enable more reproducible definition and quantification of imaging based biomarkers and has potential in high-throughput medical imaging research.

  12. Harnessing Dendritic Cells for Tumor Antigen Presentation

    Energy Technology Data Exchange (ETDEWEB)

    Nierkens, Stefan [Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Geert Grooteplein 28, Nijmegen 6525 GA (Netherlands); Janssen, Edith M., E-mail: edith.janssen@cchmc.org [Division of Molecular Immunology, Cincinnati Children' s Hospital Research Foundation, University of Cincinnati College of Medicine, 3333 Burnet Avenue, Cincinnati, OH 45229 (United States)

    2011-04-26

    Dendritic cells (DC) are professional antigen presenting cells that are crucial for the induction of anti-tumor T cell responses. As a consequence, research has focused on the harnessing of DCs for therapeutic interventions. Although current strategies employing ex vivo-generated and tumor-antigen loaded DCs have been proven feasible, there are still many obstacles to overcome in order to improve clinical trial successes and offset the cost and complexity of customized cell therapy. This review focuses on one of these obstacles and a pivotal step for the priming of tumor-specific CD8{sup +} and CD4{sup +} T cells; the in vitro loading of DCs with tumor antigens.

  13. Accumulation of worn-out GBM material substantially contributes to mesangial matrix expansion in diabetic nephropathy

    NARCIS (Netherlands)

    Kriz, Wilhelm; Loewen, Jana; Federico, Giuseppina; van den Born, Jacob; Groene, Elisabeth; Groene, Hermann Josef

    2017-01-01

    Thickening of the glomerular basement membrane (GBM) and expansion of the mesangial matrix are hallmarks of diabetic nephropathy (DN), generally considered to emerge from different sites of overproduction: GBM components from podocytes and mesangial matrix from mesangial cells. Reevaluation of 918

  14. Discovery of potent and selective cytotoxic activity of new quinazoline-ureas against TMZ-resistant glioblastoma multiforme (GBM).

    Science.gov (United States)

    Elkamhawy, Ahmed; Viswanath, Ambily Nath Indu; Pae, Ae Nim; Kim, Hyeon Young; Heo, Jin-Chul; Park, Woo-Kyu; Lee, Chong-Ock; Yang, Heekyoung; Kim, Kang Ho; Nam, Do-Hyun; Seol, Ho Jun; Cho, Heeyeong; Roh, Eun Joo

    2015-10-20

    Herein, we report new quinazoline-urea based compounds with potent cytotoxic activities against TMZ-resistant glioblastoma multiforme (GBM) cells. Low micromolar IC₅₀ values were exhibited over a panel of three primary GBM patient-derived cell cultures belonging to proneural (GBM-1), mesenchymal (GBM-2), and classical (GBM-3) subtypes. Eight compounds showed excellent selectivity indices for GBM cells comparing to a normal astrocyte cell line. In JC-1 assay, analogues 11, 12, 20, 22, and 24 exerted promising rates of mPTP opening induction towards proneural GBM subtype. Compounds 11, 20, and 24 bound to the translocator protein 18 kDa (TSPO) in submicromolar range using [(3)H] PK-11195 binding affinity assay. A homology model was built and docked models of 11, 12, 20, 22 and 24 were generated for describing their plausible binding modes in TSPO. In 3D clonogenic assay, compound 20 manifested potent tumoricidal effects on TMZ-resistant GBM cells even at submicromolar concentrations. In addition, CYP450 and hERG assays presented a safe toxicity profile of 20. Taken as a whole, this report presents compound 20 as a potent, selective and safe GBM cytotoxic agent which constitutes a promising direction against TMZ-resistant GBM. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  15. POSTTREATMENT NEUROBLASTOMA MATURATION TO GANGLIONIC CELL TUMOR

    Directory of Open Access Journals (Sweden)

    M. V. Ryzhova

    2012-01-01

    Full Text Available Tumor cells can differentiate into more mature forms in undifferentiated or poorly differentiated tumors, such as medulloblastomas with increased nodularity, as well as neuroblastomas. The authors describe 2 cases of neuroblastoma maturation into ganglioneuroblastoma 5 months after chemotherapy in a 2-year-old girl and 3 years after radiotherapy in a 16-year-old girl.

  16. Characterization of cell suspensions from solid tumors

    International Nuclear Information System (INIS)

    Pallavicini, M.

    1985-01-01

    The desirable features of cells in suspension will necessarily be dependent upon the use for which the cells were prepared. Adequate cell yield or recovery is defined by the measurement to be performed. Retention of cellular morphology is important for microscopic identification of cell types in a heterogenous cell suspension, and may be used to determine whether the cells in suspension are representative of those in the tumor in situ. Different dispersal protocols may yield cells with different degrees of clonogenicity, as well as altered biochemical features, such as loss of cellular proteins, surface antigens, nucleotide pools, etc. The quality of the cell suspension can be judged by the degree of cell clumping and level of cellular debris, both of which impact on flow cytometric measurements and studies in which the number of cells be known accurately. Finally, if the data measured on the cells in suspension are to be extrapolated to phenomena occurring in the tumor in situ, it is desirable that the cells in suspension are representative of those in the solid tumor in vivo. This report compares characteristics of tumor cell suspensions obtained by different types of selected disaggregation methods. 33 refs., 2 figs., 4 tabs

  17. Graphene Functionalized with Arginine Decreases the Development of Glioblastoma Multiforme Tumor in a Gene-Dependent Manner

    Directory of Open Access Journals (Sweden)

    Ewa Sawosz

    2015-10-01

    Full Text Available Our previous studies revealed that graphene had anticancer properties in experiments in vitro with glioblastoma multiforme (GBM cells and in tumors cultured in vivo. We hypothesized that the addition of arginine or proline to graphene solutions might counteract graphene agglomeration and increase the activity of graphene. Experiments were performed in vitro with GBM U87 cells and in vivo with GBM tumors cultured on chicken embryo chorioallantoic membranes. The measurements included cell morphology, mortality, viability, tumor morphology, histology, and gene expression. The cells and tumors were treated with reduced graphene oxide (rGO and rGO functionalized with arginine (rGO + Arg or proline (rGO + Pro. The results confirmed the anticancer effect of graphene on GBM cells and tumor tissue. After functionalization with amino acids, nanoparticles were distributed more specifically, and the flakes of graphene were less agglomerated. The molecule of rGO + Arg did not increase the expression of TP53 in comparison to rGO, but did not increase the expression of MDM2 or the MDM2/TP53 ratio in the tumor, suggesting that arginine may block MDM2 expression. The expression of NQO1, known to be a strong protector of p53 protein in tumor tissue, was greatly increased. The results indicate that the complex of rGO + Arg has potential in GBM therapy.

  18. Graphene Functionalized with Arginine Decreases the Development of Glioblastoma Multiforme Tumor in a Gene-Dependent Manner

    Science.gov (United States)

    Sawosz, Ewa; Jaworski, Sławomir; Kutwin, Marta; Vadalasetty, Krishna Prasad; Grodzik, Marta; Wierzbicki, Mateusz; Kurantowicz, Natalia; Strojny, Barbara; Hotowy, Anna; Lipińska, Ludwika; Jagiełło, Joanna; Chwalibog, André

    2015-01-01

    Our previous studies revealed that graphene had anticancer properties in experiments in vitro with glioblastoma multiforme (GBM) cells and in tumors cultured in vivo. We hypothesized that the addition of arginine or proline to graphene solutions might counteract graphene agglomeration and increase the activity of graphene. Experiments were performed in vitro with GBM U87 cells and in vivo with GBM tumors cultured on chicken embryo chorioallantoic membranes. The measurements included cell morphology, mortality, viability, tumor morphology, histology, and gene expression. The cells and tumors were treated with reduced graphene oxide (rGO) and rGO functionalized with arginine (rGO + Arg) or proline (rGO + Pro). The results confirmed the anticancer effect of graphene on GBM cells and tumor tissue. After functionalization with amino acids, nanoparticles were distributed more specifically, and the flakes of graphene were less agglomerated. The molecule of rGO + Arg did not increase the expression of TP53 in comparison to rGO, but did not increase the expression of MDM2 or the MDM2/TP53 ratio in the tumor, suggesting that arginine may block MDM2 expression. The expression of NQO1, known to be a strong protector of p53 protein in tumor tissue, was greatly increased. The results indicate that the complex of rGO + Arg has potential in GBM therapy. PMID:26512645

  19. Tumor cell-derived microparticles polarize M2 tumor-associated macrophages for tumor progression.

    Science.gov (United States)

    Ma, Ruihua; Ji, Tiantian; Chen, Degao; Dong, Wenqian; Zhang, Huafeng; Yin, Xiaonan; Ma, Jingwei; Liang, Xiaoyu; Zhang, Yi; Shen, Guanxin; Qin, Xiaofeng; Huang, Bo

    2016-04-01

    Despite identification of macrophages in tumors (tumor-associated macrophages, TAM) as potential targets for cancer therapy, the origin and function of TAM in the context of malignancy remain poorly characterized. Here, we show that microparticles (MPs), as a by-product, released by tumor cells act as a general mechanism to mediate M2 polarization of TAM. Taking up tumor MPs by macrophages is a very efficient process, which in turn results in the polarization of macrophages into M2 type, not only leading to promoting tumor growth and metastasis but also facilitating cancer stem cell development. Moreover, we demonstrate that the underlying mechanism involves the activation of the cGAS/STING/TBK1/STAT6 pathway by tumor MPs. Finally, in addition to murine tumor MPs, we show that human counterparts also possess consistent effect on human M2 polarization. These findings provide new insights into a critical role of tumor MPs in remodeling of tumor microenvironment and better understanding of the communications between tumors and macrophages.

  20. Radiation Therapy of Suprasellar Germ Cell Tumors

    International Nuclear Information System (INIS)

    Park, Woo Yoon; Choi, Doo Ho; Choi, Eun Kyung; Kim, Il Han; Ha, Sung Whan; Park, Charn Il

    1988-01-01

    A retrospective study was performed on 15 patients with suprasellar germ cell tumors treated by megavoltage external beam irradiation between Feb. 1979 and Dec. 1985. Follow-up period of survivors was 30 to 91 months. Histologic diagnosis was obtained before radiation therapy in 10 patients (9 germinomas and 1 mixed). Five patients were treated without histologic verification. In 9 patients with biopsy-proven germinomas radiation therapy was delivered to the craniospinal axis in 6, to the whole brain in 3. In 5 patients with mixed germ cell tumor or elevated tumor marker, irradiation was delivered to the craniospinal axis in 2, to the whole brain in 2, and to the primary site only in 1. Total doses ranged from 5,000 to 5,500 cGy to the primary site, 3,000 to 4,400 cGy to the whole brain, and 1,300 to 3,000 cGy to the spine. In these 14, local tumor was controlled and primary or spinal failure was not observed. One patient without elevated tumor marker was treated to the whole brain, The tumor was not controlled and he had spinal recurrence. It is proven that radiation therapy is an effective treatment for suprasellar germ cell tumors. The neuroendocrinologic presentation, tumor marker status, early response to radiation measured on CT seem to be useful means for selecting patients for radiation therapy when tissue diagnosis is not available

  1. Energy and Redox Homeostasis in Tumor Cells

    Directory of Open Access Journals (Sweden)

    Marcus Fernandes de Oliveira

    2012-01-01

    Full Text Available Cancer cells display abnormal morphology, chromosomes, and metabolism. This review will focus on the metabolism of tumor cells integrating the available data by way of a functional approach. The first part contains a comprehensive introduction to bioenergetics, mitochondria, and the mechanisms of production and degradation of reactive oxygen species. This will be followed by a discussion on the oxidative metabolism of tumor cells including the morphology, biogenesis, and networking of mitochondria. Tumor cells overexpress proteins that favor fission, such as GTPase dynamin-related protein 1 (Drp1. The interplay between proapoptotic members of the Bcl-2 family that promotes Drp 1-dependent mitochondrial fragmentation and fusogenic antiapoptotic proteins such as Opa-1 will be presented. It will be argued that contrary to the widespread belief that in cancer cells, aerobic glycolysis completely replaces oxidative metabolism, a misrepresentation of Warburg’s original results, mitochondria of tumor cells are fully viable and functional. Cancer cells also carry out oxidative metabolism and generally conform to the orthodox model of ATP production maintaining as well an intact electron transport system. Finally, data will be presented indicating that the key to tumor cell survival in an ROS rich environment depends on the overexpression of antioxidant enzymes and high levels of the nonenzymatic antioxidant scavengers.

  2. Selective targeting of brain tumors with gold nanoparticle-induced radiosensitization.

    Directory of Open Access Journals (Sweden)

    Daniel Y Joh

    Full Text Available Successful treatment of brain tumors such as glioblastoma multiforme (GBM is limited in large part by the cumulative dose of Radiation Therapy (RT that can be safely given and the blood-brain barrier (BBB, which limits the delivery of systemic anticancer agents into tumor tissue. Consequently, the overall prognosis remains grim. Herein, we report our pilot studies in cell culture experiments and in an animal model of GBM in which RT is complemented by PEGylated-gold nanoparticles (GNPs. GNPs significantly increased cellular DNA damage inflicted by ionizing radiation in human GBM-derived cell lines and resulted in reduced clonogenic survival (with dose-enhancement ratio of ~1.3. Intriguingly, combined GNP and RT also resulted in markedly increased DNA damage to brain blood vessels. Follow-up in vitro experiments confirmed that the combination of GNP and RT resulted in considerably increased DNA damage in brain-derived endothelial cells. Finally, the combination of GNP and RT increased survival of mice with orthotopic GBM tumors. Prior treatment of mice with brain tumors resulted in increased extravasation and in-tumor deposition of GNP, suggesting that RT-induced BBB disruption can be leveraged to improve the tumor-tissue targeting of GNP and thus further optimize the radiosensitization of brain tumors by GNP. These exciting results together suggest that GNP may be usefully integrated into the RT treatment of brain tumors, with potential benefits resulting from increased tumor cell radiosensitization to preferential targeting of tumor-associated vasculature.

  3. Monoclonal TCR-redirected tumor cell killing.

    Science.gov (United States)

    Liddy, Nathaniel; Bossi, Giovanna; Adams, Katherine J; Lissina, Anna; Mahon, Tara M; Hassan, Namir J; Gavarret, Jessie; Bianchi, Frayne C; Pumphrey, Nicholas J; Ladell, Kristin; Gostick, Emma; Sewell, Andrew K; Lissin, Nikolai M; Harwood, Naomi E; Molloy, Peter E; Li, Yi; Cameron, Brian J; Sami, Malkit; Baston, Emma E; Todorov, Penio T; Paston, Samantha J; Dennis, Rebecca E; Harper, Jane V; Dunn, Steve M; Ashfield, Rebecca; Johnson, Andy; McGrath, Yvonne; Plesa, Gabriela; June, Carl H; Kalos, Michael; Price, David A; Vuidepot, Annelise; Williams, Daniel D; Sutton, Deborah H; Jakobsen, Bent K

    2012-06-01

    T cell immunity can potentially eradicate malignant cells and lead to clinical remission in a minority of patients with cancer. In the majority of these individuals, however, there is a failure of the specific T cell receptor (TCR)–mediated immune recognition and activation process. Here we describe the engineering and characterization of new reagents termed immune-mobilizing monoclonal TCRs against cancer (ImmTACs). Four such ImmTACs, each comprising a distinct tumor-associated epitope-specific monoclonal TCR with picomolar affinity fused to a humanized cluster of differentiation 3 (CD3)-specific single-chain antibody fragment (scFv), effectively redirected T cells to kill cancer cells expressing extremely low surface epitope densities. Furthermore, these reagents potently suppressed tumor growth in vivo. Thus, ImmTACs overcome immune tolerance to cancer and represent a new approach to tumor immunotherapy.

  4. Epidermal growth factor receptor (EGFR mutation status and Rad51 determine the response of glioblastoma (GBM to multimodality therapy with cetuximab, temozolomide and radiation

    Directory of Open Access Journals (Sweden)

    Phyllis Rachelle Wachsberger

    2013-02-01

    Full Text Available Purpose: EGFR amplification and mutation (i.e., EGFRvIII are found in 40% of primary GBM tumors and are believed to contribute to tumor development and therapeutic resistance. This study was designed to investigate how EGFR mutational status modulates response to multimodality treatment with cetuximab, an anti-EGFR inhibitor, the chemotherapeutic agent, temozolamide (TMZ and radiation therapy (RT Methods and Materials: In vitro and in vivo experiments were performed on two isogenic U87 GBM cell lines: one overexpressing wildtype EGFR (U87wtEGFR and the other overexpressing EGFRvIII (U87EGFRvIII. Results: Xenografts harboring EGFRvIII were more sensitive to TMZ alone and TMZ in combination with RT and/or cetuximab than xenografts expressing wtEGFR. In vitro experiments demonstrated that U87EGFRvIII-expressing tumors appear to harbor defective DNA homologous recombination repair in the form of Rad51 processing, Conclusions: The difference in sensitivity between EGFR-expressing and EGFRvIII-expressing tumors to combined modality treatment may help in the future tailoring of GBM therapy to subsets of patients expressing more or less of the EGFR mutant.

  5. ADAM12 produced by tumor cells rather than stromal cells accelerates breast tumor progression

    DEFF Research Database (Denmark)

    Frohlich, Camilla; Nehammer, Camilla; Albrechtsen, Reidar

    2011-01-01

    that ADAM12 deficiency reduces breast tumor progression in the PyMT model. However, the catalytic activity of ADAM12 appears to be dispensable for its tumor-promoting effect. Interestingly, we demonstrate that ADAM12 endogenously expressed in tumor-associated stroma in the PyMT model does not influence......Expression of ADAM12 is low in most normal tissues, but is markedly increased in numerous human cancers, including breast carcinomas. We have previously shown that overexpression of ADAM12 accelerates tumor progression in a mouse model of breast cancer (PyMT). In the present study, we found...... hypothesized, however, that the tumor-associated stroma may stimulate ADAM12 expression in tumor cells, based on the fact that TGF-ß1 stimulates ADAM12 expression and is a well-known growth factor released from tumor-associated stroma. TGF-ß1 stimulation of ADAM12-negative Lewis lung tumor cells induced ADAM12...

  6. CD8+ Tumor-Infiltrating T Cells Are Trapped in the Tumor-Dendritic Cell Network

    Directory of Open Access Journals (Sweden)

    Alexandre Boissonnas

    2013-01-01

    Full Text Available Chemotherapy enhances the antitumor adaptive immune T cell response, but the immunosuppressive tumor environment often dominates, resulting in cancer relapse. Antigen-presenting cells such as tumor-associated macrophages (TAMs and tumor dendritic cells (TuDCs are the main protagonists of tumor-infiltrating lymphocyte (TIL immuno-suppression. TAMs have been widely investigated and are associated with poor prognosis, but the immuno-suppressive activity of TuDCs is less well understood. We performed two-photon imaging of the tumor tissue to examine the spatiotemporal interactions between TILs and TuDCs after chemotherapy. In a strongly immuno-suppressive murine tumor model, cyclophosphamide-mediated chemotherapy transiently enhanced the antitumor activity of adoptively transferred ovalbumin-specific CD8+ T cell receptor transgenic T cells (OTI but barely affected TuDC compartment within the tumor. Time lapse imaging of living tumor tissue showed that TuDCs are organized as a mesh with dynamic interconnections. Once infiltrated into the tumor parenchyma, OTI T cells make antigen-specific and long-lasting contacts with TuDCs. Extensive analysis of TIL infiltration on histologic section revealed that after chemotherapy the majority of OTI T cells interact with TuDCs and that infiltration is restricted to TuDC-rich areas. We propose that the TuDC network exerts antigen-dependent unproductive retention that trap T cells and limit their antitumor effectiveness.

  7. The Accuracy of GBM GRB Localizations

    Science.gov (United States)

    Briggs, Michael Stephen; Connaughton, V.; Meegan, C.; Hurley, K.

    2010-03-01

    We report an study of the accuracy of GBM GRB localizations, analyzing three types of localizations: those produced automatically by the GBM Flight Software on board GBM, those produced automatically with ground software in near real time, and localizations produced with human guidance. The two types of automatic locations are distributed in near real-time via GCN Notices; the human-guided locations are distributed on timescale of many minutes or hours using GCN Circulars. This work uses a Bayesian analysis that models the distribution of the GBM total location error by comparing GBM locations to more accurate locations obtained with other instruments. Reference locations are obtained from Swift, Super-AGILE, the LAT, and with the IPN. We model the GBM total location errors as having systematic errors in addition to the statistical errors and use the Bayesian analysis to constrain the systematic errors.

  8. The novel Hsp90 inhibitor NXD30001 induces tumor regression in a genetically engineered mouse model of glioblastoma multiforme.

    Science.gov (United States)

    Zhu, Haihao; Woolfenden, Steve; Bronson, Roderick T; Jaffer, Zahara M; Barluenga, Sofia; Winssinger, Nicolas; Rubenstein, Allan E; Chen, Ruihong; Charest, Al

    2010-09-01

    Glioblastoma multiforme (GBM) has an abysmal prognosis. We now know that the epidermal growth factor receptor (EGFR) signaling pathway and the loss of function of the tumor suppressor genes p16Ink4a/p19ARF and PTEN play a crucial role in GBM pathogenesis: initiating the early stages of tumor development, sustaining tumor growth, promoting infiltration, and mediating resistance to therapy. We have recently shown that this genetic combination is sufficient to promote the development of GBM in adult mice. Therapeutic agents raised against single targets of the EGFR signaling pathway have proven rather inefficient in GBM therapy, showing the need for combinatorial therapeutic approaches. An effective strategy for concurrent disruption of multiple signaling pathways is via the inhibition of the molecular chaperone heat shock protein 90 (Hsp90). Hsp90 inhibition leads to the degradation of so-called client proteins, many of which are key effectors of GBM pathogenesis. NXD30001 is a novel second generation Hsp90 inhibitor that shows improved pharmacokinetic parameters. Here we show that NXD30001 is a potent inhibitor of GBM cell growth in vitro consistent with its capacity to inhibit several key targets and regulators of GBM biology. We also show the efficacy of NXD30001 in vivo in an EGFR-driven genetically engineered mouse model of GBM. Our findings establish that the Hsp90 inhibitor NXD30001 is a therapeutically multivalent molecule, whose actions strike GBM at the core of its drivers of tumorigenesis and represent a compelling rationale for its use in GBM treatment.

  9. Osteoclastic giant cell tumor of the pancreas: an immunohistochemical study

    DEFF Research Database (Denmark)

    Dizon, M A; Multhaupt, H A; Paskin, D L

    1996-01-01

    A case of an osteoclastic giant cell tumor of the pancreas is presented. Immunohistochemical studies were performed, which showed keratin (CAM, AE1) and epithelial membrane antigen positivity in the tumor cells. The findings support an epithelial origin for this tumor.......A case of an osteoclastic giant cell tumor of the pancreas is presented. Immunohistochemical studies were performed, which showed keratin (CAM, AE1) and epithelial membrane antigen positivity in the tumor cells. The findings support an epithelial origin for this tumor....

  10. Whole tumor antigen vaccination using dendritic cells: Comparison of RNA electroporation and pulsing with UV-irradiated tumor cells

    Directory of Open Access Journals (Sweden)

    Benencia Fabian

    2008-04-01

    Full Text Available Abstract Because of the lack of full characterization of tumor associated antigens for solid tumors, whole antigen use is a convenient approach to tumor vaccination. Tumor RNA and apoptotic tumor cells have been used as a source of whole tumor antigen to prepare dendritic cell (DC based tumor vaccines, but their efficacy has not been directly compared. Here we compare directly RNA electroporation and pulsing of DCs with whole tumor cells killed by ultraviolet (UV B radiation using a convenient tumor model expressing human papilloma virus (HPV E6 and E7 oncogenes. Although both approaches led to DCs presenting tumor antigen, electroporation with tumor cell total RNA induced a significantly higher frequency of tumor-reactive IFN-gamma secreting T cells, and E7-specific CD8+ lymphocytes compared to pulsing with UV-irradiated tumor cells. DCs electroporated with tumor cell RNA induced a larger tumor infiltration by T cells and produced a significantly stronger delay in tumor growth compared to DCs pulsed with UV-irradiated tumor cells. We conclude that electroporation with whole tumor cell RNA and pulsing with UV-irradiated tumor cells are both effective in eliciting antitumor immune response, but RNA electroporation results in more potent tumor vaccination under the examined experimental conditions.

  11. Molecular biology of testicular germ cell tumors.

    Science.gov (United States)

    Gonzalez-Exposito, R; Merino, M; Aguayo, C

    2016-06-01

    Testicular germ cell tumors (TGCTs) are the most common solid tumors in young adult men. They constitute a unique pathology because of their embryonic and germ origin and their special behavior. Genetic predisposition, environmental factors involved in their development and genetic aberrations have been under study in many works throughout the last years trying to explain the susceptibility and the transformation mechanism of TGCTs. Despite the high rate of cure in this type of tumors because its particular sensitivity to cisplatin, there are tumors resistant to chemotherapy for which it is needed to find new therapies. In the present work, it has been carried out a literature review on the most important molecular aspects involved in the onset and development of such tumors, as well as a review of the major developments regarding prognostic factors, new prognostic biomarkers and the possibility of new targeted therapies.

  12. Fermi GBM: Results from the First Year +

    Science.gov (United States)

    Wilson-Hodge, Colleen A.

    2009-01-01

    Gamma-ray Burst Monitor (GBM) has performed well in the first year+. GBM triggers 353 Gamma-ray Bursts (GRBs), 168 SGR events, 18 TGFs, and 1 solar flare to date. Short GRBs appear contracted in time and shifted to higher energy than long GRBs. Pulsed persistent emission from SGR 1550-5418 detected. TGFs are shorter, have higher average photon energies, and much higher count rates than GRBs. GBM monitoring of accreting pulsars provides long-term spin-histories. GBM Earth occultation monitoring complements Swift.

  13. Tumor-Infiltrating Immune Cells Promoting Tumor Invasion and Metastasis: Existing Theories

    Directory of Open Access Journals (Sweden)

    Yan-gao Man, Alexander Stojadinovic, Jeffrey Mason, Itzhak Avital, Anton Bilchik, Bjoern Bruecher, Mladjan Protic, Aviram Nissan, Mina Izadjoo, Xichen Zhang, Anahid Jewett

    2013-01-01

    Full Text Available It is a commonly held belief that infiltration of immune cells into tumor tissues and direct physical contact between tumor cells and infiltrated immune cells is associated with physical destructions of the tumor cells, reduction of the tumor burden, and improved clinical prognosis. An increasing number of studies, however, have suggested that aberrant infiltration of immune cells into tumor or normal tissues may promote tumor progression, invasion, and metastasis. Neither the primary reason for these contradictory observations, nor the mechanism for the reported diverse impact of tumor-infiltrating immune cells has been elucidated, making it difficult to judge the clinical implications of infiltration of immune cells within tumor tissues. This mini-review presents several existing hypotheses and models that favor the promoting impact of tumor-infiltrating immune cells on tumor invasion and metastasis, and also analyzes their strength and weakness.

  14. Perivascular Epithelioid Cell Tumor in the Stomach

    Directory of Open Access Journals (Sweden)

    Sun Ah Shin

    2017-07-01

    Full Text Available Perivascular epithelioid cell tumors or PEComas can arise in any location in the body. However, a limited number of cases of gastric PEComa have been reported. We present two cases of gastric PEComas. The first case involved a 62-year-old woman who presented with a 4.2 cm gastric subepithelial mass in the prepyloric antrum, and the second case involved a 67-year-old man with a 5.0 cm mass slightly below the gastroesophageal junction. Microscopic examination revealed that both tumors were composed of perivascular epithelioid cells that were immunoreactive for melanocytic and smooth muscle markers. Prior to surgery, the clinical impression of both tumors was gastrointestinal stromal tumor (GIST, and the second case was erroneously diagnosed as GIST even after microscopic examination. Although gastric PEComa is a very rare neoplasm, it should be considered in the differential diagnosis of gastric submucosal lesions.

  15. Adenomatoid odontogenic tumor with clear cell changes

    Directory of Open Access Journals (Sweden)

    Neeta Mohanty

    2014-01-01

    Full Text Available Adenomatoid odontogenic tumor (AOT has a limited biological profile and been an attention-grabbing tumor for a century for its origin. Though described earlier, it was widely accepted after Harbitz from Norway reported about this uncommon benign tumor in 1915. There has been a long debate as whether this tumor is a hamartoma or a neoplasm. Here, we present a case of AOT in a 20-year-old female with details of clinical, radiological and histological features along with clear cell changes, signifying AOT to be more aggressive in nature than assessed from earlier literature. Thus, we did an extensive search of PubMed literature on AOT with all its histopathological features associated until date to find the report of clear cell changes yet.

  16. Interference with PSMB4 Expression Exerts an Anti-Tumor Effect by Decreasing the Invasion and Proliferation of Human Glioblastoma Cells

    Directory of Open Access Journals (Sweden)

    Yu-Chen Cheng

    2018-01-01

    Full Text Available Background/Aims: Glioblastoma (GBM is a malignant brain tumor with a poor prognosis. Proteasome subunit beta type-4 (PSMB4 is an essential subunit that contributes to the assembly of the 20S proteasome complex. However, the role of PSMB4 in glioblastomas remains to be clarified. The aim of this study was to investigate the role of PSMB4 in GBM tumor progression. Methods: We first analyzed the PSMB4 protein and mRNA expression in 80 clinical brain specimens and 77 datasets from the National Center for Biotechnology Information (NCBI Gene Expression Omnibus (GEO database. Next, we inhibited the PSMB4 expression by siRNA in cellular and animal models to explore PSMB4’s underlying mechanisms. The cell survival after siPSMB4 transfection was assayed by MTT assay. Annexin V and propidium iodide staining was used to monitor the apoptosis by flow cytometric analysis. Moreover, the migration and invasion were evaluated by wound healing and Transwell assays. The expression of migration-related and invasion-related proteins after PSMB4 inhibition was detected by Western blotting. In addition, an orthotropic xenograft mouse model was used to assay the effect of PSMB4 knockdown in the in vivo study. Results: Basis on the results of bioinformatics study, glioma patients with higher PSMB4 expression had a shorter survival time than those with lower PSMB4 expression. The staining of clinical brain tissues showed elevated PSMB4 expression in GBM tissues compared with normal brain tissues. The PSMB4 inhibition decreased proliferation, migration and invasion abilities in human GBM cells. Downregulated PSMB4 resulted in cell cycle arrest and apoptosis in vitro. In an orthotropic xenograft mouse model, the glioma tumors progression was reduced when PSMB4 was down-regulated. The decreased PSMB4 enhanced the anti-tumor effect of temozolomide (TMZ on tumor growth. In addition, the absence of PSMB4 decreased the expression of phosphorylated focal adhesion kinase and

  17. The Human Cell Surfaceome of Breast Tumors

    Science.gov (United States)

    da Cunha, Júlia Pinheiro Chagas; Galante, Pedro Alexandre Favoretto; de Souza, Jorge Estefano Santana; Pieprzyk, Martin; Carraro, Dirce Maria; Old, Lloyd J.; Camargo, Anamaria Aranha; de Souza, Sandro José

    2013-01-01

    Introduction. Cell surface proteins are ideal targets for cancer therapy and diagnosis. We have identified a set of more than 3700 genes that code for transmembrane proteins believed to be at human cell surface. Methods. We used a high-throuput qPCR system for the analysis of 573 cell surface protein-coding genes in 12 primary breast tumors, 8 breast cell lines, and 21 normal human tissues including breast. To better understand the role of these genes in breast tumors, we used a series of bioinformatics strategies to integrates different type, of the datasets, such as KEGG, protein-protein interaction databases, ONCOMINE, and data from, literature. Results. We found that at least 77 genes are overexpressed in breast primary tumors while at least 2 of them have also a restricted expression pattern in normal tissues. We found common signaling pathways that may be regulated in breast tumors through the overexpression of these cell surface protein-coding genes. Furthermore, a comparison was made between the genes found in this report and other genes associated with features clinically relevant for breast tumorigenesis. Conclusions. The expression profiling generated in this study, together with an integrative bioinformatics analysis, allowed us to identify putative targets for breast tumors. PMID:24195083

  18. Malignant Solitary Fibrous Tumor Metastatic to Widely Invasive Hurthle Cell Thyroid Carcinoma: A Distinct Tumor-to-Tumor Metastasis.

    Science.gov (United States)

    Kolson Kokohaare, Eva; Riva, Francesco M G; Bernstein, Jonathan M; Miah, Aisha B; Thway, Khin

    2018-04-01

    We illustrate a case of synchronous malignant solitary fibrous tumor of the thoracic cavity, and widely invasive thyroid Hurthle cell carcinoma. The Hurthle cell carcinoma was found to harbor distinct areas of malignant solitary fibrous tumor. This is a unique case of tumor-to-tumor metastasis that, to the best of our knowledge, has not been previously reported.

  19. Treatment Resistance Mechanisms of Malignant Glioma Tumor Stem Cells

    International Nuclear Information System (INIS)

    Schmalz, Philip G.R.; Shen, Michael J.; Park, John K.

    2011-01-01

    Malignant gliomas are highly lethal because of their resistance to conventional treatments. Recent evidence suggests that a minor subpopulation of cells with stem cell properties reside within these tumors. These tumor stem cells are more resistant to radiation and chemotherapies than their counterpart differentiated tumor cells and may underlie the persistence and recurrence of tumors following treatment. The various mechanisms by which tumor stem cells avoid or repair the damaging effects of cancer therapies are discussed

  20. Oriented collagen fibers direct tumor cell intravasation

    KAUST Repository

    Han, Weijing

    2016-09-24

    In this work, we constructed a Collagen I-Matrigel composite extracellular matrix (ECM). The composite ECM was used to determine the influence of the local collagen fiber orientation on the collective intravasation ability of tumor cells. We found that the local fiber alignment enhanced cell-ECM interactions. Specifically, metastatic MDA-MB-231 breast cancer cells followed the local fiber alignment direction during the intravasation into rigid Matrigel (∼10 mg/mL protein concentration).

  1. Glioblastoma cells labeled by robust Raman tags for enhancing imaging contrast.

    Science.gov (United States)

    Huang, Li-Ching; Chang, Yung-Ching; Wu, Yi-Syuan; Sun, Wei-Lun; Liu, Chan-Chuan; Sze, Chun-I; Chen, Shiuan-Yeh

    2018-05-01

    Complete removal of a glioblastoma multiforme (GBM), a highly malignant brain tumor, is challenging due to its infiltrative characteristics. Therefore, utilizing imaging agents such as fluorophores to increase the contrast between GBM and normal cells can help neurosurgeons to locate residual cancer cells during image guided surgery. In this work, Raman tag based labeling and imaging for GBM cells in vitro is described and evaluated. The cell membrane of a GBM adsorbs a substantial amount of functionalized Raman tags through overexpression of the epidermal growth factor receptor (EGFR) and "broadcasts" stronger pre-defined Raman signals than normal cells. The average ratio between Raman signals from a GBM cell and autofluorescence from a normal cell can be up to 15. In addition, the intensity of these images is stable under laser illuminations without suffering from the severe photo-bleaching that usually occurs in fluorescent imaging. Our results show that labeling and imaging GBM cells via robust Raman tags is a viable alternative method to distinguish them from normal cells. This Raman tag based method can be used solely or integrated into an existing fluorescence system to improve the identification of infiltrative glial tumor cells around the boundary, which will further reduce GBM recurrence. In addition, it can also be applied/extended to other types of cancer to improve the effectiveness of image guided surgery.

  2. Giant cell tumor of bone: Multimodal approach

    Directory of Open Access Journals (Sweden)

    Gupta A

    2007-01-01

    Full Text Available Background: The clinical behavior and treatment of giant cell tumor of bone is still perplexing. The aim of this study is to clarify the clinico-pathological correlation of tumor and its relevance in treatment and prognosis. Materials and Methods: Ninety -three cases of giant cell tumor were treated during 1980-1990 by different methods. The age of the patients varied from 18-58 yrs with male and female ratio as 5:4. The upper end of the tibia was most commonly involved (n=31, followed by the lower end of the femur(n=21, distal end of radius(n=14,upper end of fibula (n=9,proximal end of femur(n=5, upper end of the humerus(n=3, iliac bone(n=2,phalanx (n=2 and spine(n=1. The tumors were also encountered on uncommon sites like metacarpals (n=4 and metatarsal(n=1. Fifty four cases were treated by curettage and bone grafting. Wide excision and reconstruction was performed in twenty two cases . Nine cases were treated by wide excision while primary amputation was performed in four cases. One case required only curettage. Three inaccessible lesions of ilium and spine were treated by radiotherapy. Results: 19 of 54 treated by curettage and bone grafting showed a recurrence. The repeat curettage and bone grafting was performed in 18 cases while amputation was done in one. One each out of the cases treated by wide excision and reconstruction and wide excision alone recurred. In this study we observed that though curettage and bone grafting is still the most commonly adopted treatment, wide excision of tumor with reconstruction has shown lesser recurrence. Conclusion: For radiologically well-contained and histologically typical tumor, curettage and autogenous bone grafting is the treatment of choice . The typical tumors with radiologically deficient cortex, clinically aggressive tumors and tumors with histological Grade III should be treated by wide excision and reconstruction.

  3. Radiotherapy of patients with germ cell tumor

    International Nuclear Information System (INIS)

    Inomata, Taisuke; Maeda, Tomoho; Yoshida, Shoji; Ogawa, Yasuhiro; Hamada, Fumio; Imajo, Yoshinari; Gose, Kyuhei; Fujiwara, Kiyoshi.

    1986-01-01

    Twenty-one patients with germ cell tumor who received radiotherapy were discussed. There were eight patients with germinoma, two patients with malignant teratoma, three patients with pineocytoma (out of category of germ cell tumor today) and eight unverified patients. Irradiated dose was mostly from 50 Gy to 60 Gy and local irradiation was performed after whole brain irradiation in many cases. The effect of radiotherapy was not so good in patients with malignant teratoma. On the contrary, it was relatively good in patients with germinoma and five out of eight patients are alive with no symptoms of recurrence. Six out of eight unverified patients are also alive. Among them, several patients with germinoma are considered to be included. Germinoma occupies many cases of germ cell tumor and has a good response to radiotherapy. Against spinal cord metastasis and late recurrence, additional therapy, such as chemotherapy, seems to be useful to improve cure ratio. (author)

  4. A tumor-targeting p53 nanodelivery system limits chemoresistance to temozolomide prolonging survival in a mouse model of glioblastoma multiforme.

    Science.gov (United States)

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

    2015-02-01

    Development of temozolomide (TMZ) resistance contributes to the poor prognosis for glioblastoma multiforme (GBM) patients. It was previously demonstrated that delivery of exogenous wild-type tumor suppressor gene p53 via a tumor-targeted nanocomplex (SGT-53) which crosses the blood-brain barrier could sensitize highly TMZ-resistant GBM tumors to TMZ. Here we assessed whether SGT-53 could inhibit development of TMZ resistance. SGT-53 significantly chemosensitized TMZ-sensitive human GBM cell lines (U87 and U251), in vitro and in vivo. Furthermore, in an intracranial GBM tumor model, two cycles of concurrent treatment with systemically administered SGT-53 and TMZ inhibited tumor growth, increased apoptosis and most importantly, significantly prolonged median survival. In contrast TMZ alone had no significant effect on median survival compared to a single cycle of TMZ. These results suggest that combining SGT-53 with TMZ appears to limit development of TMZ resistance, prolonging its anti-tumor effect and could be a more effective therapy for GBM. Using human glioblastoma multiforma cell lines, this research team demonstrated that the delivery of exogenous wild-type tumor suppressor gene p53 via a tumor-targeted nanocomplex limited the development of temozolomide resistance and prolonged its anti-tumor effect, which may enable future human application of this or similar techniques. Copyright © 2015 Elsevier Inc. All rights reserved.

  5. New Molecules and Old Drugs as Emerging Approaches to Selectively Target Human Glioblastoma Cancer Stem Cells

    Directory of Open Access Journals (Sweden)

    Roberto Würth

    2014-01-01

    Full Text Available Despite relevant progress obtained by multimodal treatment, glioblastoma (GBM, the most aggressive primary brain tumor, is still incurable. The most encouraging advancement of GBM drug research derives from the identification of cancer stem cells (CSCs, since these cells appear to represent the determinants of resistance to current standard therapies. The goal of most ongoing studies is to identify drugs able to affect CSCs biology, either inducing selective toxicity or differentiating this tumor cell population into nontumorigenic cells. Moreover, the therapeutic approach for GBM could be improved interfering with chemo- or radioresistance mechanisms, microenvironment signals, and the neoangiogenic process. During the last years, molecular targeted compounds such as sorafenib and old drugs, like metformin, displayed interesting efficacy in preclinical studies towards several tumors, including GBM, preferentially affecting CSC viability. In this review, the latest experimental results, controversies, and prospective application concerning these promising anticancer drugs will be discussed.

  6. Granular cells Tumor in the gastrointestinal tract

    International Nuclear Information System (INIS)

    Castano LL, Rodrigo; Gaitan B, Maria H; Juliao E, Fabian

    2005-01-01

    Granular cells tumors are ubiquitous lesions in the gastrointestinal tract, are rare and asymptomatic and they are generally an incidental discovery at gastroduodenoscopy or colonoscopy. In the gastrointestinal tract they are more frequently located in the esophagus, right colon and rectum, stomach, appendix, small intestine or biliopancreatic tract. This article describes three patients with four tumors of granular cells in rectum, esophagus (2 lesions) and appendix. It becomes special emphasis in their neural origin, their benign behavior that justifies the endoscopic resections or limited surgical excisions and the necessity of a pursuit for the possibility, although little, of malignant transformation

  7. Escape from Tumor Cell Dormancy

    Science.gov (United States)

    2012-10-01

    for metastatic cell arrest in distant organs. Neoplasia, 7(5), 522-7 (2005) 170. K. A . Paschos, D. Canovas and N. C. Bird : The role of cell adhesion...overnight in a 608C oven . Polymerized PDMS micropatterned stamps were peeled off the silicon master and used for patterning the PEG–fibrinogen...to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE

  8. Innate Lymphoid Cells in Tumor Immunity.

    Science.gov (United States)

    van Beek, Jasper J P; Martens, Anne W J; Bakdash, Ghaith; de Vries, I Jolanda M

    2016-02-25

    Innate lymphoid cells (ILCs) are a group of immune cells of the lymphoid lineage that do not possess antigen specificity. The group includes natural killer (NK) cells, lymphoid tissue inducer (LTi) cells and the recently identified ILC1s, ILC2s and ILC3s. Although the role of NK cells in the context of cancer has been well established, the involvement of other ILC subsets in cancer progression and resistance is just emerging. Here, we review the literature on the role of the different ILC subsets in tumor immunity and discuss its implications for cancer treatment and monitoring.

  9. Granulosa cell tumor of ovary: US findings

    International Nuclear Information System (INIS)

    Jin, Yong Hyun; Jeon, Hae Jeong; Lee, Chang Dea; Cho, Young Kwon; Kang, Chang Ho; Park, Yong Hyun; Kim, Myung Gyu; Lee, Yeon Hee; Kim, Young Hwa; Lee, Hye Kyung

    1999-01-01

    To describe ultrasonographic findings of ovarian granulosa cell tumor (GCT) and to determine their possible value in the differential diagnosis of ovarian tumors. Sonographic appearances of ten cases of pathologically proven GC Ts were retrospectively reviewed regarding their location, size, outer margin, the echo pattern of the tumor, endometrial thickness, presence of ascites, and metastasis to adjacent tissue or distant sites. 3.0-3.5 MHz trans-abdominal US or 5.0-6.5 MHz transvaginal US were used. The sonographic features could be classified as follows: unilocular cystic mass without nodule or septation (type 1), multilocular cystic mass (type 2), and solid mass (type 3). Pathologically nine cases were adult type granulosa cell tumors (GCT) and one was a juvenile type. All cases were unilateral. GCT arising from left ovary were seven, right, three. The largest diameter of the tumors ranged from 6.8 to 24 cm (mean: 11.9 cm). All had well-defined margins. Ascites was seen in four cases. Among ten cases of GCT, six were mainly solid (type 3). One case manifested as a unilocular cystic mass without mural nodule or septation. Three were multilocular cystic masses and no mural nodule was found in all three cases. Metastases to peritoneum and lymph nodes was seen in one case. The ultrasonographic findings of GCT are various but combined with clinical and laboratory findings they could be helpful in the differential diagnosis of ovarian tumors.

  10. Granulosa cell tumor of ovary: US findings

    Energy Technology Data Exchange (ETDEWEB)

    Jin, Yong Hyun; Jeon, Hae Jeong; Lee, Chang Dea; Cho, Young Kwon [Kun Kuk University School of Medicine, Seoul (Korea, Republic of); Kang, Chang Ho; Park, Yong Hyun [Korea University School of Medicine, Seoul (Korea, Republic of); Kim, Myung Gyu [Korea University School of Medicine, Seoul (Korea, Republic of); Lee, Yeon Hee [Kang Nam Cha General Hospital, Seoul (Korea, Republic of); Kim, Young Hwa; Lee, Hye Kyung [Dan Kuk University School of Medicine (Korea, Republic of)

    1999-06-15

    To describe ultrasonographic findings of ovarian granulosa cell tumor (GCT) and to determine their possible value in the differential diagnosis of ovarian tumors. Sonographic appearances of ten cases of pathologically proven GC Ts were retrospectively reviewed regarding their location, size, outer margin, the echo pattern of the tumor, endometrial thickness, presence of ascites, and metastasis to adjacent tissue or distant sites. 3.0-3.5 MHz trans-abdominal US or 5.0-6.5 MHz transvaginal US were used. The sonographic features could be classified as follows: unilocular cystic mass without nodule or septation (type 1), multilocular cystic mass (type 2), and solid mass (type 3). Pathologically nine cases were adult type granulosa cell tumors (GCT) and one was a juvenile type. All cases were unilateral. GCT arising from left ovary were seven, right, three. The largest diameter of the tumors ranged from 6.8 to 24 cm (mean: 11.9 cm). All had well-defined margins. Ascites was seen in four cases. Among ten cases of GCT, six were mainly solid (type 3). One case manifested as a unilocular cystic mass without mural nodule or septation. Three were multilocular cystic masses and no mural nodule was found in all three cases. Metastases to peritoneum and lymph nodes was seen in one case. The ultrasonographic findings of GCT are various but combined with clinical and laboratory findings they could be helpful in the differential diagnosis of ovarian tumors.

  11. The Fermi GBM catalog (Paciesas+, 2012) [Dataset

    NARCIS (Netherlands)

    Paciesas, W.S.; Meegan, C.A.; von Kienlin, A.; Bhat, P.N.; Bissaldi, E.; Briggs, M.S.; Burgess, J.M.; Chaplin, V.; Connaughton, V.; Diehl, R.; Fishman, G.J.; Fitzpatrick, G.; Foley, S.; H. Gibby, M.; Giles, M.; Goldstein, A.; Greiner, J.; Gruber, D.; Guiriec, S.; van der Horst, A.J.; Kippen, R.M.; Kouveliotou, C.; Lichti, G.; Lin, L.; McBreen, S.; Preece, R.D.; Rau, A.; Tierney, D.; Wilson-Hodge, C.

    2012-01-01

    The Fermi Gamma-ray Space Telescope was launched on 2008 June 11 on a mission to study the universe at high energies. The onboard Gamma-ray Burst Monitor (GBM) trigger system for detecting GRBs was first enabled on 2008 July 12. In this paper, we provide a catalog of GRBs that triggered the GBM

  12. Preclinical models to study the impact of the blood-brain barrier in brain tumor chemotherapy

    NARCIS (Netherlands)

    Vries, N.A. de

    2009-01-01

    High-grade gliomas, in particular Glioblastoma Multiforme (GBM), are the most common primary brain tumors in adults and among the deadliest of human cancers. Their location and the extensively infiltrative character of tumor cells into surrounding normal brain structures is an impediment for all

  13. SHMT2 drives glioma cell survival in the tumor microenvironment but imposes a dependence on glycine clearance

    Science.gov (United States)

    Kim, Dohoon; Fiske, Brian P.; Birsoy, Kivanc; Freinkman, Elizaveta; Kami, Kenjiro; Possemato, Richard; Chudnovsky, Yakov; Pacold, Michael E.; Chen, Walter W.; Cantor, Jason R.; Shelton, Laura M.; Gui, Dan Y.; Kwon, Manjae; Ramkissoon, Shakti H.; Ligon, Keith L.; Kang, Seong Woo; Snuderl, Matija; Heiden, Matthew G. Vander; Sabatini, David M.

    2015-01-01

    SUMMARY Cancer cells adapt their metabolic processes to support rapid proliferation, but less is known about how cancer cells alter metabolism to promote cell survival in a poorly vascularized tumor microenvironment1–3. Here, we identify a key role for serine and glycine metabolism in the survival of brain cancer cells within the ischemic zones of gliomas. In human glioblastoma multiforme (GBM), mitochondrial serine hydroxymethyltransferase (SHMT2) and glycine decarboxylase (GLDC) are highly expressed in the pseudopalisading cells that surround necrotic foci. We find that SHMT2 activity limits that of pyruvate kinase (PKM2) and reduces oxygen consumption, eliciting a metabolic state that confers a profound survival advantage to cells in poorly vascularized tumor regions. GLDC inhibition impairs cells with high SHMT2 levels as the excess glycine not metabolized by GLDC can be converted to the toxic molecules aminoacetone and methylglyoxal. Thus, SHMT2 is required for cancer cells to adapt to the tumor environment, but also renders these cells sensitive to glycine cleavage system inhibition. PMID:25855294

  14. Peculiarities in the CT findings of germ cell tumors in various tumor localizations

    International Nuclear Information System (INIS)

    Tazoe, Makoto; Miyagami, Mitsusuke; Tsubokawa, Takashi

    1991-01-01

    The CT findings of 17 germ cell tumors were studied in relation to the locations of the tumor, the pathological diagnoses, and the tumor markers (AFP and HCG). Generally, the CT findings of germ cell tumors depended on the pathological diagnoses more strongly than on the location of the tumors. On plain CT of 7 germ cell tumors in the pineal region, all of them demonstrated heterogeneous findings. Hydrocephalus was seen in 6 cases (86%) and calcification in 6 cases (86%) of the germ cell tumors in the pineal region. Calcification and hydrocephalus that appeared more often than in other regions were characteristic of germ cell tumors of the pineal region. The germ cell tumors in the basal ganglia had a slightly homogenous high density, with small cysts and calcification in most of them on plain CT. On enhanced CT, the tumors were moderately enhanced in all cases located in the basal ganglia. Four cases of germ cell tumors located in the basal ganglia revealed the dilatation of lateral ventricle due to hemispheric atrophy in the tumor side. The germ cell tumors showing an increase in the tumor markers such as AFP and HCG, which were usually malignant germ cell tumors, were strongly enhanced on enhanced CT. (author)

  15. Ovarian Germ Cell Tumors Treatment

    Science.gov (United States)

    ... diagnosed, tests are done to find out if cancer cells have spread within the ovary or to other parts of the body. The process used to find out whether cancer has spread within the ovary or to other parts of the body is ...

  16. Circulating tumor cells: utopia or reality?

    Science.gov (United States)

    Conteduca, Vincenza; Zamarchi, Rita; Rossi, Elisabetta; Condelli, Valentina; Troiani, Laura; Aieta, Michele

    2013-09-01

    Circulating tumor cells (CTCs) could be considered a sign of tumor aggressiveness, but highly sensitive and specific methods of CTC detection are necessary owing to the rarity and heterogeneity of CTCs in peripheral blood. This review summarizes recent studies on tumor biology, with particular attention to the metastatic cascade, and the molecular characterization and clinical significance of CTCs. Recent technological approaches to enrich and detect these cells and challenges of CTCs for individualized cancer treatment are also discussed. This review also provides an insight into the positive and negative features of the future potential applications of CTC detection, which sometimes remains still a 'utopia', but its actual utility remains among the fastest growing research fields in oncology.

  17. Tumor of granular cells of esophagus

    International Nuclear Information System (INIS)

    Gonzalez Fabian, Licet; Diaz Anaya, Amnia; Perez de la Torre, Georgina

    2010-01-01

    Granular cells tumors are rare and asymptomatic lesions and by general, it is an incidental finding en high or low endoscopy. They were described for the first time by Abrikossoff in 1926. The more frequent locations are the buccal mucosa, dermis and subcutaneous cellular tissue, most of these tumors has a benign origin. This is the case of a woman aged 44 with a pyrosis history from a year ago; by high endoscopy it is noted a 8 mm lesion distal to esophagus and confirmed by histological study of granular cells tumor. Elective treatment of this lesion is the endoscopic polypectomy. Despite that the malign potential is low; we suggested a close clinical and endoscopic follow-up.

  18. Circulating Tumor Cells in Prostate Cancer

    International Nuclear Information System (INIS)

    Hu, Brian; Rochefort, Holly; Goldkorn, Amir

    2013-01-01

    Circulating tumor cells (CTCs) can provide a non-invasive, repeatable snapshot of an individual patient’s tumor. In prostate cancer, CTC enumeration has been extensively studied and validated as a prognostic tool and has received FDA clearance for use in monitoring advanced disease. More recently, CTC analysis has been shifting from enumeration to more sophisticated molecular characterization of captured cells, which serve as a “liquid biopsy” of the tumor, reflecting molecular changes in an individual’s malignancy over time. Here we will review the main CTC studies in advanced and localized prostate cancer, highlighting the important gains as well as the challenges posed by various approaches, and their implications for advancing prostate cancer management

  19. Sprouty2 enhances the tumorigenic potential of glioblastoma cells.

    Science.gov (United States)

    Park, Jong-Whi; Wollmann, Guido; Urbiola, Carles; Fogli, Barbara; Florio, Tullio; Geley, Stephan; Klimaschewski, Lars

    2018-02-23

    Sprouty2 (SPRY2), a feedback regulator of receptor tyrosine kinase (RTK) signaling, has been shown to be associated with drug resistance and cell proliferation in glioblastoma (GBM), but the underlying mechanisms are still poorly defined. SPRY2 expression and survival patterns of patients with gliomas were analyzed using publicly available databases. Effects of RNA interference targeting SPRY2 on cellular proliferation in established GBM or patient-derived GBM stemlike cells were examined. Loss- or gain-of-function of SPRY2 to regulate the tumorigenic capacity was assessed in both intracranial and subcutaneous xenografts. SPRY2 was found to be upregulated in GBM, which correlated with reduced survival in GBM patients. SPRY2 knockdown significantly impaired proliferation of GBM cells but not of normal astrocytes. Silencing of SPRY2 increased epidermal growth factor-induced extracellular signal-regulated kinase (ERK) and Akt activation causing premature onset of DNA replication, increased DNA damage, and impaired proliferation, suggesting that SPRY2 suppresses DNA replication stress. Abrogating SPRY2 function strongly inhibited intracranial tumor growth and led to significantly prolonged survival of U87 xenograft-bearing mice. In contrast, SPRY2 overexpression promoted tumor propagation of low-tumorigenic U251 cells. The present study highlights an antitumoral effect of SPRY2 inhibition that is based on excessive activation of ERK signaling and DNA damage response, resulting in reduced cell proliferation and increased cytotoxicity, proposing SPRY2 as a promising pharmacological target in GBM patients.

  20. Enhanced radiosensitivity and radiation-induced apoptosis in glioma CD133-positive cells by knockdown of SirT1 expression

    International Nuclear Information System (INIS)

    Chang, C.-J.; Hsu, C.-C.; Yung, M.-C.; Chen, K.-Y.; Tzao Ching; Wu, W.-F.; Chou, H.-Y.; Lee, Y.-Y.; Lu, K.-H.; Chiou, S.-H.; Ma, H.-I

    2009-01-01

    CD133-expressing glioma cells play a critical role in tumor recovery after treatment and are resistant to radiotherapy. Herein, we demonstrated that glioblastoma-derived CD133-positive cells (GBM-CD133 + ) are capable of self-renewal and express high levels of embryonic stem cell genes and SirT1 compared to GBM-CD133 - cells. To evaluate the role of SirT1 in GBM-CD133 + , we used a lentiviral vector expressing shRNA to knock-down SirT1 expression (sh-SirT1) in GBM-CD133 + . Silencing of SirT1 significantly enhanced the sensitivity of GBM-CD133 + to radiation and increased the level of radiation-mediated apoptosis. Importantly, knock-down of SirT1 increased the effectiveness of radiotherapy in the inhibition of tumor growth in nude mice transplanted with GBM-CD133 + . Kaplan-Meier survival analysis indicated that the mean survival rate of GBM-CD133 + mice treated with radiotherapy was significantly improved by Sh-SirT1 as well. In sum, these results suggest that SirT1 is a potential target for increasing the sensitivity of GBM and glioblastoma-associated cancer stem cells to radiotherapy.

  1. Colony stimulating factor 1 receptor inhibition delays recurrence of glioblastoma after radiation by altering myeloid cell recruitment and polarization

    Science.gov (United States)

    Stafford, Jason H.; Hirai, Takahisa; Deng, Lei; Chernikova, Sophia B.; Urata, Kimiko; West, Brian L.; Brown, J. Martin

    2016-01-01

    Background Glioblastoma (GBM) may initially respond to treatment with ionizing radiation (IR), but the prognosis remains extremely poor because the tumors invariably recur. Using animal models, we previously showed that inhibiting stromal cell–derived factor 1 signaling can prevent or delay GBM recurrence by blocking IR-induced recruitment of myeloid cells, specifically monocytes that give rise to tumor-associated macrophages. The present study was aimed at determining if inhibiting colony stimulating factor 1 (CSF-1) signaling could be used as an alternative strategy to target pro-tumorigenic myeloid cells recruited to irradiated GBM. Methods To inhibit CSF-1 signaling in myeloid cells, we used PLX3397, a small molecule that potently inhibits the tyrosine kinase activity of the CSF-1 receptor (CSF-1R). Combined IR and PLX3397 therapy was compared with IR alone using 2 different human GBM intracranial xenograft models. Results GBM xenografts treated with IR upregulated CSF-1R ligand expression and increased the number of CD11b+ myeloid-derived cells in the tumors. Treatment with PLX3397 both depleted CD11b+ cells and potentiated the response of the intracranial tumors to IR. Median survival was significantly longer for mice receiving combined therapy versus IR alone. Analysis of myeloid cell differentiation markers indicated that CSF-1R inhibition prevented IR-recruited monocyte cells from differentiating into immunosuppressive, pro-angiogenic tumor-associated macrophages. Conclusion CSF-1R inhibition may be a promising strategy to improve GBM response to radiotherapy. PMID:26538619

  2. Radiologic findings of ovarian granulosa cell tumor

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Jong Chul [Chungnam National Univ. College of Medicine, Taejon (Korea, Republic of)

    1997-10-01

    To determine, through an analysis of radiologic findings, whether the findings of granulosa cell tumors (GCTs) of the ovary are specific. The radiologic findings (ultrasonography, computed tomography, and magnetic resonance imaging) of 16 pathologically proven ovarian GCTs in 15 patients were retrospectively analysed for the site of origin, staging, largest diameter, margin, solid and/or cystic components, degree of enhancement, and associated endometrial hyperplasia, ascites, and local and/or distant metastasis. Unilateral ovarian GCTs were found in 14 patients, and bilateral tumors in one. Of a total of 16 tumors, 13 were of the adult type, and three were juvenile; their largest diameter ranged from 1 to 26(mean, 15.6)cm. Eleven tumors were well-defined, two were cystic, and one small tumor was solid. Of 13 mixed tumors, three had hemorrhagic portions, and five had multilocular cystic portions. Metastases to the uterus, tubes, rectum, lymph nodes, or liver were found in six patients, and associated endometrial hyperplasia in two. Radiologically, ovarian GCTs showed well-defined or encapsulated soft tissue masses with some hemorrhagic, multilocular or focal cystic components, as well as associated endometrial thickening and local or distant metastasis. These and clinical findings may be useful in the diagnosis of ovarian GCTs.

  3. Microfluidic Platform for Circulating Tumor Cells Isolation

    Energy Technology Data Exchange (ETDEWEB)

    Figueras-Mari, I.; Rodriguez-Trujillo, L.; Samitier-Marti, J.

    2016-07-01

    Circulating tumor cells (CTCs) are released from primary tumors into the bloodstream and transported to distant organs, promoting metastasis, which is known to be responsible for most cancer‐related deaths. Currently tumors are not found until symptoms appear or by chance when the patient undergoes a medical test, which in both situations can be too late. Once a tumor is found it is studied from tissue samples obtained directly from the patient in an invasive way. This invasive procedure is known as biopsy and apart from being invasive, it is costly, time consuming and can sometimes be painful and even risky for the patients’ health condition. Therefore, CTCs detection in blood also addressed as “liquid biopsy” would be very useful because by running routine blood analysis CTCs could be detected and collected suggesting tumor presence. However, due to the scarce presence in blood of these cells and to the huge amount of contamination from other cellular components a perfect method providing good capture and purity of CTCs has not been developed yet. In this project, a spiral size sorter microfluidic device has been manufactured and tested in order to determine its performance and limitations. Device performance was tested with different dilutions of healthy donor blood samples mixed with 30 micron particles simulating CTCs. The results obtained from these experiments show very good CTC recovery of up to 100% and the depletion of blood cellular components is around 99.9%. (Author)

  4. Intravital imaging of cancer stem cell plasticity in mammary tumors

    NARCIS (Netherlands)

    Zomer, A.; Ellenbroek, S.I.; Ritsma, L.; Beerling, E.; Vrisekoop, N.; van Rheenen, J.

    2013-01-01

    It is widely debated whether all tumor cells in mammary tumors have the same potential to propagate and maintain tumor growth or whether there is a hierarchical organization. Evidence for the latter theory is mainly based on the ability or failure of transplanted tumor cells to produce detectable

  5. The Anti-Warburg Effect Elicited by the cAMP-PGC1α Pathway Drives Differentiation of Glioblastoma Cells into Astrocytes

    Directory of Open Access Journals (Sweden)

    Fan Xing

    2017-01-01

    Full Text Available Summary: Glioblastoma multiforme (GBM is among the most aggressive of human cancers. Although differentiation therapy has been proposed as a potential approach to treat GBM, the mechanisms of induced differentiation remain poorly defined. Here, we established an induced differentiation model of GBM using cAMP activators that specifically directed GBM differentiation into astroglia. Transcriptomic and proteomic analyses revealed that oxidative phosphorylation and mitochondrial biogenesis are involved in induced differentiation of GBM. Dibutyryl cyclic AMP (dbcAMP reverses the Warburg effect, as evidenced by increased oxygen consumption and reduced lactate production. Mitochondrial biogenesis induced by activation of the CREB-PGC1α pathway triggers metabolic shift and differentiation. Blocking mitochondrial biogenesis using mdivi1 or by silencing PGC1α abrogates differentiation; conversely, overexpression of PGC1α elicits differentiation. In GBM xenograft models and patient-derived GBM samples, cAMP activators also induce tumor growth inhibition and differentiation. Our data show that mitochondrial biogenesis and metabolic switch to oxidative phosphorylation drive the differentiation of tumor cells. : Xing et al. show that the metabolic shift from glycolysis to oxidative phosphorylation drives differentiation of GBM cells into astrocytes by cAMP activation. Mechanistically, the cAMP-CREB-PGC1α signal mediates mitochondrial biogenesis, which leads to metabolic reprogramming, induced differentiation, and tumor growth inhibition. Keywords: glioblastoma, induced differentiation, Warburg effect, metabolic reprogramming, oxidative phosphorylation, glycolysis, mitochondrial biogenesis, cyclic adenosine monophosphate, cAMP, PPARγ coactivator-1α, PGC1α

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

    Science.gov (United States)

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

    2015-12-01

    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. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  7. The post-surgical era of GBM: How molecular biology has impacted on our clinical management. A review.

    Science.gov (United States)

    Monticelli, M; Zeppa, P; Zenga, F; Altieri, R; Mammi, M; Bertero, L; Castellano, I; Cassoni, P; Melcarne, A; La Rocca, G; Sabatino, G; Ducati, A; Garbossa, D

    2018-07-01

    Glioblastoma (GBM) is the most common glioma in adults, with incidence increasing by 3% per year. According to the World Health Organization Classification of Central Nervous System Tumors, GBM is considered a grade IV tumor due to its malignant behavior. The aim of this review is to summarize the main biological aspects of GBM. In particular, we focused our attention on those alterations which have been proven to have an impact on patients' outcome, mainly in terms of overall survival (OS), or on the tumor response to therapies. We have also analyzed the cellular biology and the interactions between GBM and the surrounding environment. Copyright © 2018 Elsevier B.V. All rights reserved.

  8. In Vitro Efficient Expansion of Tumor Cells Deriving from Different Types of Human Tumor Samples

    Directory of Open Access Journals (Sweden)

    Ilaria Turin

    2014-03-01

    Full Text Available Obtaining human tumor cell lines from fresh tumors is essential to advance our understanding of antitumor immune surveillance mechanisms and to develop new ex vivo strategies to generate an efficient anti-tumor response. The present study delineates a simple and rapid method for efficiently establishing primary cultures starting from tumor samples of different types, while maintaining the immuno-histochemical characteristics of the original tumor. We compared two different strategies to disaggregate tumor specimens. After short or long term in vitro expansion, cells analyzed for the presence of malignant cells demonstrated their neoplastic origin. Considering that tumor cells may be isolated in a closed system with high efficiency, we propose this methodology for the ex vivo expansion of tumor cells to be used to evaluate suitable new drugs or to generate tumor-specific cytotoxic T lymphocytes or vaccines.

  9. Level of Notch activation determines the effect on growth and stem cell-like features in glioblastoma multiforme neurosphere cultures

    DEFF Research Database (Denmark)

    Kristoffersen, Karina; Villingshøj, Mette; Poulsen, Hans Skovgaard

    2013-01-01

    Brain cancer stem-like cells (bCSC) are cancer cells with neural stem cell (NSC)-like properties found in glioblastoma multiforme (GBM) and they are assigned a central role in tumor initiation, progression and relapse. The Notch pathway is important for maintenance and cell fate decisions...... in the normal NSC population. Notch signaling is often deregulated in GBM and recent results suggest that this pathway plays a significant role in bCSC as well. We therefore wished to further elucidate the role of Notch activation in GBM-derived bCSC....

  10. Cytomegalovirus infection induces a stem cell phenotype in human primary glioblastoma cells

    DEFF Research Database (Denmark)

    Fornara, O; Bartek, J; Rahbar, A

    2016-01-01

    Glioblastoma (GBM) is associated with poor prognosis despite aggressive surgical resection, chemotherapy, and radiation therapy. Unfortunately, this standard therapy does not target glioma cancer stem cells (GCSCs), a subpopulation of GBM cells that can give rise to recurrent tumors. GBMs express...... human cytomegalovirus (HCMV) proteins, and previously we found that the level of expression of HCMV immediate-early (IE) protein in GBMs is a prognostic factor for poor patient survival. In this study, we investigated the relation between HCMV infection of GBM cells and the presence of GCSCs. Primary...... GBMs were characterized by their expression of HCMV-IE and GCSCs marker CD133 and by patient survival. The extent to which HCMV infection of primary GBM cells induced a GCSC phenotype was evaluated in vitro. In primary GBMs, a large fraction of CD133-positive cells expressed HCMV-IE, and higher co...

  11. HAMLET (human alpha-lactalbumin made lethal to tumor cells) triggers autophagic tumor cell death.

    Science.gov (United States)

    Aits, Sonja; Gustafsson, Lotta; Hallgren, Oskar; Brest, Patrick; Gustafsson, Mattias; Trulsson, Maria; Mossberg, Ann-Kristin; Simon, Hans-Uwe; Mograbi, Baharia; Svanborg, Catharina

    2009-03-01

    HAMLET, a complex of partially unfolded alpha-lactalbumin and oleic acid, kills a wide range of tumor cells. Here we propose that HAMLET causes macroautophagy in tumor cells and that this contributes to their death. Cell death was accompanied by mitochondrial damage and a reduction in the level of active mTOR and HAMLET triggered extensive cytoplasmic vacuolization and the formation of double-membrane-enclosed vesicles typical of macroautophagy. In addition, HAMLET caused a change from uniform (LC3-I) to granular (LC3-II) staining in LC3-GFP-transfected cells reflecting LC3 translocation during macroautophagy, and this was blocked by the macroautophagy inhibitor 3-methyladenine. HAMLET also caused accumulation of LC3-II detected by Western blot when lysosomal degradation was inhibited suggesting that HAMLET caused an increase in autophagic flux. To determine if macroautophagy contributed to cell death, we used RNA interference against Beclin-1 and Atg5. Suppression of Beclin-1 and Atg5 improved the survival of HAMLET-treated tumor cells and inhibited the increase in granular LC3-GFP staining. The results show that HAMLET triggers macroautophagy in tumor cells and suggest that macroautophagy contributes to HAMLET-induced tumor cell death.

  12. Cells competition in tumor growth poroelasticity

    Science.gov (United States)

    Fraldi, Massimiliano; Carotenuto, Angelo R.

    2018-03-01

    Growth of biological tissues has been recently treated within the framework of Continuum Mechanics, by adopting heterogeneous poroelastic models where the interaction between soft matrix and interstitial fluid flow is coupled with inelastic effects ad hoc introduced to simulate the macroscopic volumetric growth determined by cells division, cells growth and extracellular matrix changes occurring at the micro-scale level. These continuum models seem to overcome some limitations intrinsically associated to other alternative approaches based on mass balances in multiphase systems, because the crucial role played by residual stresses accompanying growth and nutrients walkway is preserved. Nevertheless, when these strategies are applied to analyze solid tumors, mass growth is usually assigned in a prescribed form that essentially copies the in vitro measured intrinsic growth rates of the cell species. As a consequence, some important cell-cell dynamics governing mass evolution and invasion rates of cancer cells, as well as their coupling with feedback mechanisms associated to in situ stresses, are inevitably lost and thus the spatial distribution and the evolution with time of the growth inside the tumor -which would be results rather than inputs- are forced to enter in the model simply as data. In order to solve this paradox, it is here proposed an enhanced multi-scale poroelastic model undergoing large deformations and embodying inelastic growth, where the net growth terms directly result from the "interspecific" predator-prey (Volterra/Lotka-like) competition occurring at the micro-scale level between healthy and abnormal cell species. In this way, a system of fully-coupled non-linear PDEs is derived to describe how the fight among cell species to grab the available common resources, stress field, pressure gradients, interstitial fluid flows driving nutrients and inhomogeneous growth all simultaneously interact to decide the tumor fate.

  13. Inhibition of GLO1 in Glioblastoma Multiforme Increases DNA-AGEs, Stimulates RAGE Expression, and Inhibits Brain Tumor Growth in Orthotopic Mouse Models

    Directory of Open Access Journals (Sweden)

    Rahul Jandial

    2018-01-01

    Full Text Available Cancers that exhibit the Warburg effect may elevate expression of glyoxylase 1 (GLO1 to detoxify the toxic glycolytic byproduct methylglyoxal (MG and inhibit the formation of pro-apoptotic advanced glycation endproducts (AGEs. Inhibition of GLO1 in cancers that up-regulate glycolysis has been proposed as a therapeutic targeting strategy, but this approach has not been evaluated for glioblastoma multiforme (GBM, the most aggressive and difficult to treat malignancy of the brain. Elevated GLO1 expression in GBM was established in patient tumors and cell lines using bioinformatics tools and biochemical approaches. GLO1 inhibition in GBM cell lines and in an orthotopic xenograft GBM mouse model was examined using both small molecule and short hairpin RNA (shRNA approaches. Inhibition of GLO1 with S-(p-bromobenzyl glutathione dicyclopentyl ester (p-BrBzGSH(Cp2 increased levels of the DNA-AGE N2-1-(carboxyethyl-2′-deoxyguanosine (CEdG, a surrogate biomarker for nuclear MG exposure; substantially elevated expression of the immunoglobulin-like receptor for AGEs (RAGE; and induced apoptosis in GBM cell lines. Targeting GLO1 with shRNA similarly increased CEdG levels and RAGE expression, and was cytotoxic to glioma cells. Mice bearing orthotopic GBM xenografts treated systemically with p-BrBzGSH(Cp2 exhibited tumor regression without significant off-target effects suggesting that GLO1 inhibition may have value in the therapeutic management of these drug-resistant tumors.

  14. Inhibition of GLO1 in Glioblastoma Multiforme Increases DNA-AGEs, Stimulates RAGE Expression, and Inhibits Brain Tumor Growth in Orthotopic Mouse Models.

    Science.gov (United States)

    Jandial, Rahul; Neman, Josh; Lim, Punnajit P; Tamae, Daniel; Kowolik, Claudia M; Wuenschell, Gerald E; Shuck, Sarah C; Ciminera, Alexandra K; De Jesus, Luis R; Ouyang, Ching; Chen, Mike Y; Termini, John

    2018-01-30

    Cancers that exhibit the Warburg effect may elevate expression of glyoxylase 1 (GLO1) to detoxify the toxic glycolytic byproduct methylglyoxal (MG) and inhibit the formation of pro-apoptotic advanced glycation endproducts (AGEs). Inhibition of GLO1 in cancers that up-regulate glycolysis has been proposed as a therapeutic targeting strategy, but this approach has not been evaluated for glioblastoma multiforme (GBM), the most aggressive and difficult to treat malignancy of the brain. Elevated GLO1 expression in GBM was established in patient tumors and cell lines using bioinformatics tools and biochemical approaches. GLO1 inhibition in GBM cell lines and in an orthotopic xenograft GBM mouse model was examined using both small molecule and short hairpin RNA (shRNA) approaches. Inhibition of GLO1 with S -( p -bromobenzyl) glutathione dicyclopentyl ester ( p- BrBzGSH(Cp)₂) increased levels of the DNA-AGE N ²-1-(carboxyethyl)-2'-deoxyguanosine (CEdG), a surrogate biomarker for nuclear MG exposure; substantially elevated expression of the immunoglobulin-like receptor for AGEs (RAGE); and induced apoptosis in GBM cell lines. Targeting GLO1 with shRNA similarly increased CEdG levels and RAGE expression, and was cytotoxic to glioma cells. Mice bearing orthotopic GBM xenografts treated systemically with p -BrBzGSH(Cp)₂ exhibited tumor regression without significant off-target effects suggesting that GLO1 inhibition may have value in the therapeutic management of these drug-resistant tumors.

  15. Glioblastoma (GBM) effects on quantitative MRI of contralateral normal appearing white matter.

    Science.gov (United States)

    Mehrabian, Hatef; Lam, Wilfred W; Myrehaug, Sten; Sahgal, Arjun; Stanisz, Greg J

    2018-03-28

    The objective was to investigate (with quantitative MRI) whether the normal appearing white matter (NAWM) of glioblastoma (GBM) patients on the contralateral side (cNAWM) was different from NAWM of healthy controls. Thirteen patients with newly diagnosed GBM and nine healthy age-matched controls were MRI-scanned with quantitative magnetization transfer (qMT), chemical exchange saturation transfer (CEST), and transverse relaxation time (T 2 )-mapping. MRI scans were performed after surgery and before chemo-radiation treatment. Comprehensive qMT, CEST, T 2 data were acquired. A two-pool MT model was fit to qMT data in transient state, to calculate MT model parameters [Formula: see text]. CEST signal was isolated by removing the contributions from the MT and direct water saturation, and CEST signal was calculated for Amide (CEST Amide ), Amine (CEST Amine ) and nuclear overhauser effect, NOE (CEST NOE ). There was no difference between GBM patients and normal controls in the qMT properties of the macromolecular pool [Formula: see text]. However, their free water pool spectrum was different (1/R a T 2a , patient  = 28.1 ± 3.9, 1/R a T 2a , control  = 25.0 ± 1.1, p = 0.03). This difference could be attributed to the difference in their T 2 time ([Formula: see text] = 83 ± 4, [Formula: see text] = 88 ± 1, p = 0.004). CEST signals were statistically significantly different with the CEST Amide having the largest difference between the two cohorts (CEST Amide,patient  = 2.8 ± 0.4, CEST Amide,control  = 3.4 ± 0.5, p = 0.009). CEST in cNAWM of GBM patients was lower than healthy controls which could be caused by modified brain metabolism due to tumor cell infiltration. There was no difference in MT properties of the patients and controls, however, the differences in free water pool properties were mainly due to reduced T 2 in cNAWM of the patients (resulting from structural changes and increased cellularity).

  16. Are Breast Tumor Stem Cells Responsible for Metastasis and Angiogenesis?

    National Research Council Canada - National Science Library

    Pan, Quintin

    2005-01-01

    .... The current dogma of metastasis is that most primary tumor cells have low metastatic potential, but rare cells, less than one in ten million, within large primary tumors acquire metastatic capacity...

  17. Granular cell tumors of the urinary bladder

    Directory of Open Access Journals (Sweden)

    Kayani Naila

    2007-03-01

    Full Text Available Abstract Background Granular cell tumors (GCTs are extremely rare lesions of the urinary bladder with only nine cases being reported in world literature of which one was malignant. Generally believed to be of neural origin based on histochemical, immunohistochemical, and ultrastructural studies; they mostly follow a clinically benign course but are commonly mistaken for malignant tumors since they are solid looking, ulcerated tumors with ill-defined margins. Materials and methods We herein report two cases of GCTs, one benign and one malignant, presenting with gross hematuria in a 14- and a 47-year-old female, respectively. Results Histopathology revealed characteristic GCTs with positive immunostaining for neural marker (S-100 and negative immunostaining for epithelial (cytokeratin, Cam 5.2, AE/A13, neuroendocrine (neuron specific enolase, chromogranin A, and synaptophysin and sarcoma (desmin, vimentin markers. The benign tumor was successfully managed conservatively with transurethral resection alone while for the malignant tumor, radical cystectomy, hysterectomy with bilateral salpingo-oophorectomy, anterior vaginectomy, plus lymph node dissection was done. Both cases show long-term disease free survival. Conclusion We recommend careful pathologic assessment for establishing the appropriate diagnosis and either a conservative or aggressive surgical treatment for benign or localized malignant GCT of the urinary bladder, respectively.

  18. Does Royal jelly affect tumor cells?

    Directory of Open Access Journals (Sweden)

    Shirzad Maryam

    2013-04-01

    Full Text Available Introduction: Royal jelly is a substance that appears to be effective on immune system and it appears to be effective on both prevention and growth of cancer cells. In this study, we aimed to carry out a research to investigate the effect of royal jelly on the growth of WEHI-164 fibrosarcoma cell in syngenic Balb/c mice. Methods: In an experimental study, 28 male Balb/c mice were designated into four equal groups. The mice were subcutaneously injected with 5x105 WEHI-164 tumor cells on the day zero in the chest area of the animal. Animals in groups 1 to 4 were orally given 100, 200, 300 mg/kg of royal jelly or vehicle, respectively. In every individual mouse, the tumour size was measured every 2 days from day 5 (days 5, 7, 9, 11, 13, 15 and 17. Data were statistically analyzed using Kruskal-Wallis and Mann Whitney-U tests. Result: Our results showed that the mean size of tumor in case group was significantly smaller than the control group in days 11, 13, 15 and 17 (P<0.05. No metastasis was seen in test and control groups. Conclusion: With emphasize on antitumor effect of royal jelly, it seems that royal jelly has important role in control and regression of fibrosarcoma cells. Since royal jelly showed a delayed effect in control of fibrosarcoma, we suggest that royal jelly be used at least 10 days before tumor inoculation.

  19. Circulating Tumor Cells Measurements in Hepatocellular Carcinoma

    Directory of Open Access Journals (Sweden)

    Franck Chiappini

    2012-01-01

    Full Text Available Liver cancer is the fifth most common cancer in men and the seventh in women. During the past 20 years, the incidence of HCC has tripled while the 5-year survival rate has remained below 12%. The presence of circulating tumor cells (CTC reflects the aggressiveness nature of a tumor. Many attempts have been made to develop assays that reliably detect and enumerate the CTC during the development of the HCC. In this case, the challenges are (1 there are few markers specific to the HCC (tumor cells versus nontumor cells and (2 they can be used to quantify the number of CTC in the bloodstream. Another technical challenge consists of finding few CTC mixed with million leukocytes and billion erythrocytes. CTC detection and identification can be used to estimate prognosis and may serve as an early marker to assess antitumor activity of treatment. CTC can also be used to predict progression-free survival and overall survival. CTC are an interesting source of biological information in order to understand dissemination, drug resistance, and treatment-induced cell death. Our aim is to review and analyze the different new methods existing to detect, enumerate, and characterize the CTC in the peripheral circulation of patients with HCC.

  20. Cyclophilin B Supports Myc and Mutant p53 Dependent Survival of Glioblastoma Multiforme Cells

    Science.gov (United States)

    Choi, Jae Won; Schroeder, Mark A.; Sarkaria, Jann N.; Bram, Richard J.

    2014-01-01

    Glioblastoma multiforme (GBM) is an aggressive, treatment-refractory type of brain tumor for which effective therapeutic targets remain important to identify. Here we report that cyclophilin B (CypB), a prolyl isomerase residing in the endoplasmic reticulum (ER), provides an essential survival signal in GBM cells. Analysis of gene expression databases revealed that CypB is upregulated in many cases of malignant glioma. We found that suppression of CypB reduced cell proliferation and survival in human GBM cells in vitro and in vivo. We also found that treatment with small molecule inhibitors of cyclophilins, including the approved drug cyclosporine, greatly reduced the viability of GBM cells. Mechanistically, depletion or pharmacologic inhibition of CypB caused hyperactivation of the oncogenic RAS-MAPK pathway, induction of cellular senescence signals, and death resulting from loss of MYC, mutant p53, Chk1 and JAK/STAT3 signaling. Elevated reactive oxygen species, ER expansion and abnormal unfolded protein responses in CypB-depleted GBM cells indicated that CypB alleviates oxidative and ER stresses and coordinates stress adaptation responses. Enhanced cell survival and sustained expression of multiple oncogenic proteins downstream of CypB may thus contribute to the poor outcome of GBM tumors. Our findings link chaperone-mediated protein folding in the ER to mechanisms underlying oncogenic transformation, and they make CypB an attractive and immediately targetable molecule for GBM therapy. PMID:24272483

  1. PDE7B is a novel, prognostically significant mediator of glioblastoma growth whose expression is regulated by endothelial cells.

    Directory of Open Access Journals (Sweden)

    Michael D Brooks

    Full Text Available Cell-cell interactions between tumor cells and constituents of their microenvironment are critical determinants of tumor tissue biology and therapeutic responses. Interactions between glioblastoma (GBM cells and endothelial cells (ECs establish a purported cancer stem cell niche. We hypothesized that genes regulated by these interactions would be important, particularly as therapeutic targets. Using a computational approach, we deconvoluted expression data from a mixed physical co-culture of GBM cells and ECs and identified a previously undescribed upregulation of the cAMP specific phosphodiesterase PDE7B in GBM cells in response to direct contact with ECs. We further found that elevated PDE7B expression occurs in most GBM cases and has a negative effect on survival. PDE7B overexpression resulted in the expansion of a stem-like cell subpopulation in vitro and increased tumor growth and aggressiveness in an in vivo intracranial GBM model. Collectively these studies illustrate a novel approach for studying cell-cell interactions and identifying new therapeutic targets like PDE7B in GBM.

  2. Colorectal cancer: genetic abnormalities, tumor progression, tumor heterogeneity, clonal evolution and tumor-initiating cells.

    Science.gov (United States)

    Testa, Ugo; Pelosi, Elvira; Castelli, Germana

    2018-04-13

    Colon cancer is the third most common cancer worldwide. Most colorectal cancer occurrences are sporadic, not related to genetic predisposition or family history; however, 20-30% of patients with colorectal cancer have a family history of colorectal cancer and 5% of these tumors arise in the setting of a Mendelian inheritance syndrome. In many patients, the development of a colorectal cancer is preceded by a benign neoplastic lesion: either an adenomatous polyp or a serrated polyp. Studies carried out in the last years have characterized the main molecular alterations occurring in colorectal cancers, showing that the tumor of each patient displays from two to eight driver mutations. The ensemble of molecular studies, including gene expression studies, has led to two proposed classifications of colorectal cancers, with the identification of four/five non-overlapping groups. The homeostasis of the rapidly renewing intestinal epithelium is ensured by few stem cells present at the level of the base of intestinal crypts. Various experimental evidence suggests that colorectal cancers may derive from the malignant transformation of intestinal stem cells or of intestinal cells that acquire stem cell properties following malignant transformation. Colon cancer stem cells seem to be involved in tumor chemoresistance, radioresistance and relapse.

  3. The Role of Tumor Associated Macrophage in Recurrent Growth of Tumor Stem Cell

    Science.gov (United States)

    2011-09-01

    recent cancer stem cell (CSC) theory, recurrent tumor must arise from a dormant tumor stem cell whose re-growth is triggered by shifting of...microenvironment. This project aims at clarifying the roles of TAM in recurrent growth of dormant stem cell in breast cancer. We hypothesize that the balance of...dormancy and recurrence is determined by the ability of the tumor stem cells to recruit TAM which in turn promotes self-renewal of the stem cell . We

  4. Dendritic cell-tumor cell hybrids and immunotherapy

    DEFF Research Database (Denmark)

    Cathelin, Dominique; Nicolas, Alexandra; Bouchot, André

    2011-01-01

    Dendritic cells (DC) are professional antigen-presenting cells currently being used as a cellular adjuvant in cancer immunotherapy strategies. Unfortunately, DC-based vaccines have not demonstrated spectacular clinical results. DC loading with tumor antigens and DC differentiation and activation...

  5. Prognostic Importance of Circulating Tumor Cells in Nonsmall Cell ...

    African Journals Online (AJOL)

    Purpose: To investigate the prognostic value of circulating tumor cells (CTCs) and to predict the treatment response in a non-small cell lung cancer (NSCLC). Methodology: A single-center prospective study involving 93 patients with NSCLC was conducted. Blood samples were analyzed for CTC count before and after ...

  6. Circulating tumor cells: clinical validity and utility.

    Science.gov (United States)

    Cabel, Luc; Proudhon, Charlotte; Gortais, Hugo; Loirat, Delphine; Coussy, Florence; Pierga, Jean-Yves; Bidard, François-Clément

    2017-06-01

    Circulating tumor cells (CTCs) are rare tumor cells and have been investigated as diagnostic, prognostic and predictive biomarkers in many types of cancer. Although CTCs are not currently used in clinical practice, CTC studies have accumulated a high level of clinical validity, especially in breast, lung, prostate and colorectal cancers. In this review, we present an overview of the current clinical validity of CTCs in metastatic and non-metastatic disease, and the main concepts and studies investigating the clinical utility of CTCs. In particular, this review will focus on breast, lung, colorectal and prostate cancer. Three major topics concerning the clinical utility of CTC are discussed-(1) treatment based on CTCs used as liquid biopsy, (2) treatment based on CTC count or CTC variations, and (3) treatment based on CTC biomarker expression. A summary of published or ongoing phase II and III trials is also presented.

  7. Vacquinol-1 inducible cell death in glioblastoma multiforme is counter regulated by TRPM7 activity induced by exogenous ATP

    OpenAIRE

    Sander, Philip; Mostafa, Haouraa; Soboh, Ayman; Schneider, Julian M.; Pala, Andrej; Baron, Ann-Kathrin; Moepps, Barbara; Wirtz, C. Rainer; Georgieff, Michael; Schneider, Marion

    2017-01-01

    Glioblastomas (GBM) are the most malignant brain tumors in humans and have a very poor prognosis. New therapeutic options are urgently needed. A novel drug, Vacquinol-1 (Vac), a quinolone derivative, displays promising properties by inducing rapid cell death in GBM but not in non-transformed tissues. Features of this type of cell death are compatible with a process termed methuosis. Here we tested Vac on a highly malignant glioma cell line observed by long-term video microscopy. Human dental-...

  8. Repair in Ehrlich ascites tumor cells

    International Nuclear Information System (INIS)

    Wanna-Nakamura, S.S.

    1981-01-01

    Unscheduled DNA synthesis (UDS), an indicator of excision repair, was induced in freshly drawn Ehrlich ascites tumor cells (EAT), using ionizing radiation, far ultraviolet light (254 nm) or near uv light (365 nm) in combination with 8-methoxypsoralen. UDS was scored by grain counts in autoradiographs following the incorporation of tritium-labelled thymidine. The amount of UDS after each of these agents was expressed in terms of two parameters, viz. numer of cells showing repair and the mean number of grains per nucleus. The influence of radiation dose and of the duration of radioactive thymidine incubation were also examined. To test for a possible relationship between low mitotic index and repair capability, EAT cells were incubated in buffered salt media to lower the mitotic index. Cells kept in a buffered salt solution for 7 h show a marked drop in mitotic index compared to those incubated in minimal medium containing 15% fetal calf serum (MEM + FCS). This drop in mitotic index was reversible for up to 5 h, if cells were returned to MEM + FCS. Cells incubated in MEM + FCS also showed a decrease in mitotic activity compared to freshly drawn cells. This reduced mitotic index is approximately constant for up to 24 h. With the drop in mitotic index, EAT cells also show a drop in repair compared to freshly drawn cells. The repair capability of cells incubated in buffer can be restored by returning cells to MEM + FCS

  9. Genetic instability in nerve sheath cell tumors

    DEFF Research Database (Denmark)

    Rogatto, Silvia Regina; Casartelli, Cacilda; Rainho, Claudia Aparecida

    1995-01-01

    After in vitro culture, we analyzed cytogenetically four acoustic nerve neurinomas, one intraspinal neurinoma and one neurofibroma obtainedfrom unrelated patients. Monosomy of chromosomes 22 and 16 was an abnormality common to all cases, followed in frequency by loss of chromosomes 18 (three cases...... by the presence of polyploid cells with inconsistent abnormalities, endoreduplications and telomeric associations resulting in dicentric chromosomes. It is probable that these cytogenetic abnormalities represent some kind of evolutionary advantage for the in vitro progression of nerve sheath tumors....

  10. Implications of the Endothelial Cell Response in Glioblastoma to Stimulation by Mesenchymal Stem Cells and Ionizing Radiation

    Science.gov (United States)

    Zhao, Tansy Y.

    Heightened angiogenesis is both the pathophysiologic hallmark and the potential cause of therapy resistance for glioblastoma (GBM), a deadly brain tumor. It is thought that mesenchymal stem cells (MSCs) play important roles in neovascularization and tumor progression. We postulated that MSCs protect ECs against radiotherapy, which subsequently enhances tumor angiogenesis, and promotes GBM tumor recurrence following therapy. We therefore sought to establish the in-vitro endothelial cell response to stimulation by MSC condition media and ionizing radiation (IR) treatment. We established the gene expression profiles of endothelial cells in response to IR, MSCs and the combination of both. Within the same gene profiles, we identified a unique gene signature that was highly predictive of response to Bevacizumab for GBM patients. We also demonstrated that MSC increased the viability of ECs in response to IR. Protein analysis in ECs suggested MSC-mediated cell cycle arrest as a mechanism for radio-resistance in ECs.

  11. Mast cells: potential positive and negative roles in tumor biology.

    Science.gov (United States)

    Marichal, Thomas; Tsai, Mindy; Galli, Stephen J

    2013-11-01

    Mast cells are immune cells that reside in virtually all vascularized tissues. Upon activation by diverse mechanisms, mast cells can secrete a broad array of biologically active products that either are stored in the cytoplasmic granules of the cells (e.g., histamine, heparin, various proteases) or are produced de novo upon cell stimulation (e.g., prostaglandins, leukotrienes, cytokines, chemokines, and growth factors). Mast cells are best known for their effector functions during anaphylaxis and acute IgE-associated allergic reactions, but they also have been implicated in a wide variety of processes that maintain health or contribute to disease. There has been particular interest in the possible roles of mast cells in tumor biology. In vitro studies have shown that mast cells have the potential to influence many aspects of tumor biology, including tumor development, tumor-induced angiogenesis, and tissue remodeling, and the shaping of adaptive immune responses to tumors. Yet, the actual contributions of mast cells to tumor biology in vivo remain controversial. Here, we review some basic features of mast cell biology with a special emphasis on those relevant to their potential roles in tumors. We discuss how using in vivo tumor models in combination with models in which mast cell function can be modulated has implicated mast cells in the regulation of host responses to tumors. Finally, we summarize data from studies of human tumors that suggest either beneficial or detrimental roles for mast cells in tumors. ©2013 AACR.

  12. Single-Cell RNA-Seq Analysis of Infiltrating Neoplastic Cells at the Migrating Front of Human Glioblastoma

    Directory of Open Access Journals (Sweden)

    Spyros Darmanis

    2017-10-01

    Full Text Available Summary: Glioblastoma (GBM is the most common primary brain cancer in adults and is notoriously difficult to treat because of its diffuse nature. We performed single-cell RNA sequencing (RNA-seq on 3,589 cells in a cohort of four patients. We obtained cells from the tumor core as well as surrounding peripheral tissue. Our analysis revealed cellular variation in the tumor’s genome and transcriptome. We were also able to identify infiltrating neoplastic cells in regions peripheral to the core lesions. Despite the existence of significant heterogeneity among neoplastic cells, we found that infiltrating GBM cells share a consistent gene signature between patients, suggesting a common mechanism of infiltration. Additionally, in investigating the immunological response to the tumors, we found transcriptionally distinct myeloid cell populations residing in the tumor core and the surrounding peritumoral space. Our data provide a detailed dissection of GBM cell types, revealing an abundance of information about tumor formation and migration. : Darmanis et al. perform single-cell transcriptomic analyses of neoplastic and stromal cells within and proximal to primary glioblastomas. The authors describe a population of neoplastic-infiltrating glioblastoma cells as well as a putative role of tumor-infiltrating immune cells in supporting tumor growth. Keywords: single cell, RNA-seq, glioma, glioblastoma, GBM, brain, heterogeneity, infiltrating, diffuse, checkpoint

  13. Immune response to UV-induced tumors: mediation of progressor tumor rejection by natural killer cells

    International Nuclear Information System (INIS)

    Streeter, P.R.; Fortner, G.W.

    1986-01-01

    Skin tumors induced in mice by chronic ultraviolet (UV) irradiation are highly antigenic and can induce a state of transplantation immunity in syngeneic animals. In the present study, the authors compared the in vitro cytolytic activity of splenic lymphocytes from mice immunized with either regressor or progressor UV-tumors. The results of this comparison implicated tumor-specific cytolytic T (Tc) lymphocytes in rejection of regressor UV-tumors, and revealed that immunization with the progressor UV-tumor 2237 failed to elicit detectable levels of progressor tumor-specific Tc cells even as the tumors rejected. Following in vitro resensitization of spleen cells from either regressor or progressor tumor immune animals, the authors found NK-like lymphocytes with anti-tumor activity. As the authors had not detected cells with this activity in splenic lymphocyte preparations prior to in vitro resensitization, the authors examined lymphocytes from the local tumor environment during the course of progressor tumor rejection for this activity. This analysis revealed NK lymphocytes exhibiting significant levels of cytolytic activity against UV-tumors. These results implicate NK cells as potential effector cells in the rejection of progressor UV-tumors by immune animals, and suggests that these cells may be regulated by T lymphocytes

  14. Electrospun nanofibrous scaffolds increase the efficacy of stem cell-mediated therapy of surgically resected glioblastoma

    Science.gov (United States)

    Bagó, Juli R.; Pegna, Guillaume J.; Okolie, Onyi; Mohiti-Asli, Mahsa; Loboa, Elizabeth G.; Hingtgen, Shawn D.

    2017-01-01

    Engineered stem cell (SC)-based therapy holds enormous promise for treating the incurable brain cancer glioblastoma (GBM). Retaining the cytotoxic SCs in the surgical cavity after GBM resection is one of the greatest challenges to this approach. Here, we describe a biocompatible electrospun nanofibrous scaffold (bENS) implant capable of delivering and retaining tumor-homing cytotoxic stem cells that suppress recurrence of post-surgical GBM. As a new approach to GBM therapy, we created poly(l-lactic acid) (PLA) bENS bearing drug-releasing human mesenchymal stem cells (hMSCs). We discovered that bENS-based implant increased hMSC retention in the surgical cavity 5-fold and prolonged persistence 3-fold compared to standard direct injection using our mouse model of GBM surgical resection/recurrence. Time-lapse imaging showed cytotoxic hMSC/bENS treatment killed co-cultured human GBM cells, and allowed hMSCs to rapidly migrate off the scaffolds as they homed to GBMs. In vivo, bENS loaded with hMSCs releasing the anti-tumor protein TRAIL (bENSsTR) reduced the volume of established GBM xenografts 3-fold. Mimicking clinical GBM patient therapy, lining the post-operative GBM surgical cavity with bENSsTR implants inhibited the re-growth of residual GBM foci 2.3-fold and prolonged post-surgical median survival from 13.5 to 31 days in mice. These results suggest that nanofibrous-based SC therapies could be an innovative new approach to improve the outcomes of patients suffering from terminal brain cancer. PMID:27016620

  15. Cerebellar giant cell glioblastoma multiforme in an adult

    Directory of Open Access Journals (Sweden)

    Sudhansu Sekhar Mishra

    2014-01-01

    Full Text Available Cerebellar glioblastoma multiforme (GBM is a rare tumor that accounts for only 1% of all cases of GBM and its giant cell variant is even much rarely encountered in adults. A case of cerebellar giant cell GBM managed at our institution reporting its clinical presentation, radiological and histological findings, and treatment instituted is described. In conjunction, a literature review, including particular issues, clinical data, advances in imaging studies, pathological characteristics, treatment options, and the behavior of such malignant tumor is presented. It is very important for the neurosurgeon to make the differential diagnosis between the cerebellar GBM, and other diseases such as metastasis, anaplastic astrocytomas, and cerebellar infarct because their treatment modalities, prognosis, and outcome are different.

  16. Giant Cell Tumors of the Axial Skeleton

    Directory of Open Access Journals (Sweden)

    Maurice Balke

    2012-01-01

    Full Text Available Background. We report on 19 cases of giant cell tumor of bone (GCT affecting the spine or sacrum and evaluate the outcome of different treatment modalities. Methods. Nineteen patients with GCT of the spine (=6 or sacrum (=13 have been included in this study. The mean followup was 51.6 months. Ten sacral GCT were treated by intralesional procedures of which 4 also received embolization, and 3 with irradiation only. All spinal GCT were surgically treated. Results. Two (15.4% patients with sacral and 4 (66.7% with spinal tumors had a local recurrence, two of the letter developed pulmonary metastases. One local recurrence of the spine was successfully treated by serial arterial embolization, a procedure previously described only for sacral tumors. At last followup, 9 patients had no evidence of disease, 8 had stable disease, 1 had progressive disease, 1 died due to disease. Six patients had neurological deficits. Conclusions. GCT of the axial skeleton have a high local recurrence rate. Neurological deficits are common. En-bloc spondylectomy combined with embolization is the treatment of choice. In case of inoperability, serial arterial embolization seems to be an alternative not only for sacral but also for spinal tumors.

  17. Vertebral bony tumor of giant cells

    International Nuclear Information System (INIS)

    Jaramillo Carling, Eduardo

    2005-01-01

    This is a report of a 37 years old, masculine patient, in whom a unique primary bone injury was demonstrated, located at T-11, diagnosed as a giant cells tumor (osteoclastoma). Location is described in the literature as unusual. The clinical presentation of the injury is described, as the initial radiological studies and magnetic resonance images 8 years after surgical treatment, with no neoplasic recurrences. The medical literature of these primary bone injuries and its treatment was also reviewed. Objectives: to present a patient with an unusual extramedullar tumor injury, of primary bone origin, benign, treated surgically and who has a post surgical follow-up of 8 years. Local tumor recurrence and not pulmonary metastasis was demonstrated. The medical literature of this bone pathology that affects the spine in an infrequent manner, was also reviewed, specially the related to medical, surgical and radio-therapeutic treatments. Methodology: the clinical history of the patient is described, who was successfully operated, because the expansive tumor was totally drawn out, without neurological injury; inter operating or post-operating vertebral instability was not observed or diagnosed. The patient was controlled in periodic form, with last medical checkup and of magnetic resonance 8 years after the surgery. The medical publications existing are reviewed

  18. Littoral cell angioma mimicking metastatic tumors

    Directory of Open Access Journals (Sweden)

    Szumilo Justyna

    2015-12-01

    Full Text Available Littoral cell angioma is a rare primary, vascular tumor thought to originate from the endothelial cells lining the sinuses of the splenic red pulp (the “littoral cells”. It is a benign, usually asymptomatic lesion diagnosed incidentally. Ultrasound and tomography appearance is not characteristic and histopathological examination is required. This work provides a case-study of littoral cell angioma which was seen in a 55-year-old female who complained of non-specific upper abdominal pain. Computed tomography revealed multiple hypo-attenuated splenic lesions suggestive for metastasis. A splenectomy was performed and routine microscopic examination supported by immunohistochemistry reactions with CD68, CD34 and CD31 showed littoral cell angioma.

  19. Rituximab for the treatment of refractory simultaneous anti-glomerular basement membrane (anti-GBM) and membranous nephropathy.

    Science.gov (United States)

    Bandak, Ghassan; Jones, Bruce A; Li, Jian; Yee, Jerry; Umanath, Kausik

    2014-02-01

    Antibody-mediated anti-glomerular basement membrane (anti-GBM) disease occurs rarely in the presence of another B-cell disorder, membranous nephropathy. The coexistence of these two autoimmune disorders would be anticipated to require differing, specific therapies targeted to each disease process. We describe a case of concomitant membranous nephropathy and anti-GBM disease in which conventional therapy, including steroids, plasmapheresis and cyclophosphamide, failed to attenuate the anti-GBM disease, yet responded to an alternative treatment of rituximab. This B-cell directed, monoclonal, chimeric antibody treatment substantially reduced anti-GBM antibody titers and led to discontinuation of plasmapheresis, while maintaining the remission of membranous nephropathy and anti-GBM disease.

  20. Tumor Cells and Tumor-Associated Macrophages: Secreted Proteins as Potential Targets for Therapy

    OpenAIRE

    Baay, Marc; Brouwer, Anja; Pauwels, Patrick; Peeters, Marc; Lardon, Filip

    2011-01-01

    Inflammatory pathways, meant to defend the organism against infection and injury, as a byproduct, can promote an environment which favors tumor growth and metastasis. Tumor-associated macrophages (TAMs), which constitute a significant part of the tumor-infiltrating immune cells, have been linked to the growth, angiogenesis, and metastasis of a variety of cancers, most likely through polarization of TAMs to the M2 (alternative) phenotype. The interaction between tumor cells and macrophages pro...

  1. Isolation of Circulating Tumor Cells by Dielectrophoresis

    Directory of Open Access Journals (Sweden)

    Peter R. C. Gascoyne

    2014-03-01

    Full Text Available Dielectrophoresis (DEP is an electrokinetic method that allows intrinsic dielectric properties of suspended cells to be exploited for discrimination and separation. It has emerged as a promising method for isolating circulation tumor cells (CTCs from blood. DEP-isolation of CTCs is independent of cell surface markers. Furthermore, isolated CTCs are viable and can be maintained in culture, suggesting that DEP methods should be more generally applicable than antibody-based approaches. The aim of this article is to review and synthesize for both oncologists and biomedical engineers interested in CTC isolation the pertinent characteristics of DEP and CTCs. The aim is to promote an understanding of the factors involved in realizing DEP-based instruments having both sufficient discrimination and throughput to allow routine analysis of CTCs in clinical practice. The article brings together: (a the principles of DEP; (b the biological basis for the dielectric differences between CTCs and blood cells; (c why such differences are expected to be present for all types of tumors; and (d instrumentation requirements to process 10 mL blood specimens in less than 1 h to enable routine clinical analysis. The force equilibrium method of dielectrophoretic field-flow fractionation (DEP-FFF is shown to offer higher discrimination and throughput than earlier DEP trapping methods and to be applicable to clinical studies.

  2. Isolation of Circulating Tumor Cells by Dielectrophoresis

    Energy Technology Data Exchange (ETDEWEB)

    Gascoyne, Peter R. C., E-mail: pgascoyn@mdanderson.org [Department of Imaging Physics Research, The University of Texas M.D. Anderson Cancer Center Unit 951, 1515 Holcombe Boulevard, Houston, TX 77030 (United States); Shim, Sangjo [Department of Imaging Physics Research, The University of Texas M.D. Anderson Cancer Center Unit 951, 1515 Holcombe Boulevard, Houston, TX 77030 (United States); Department of Biomedical Engineering, The University of Texas at Austin, 1 University Station, C0800, Austin, TX 78712 (United States); Present address: Micro & Nanotechnology Laboratory, University of Illinois at Urbana-Champaign, Urbana, 208 North Wright Street, Urbana, IL 61801 (United States)

    2014-03-12

    Dielectrophoresis (DEP) is an electrokinetic method that allows intrinsic dielectric properties of suspended cells to be exploited for discrimination and separation. It has emerged as a promising method for isolating circulation tumor cells (CTCs) from blood. DEP-isolation of CTCs is independent of cell surface markers. Furthermore, isolated CTCs are viable and can be maintained in culture, suggesting that DEP methods should be more generally applicable than antibody-based approaches. The aim of this article is to review and synthesize for both oncologists and biomedical engineers interested in CTC isolation the pertinent characteristics of DEP and CTCs. The aim is to promote an understanding of the factors involved in realizing DEP-based instruments having both sufficient discrimination and throughput to allow routine analysis of CTCs in clinical practice. The article brings together: (a) the principles of DEP; (b) the biological basis for the dielectric differences between CTCs and blood cells; (c) why such differences are expected to be present for all types of tumors; and (d) instrumentation requirements to process 10 mL blood specimens in less than 1 h to enable routine clinical analysis. The force equilibrium method of dielectrophoretic field-flow fractionation (DEP-FFF) is shown to offer higher discrimination and throughput than earlier DEP trapping methods and to be applicable to clinical studies.

  3. Isolation of Circulating Tumor Cells by Dielectrophoresis

    International Nuclear Information System (INIS)

    Gascoyne, Peter R. C.; Shim, Sangjo

    2014-01-01

    Dielectrophoresis (DEP) is an electrokinetic method that allows intrinsic dielectric properties of suspended cells to be exploited for discrimination and separation. It has emerged as a promising method for isolating circulation tumor cells (CTCs) from blood. DEP-isolation of CTCs is independent of cell surface markers. Furthermore, isolated CTCs are viable and can be maintained in culture, suggesting that DEP methods should be more generally applicable than antibody-based approaches. The aim of this article is to review and synthesize for both oncologists and biomedical engineers interested in CTC isolation the pertinent characteristics of DEP and CTCs. The aim is to promote an understanding of the factors involved in realizing DEP-based instruments having both sufficient discrimination and throughput to allow routine analysis of CTCs in clinical practice. The article brings together: (a) the principles of DEP; (b) the biological basis for the dielectric differences between CTCs and blood cells; (c) why such differences are expected to be present for all types of tumors; and (d) instrumentation requirements to process 10 mL blood specimens in less than 1 h to enable routine clinical analysis. The force equilibrium method of dielectrophoretic field-flow fractionation (DEP-FFF) is shown to offer higher discrimination and throughput than earlier DEP trapping methods and to be applicable to clinical studies

  4. Circulating Tumor Cells, Enumeration and Beyond

    Energy Technology Data Exchange (ETDEWEB)

    Hou, Jian-Mei [Clinical and Experimental Pharmacology Group, Paterson Institute for Cancer Research, Manchester M20 4BX (United Kingdom); Krebs, Matthew [Clinical and Experimental Pharmacology Group, Paterson Institute for Cancer Research, Manchester M20 4BX (United Kingdom); Christie Hospital Foundation NHS Trust, Manchester M20 4BX (United Kingdom); Ward, Tim; Morris, Karen; Sloane, Robert [Clinical and Experimental Pharmacology Group, Paterson Institute for Cancer Research, Manchester M20 4BX (United Kingdom); Blackhall, Fiona [Clinical and Experimental Pharmacology Group, Paterson Institute for Cancer Research, Manchester M20 4BX (United Kingdom); School of Cancer and Enabling Sciences, University of Manchester, Manchester Cancer Research Centre, Manchester Academic Health Sciences Centre, Manchester M20 4BX (United Kingdom); Christie Hospital Foundation NHS Trust, Manchester M20 4BX (United Kingdom); Dive, Caroline, E-mail: cdive@picr.man.ac.uk [Clinical and Experimental Pharmacology Group, Paterson Institute for Cancer Research, Manchester M20 4BX (United Kingdom); School of Cancer and Enabling Sciences, University of Manchester, Manchester Cancer Research Centre, Manchester Academic Health Sciences Centre, Manchester M20 4BX (United Kingdom)

    2010-06-09

    The detection and enumeration of circulating tumor cells (CTCs) has shown significant clinical utility with respect to prognosis in breast, colorectal and prostate cancers. Emerging studies show that CTCs can provide pharmacodynamic information to aid therapy decision making. CTCs as a ‘virtual and real-time biopsy’ have clear potential to facilitate exploration of tumor biology, and in particular, the process of metastasis. The challenge of profiling CTC molecular characteristics and generating CTC signatures using current technologies is that they enrich rather than purify CTCs from whole blood; we face the problem of looking for the proverbial ‘needle in the haystack’. This review summarizes the current methods for CTC detection and enumeration, focuses on molecular characterization of CTCs, unveils some aspects of CTC heterogeneity, describes attempts to purify CTCs and scans the horizon for approaches leading to comprehensive dissection of CTC biology.

  5. Circulating tumor cells in breast cancer.

    Science.gov (United States)

    Bidard, Francois-Clement; Proudhon, Charlotte; Pierga, Jean-Yves

    2016-03-01

    Over the past decade, technically reliable circulating tumor cell (CTC) detection methods allowed the collection of large datasets of CTC counts in cancer patients. These data can be used either as a dynamic prognostic biomarker or as tumor material for "liquid biopsy". Breast cancer appears to be the cancer type in which CTC have been the most extensively studied so far, with level-of-evidence-1 studies supporting the clinical validity of CTC count in both early and metastatic stage. This review summarizes and discusses the clinical results obtained in breast cancer patients, the issues faced by the molecular characterization of CTC and the biological findings about cancer biology and metastasis that were obtained from CTC. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  6. Circulating Tumor Cells, Enumeration and Beyond

    International Nuclear Information System (INIS)

    Hou, Jian-Mei; Krebs, Matthew; Ward, Tim; Morris, Karen; Sloane, Robert; Blackhall, Fiona; Dive, Caroline

    2010-01-01

    The detection and enumeration of circulating tumor cells (CTCs) has shown significant clinical utility with respect to prognosis in breast, colorectal and prostate cancers. Emerging studies show that CTCs can provide pharmacodynamic information to aid therapy decision making. CTCs as a ‘virtual and real-time biopsy’ have clear potential to facilitate exploration of tumor biology, and in particular, the process of metastasis. The challenge of profiling CTC molecular characteristics and generating CTC signatures using current technologies is that they enrich rather than purify CTCs from whole blood; we face the problem of looking for the proverbial ‘needle in the haystack’. This review summarizes the current methods for CTC detection and enumeration, focuses on molecular characterization of CTCs, unveils some aspects of CTC heterogeneity, describes attempts to purify CTCs and scans the horizon for approaches leading to comprehensive dissection of CTC biology

  7. Circulating Tumor Cells, Enumeration and Beyond

    Directory of Open Access Journals (Sweden)

    Jian-Mei Hou

    2010-06-01

    Full Text Available The detection and enumeration of circulating tumor cells (CTCs has shown significant clinical utility with respect to prognosis in breast, colorectal and prostate cancers. Emerging studies show that CTCs can provide pharmacodynamic information to aid therapy decision making. CTCs as a ‘virtual and real-time biopsy’ have clear potential to facilitate exploration of tumor biology, and in particular, the process of metastasis. The challenge of profiling CTC molecular characteristics and generating CTC signatures using current technologies is that they enrich rather than purify CTCs from whole blood; we face the problem of looking for the proverbial ‘needle in the haystack’. This review summarizes the current methods for CTC detection and enumeration, focuses on molecular characterization of CTCs, unveils some aspects of CTC heterogeneity, describes attempts to purify CTCs and scans the horizon for approaches leading to comprehensive dissection of CTC biology.

  8. Tumor Cells Express FcγRl Which Contributes to Tumor Cell Growth and a Metastatic Phenotype

    Directory of Open Access Journals (Sweden)

    M. Bud Nelson

    2001-01-01

    Full Text Available High levels of circulating immune complexes containing tumor-associated antigens are associated with a poor prognosis for individuals with cancer. The ability of B cells, previously exposed to tumor-associated antigens, to promote both in vitro and in vivo tumor growth formed the rationale to evaluate the mechanism by which immune complexes may promote tumor growth. In elucidating this mechanism, FcγRl expression by tumor cells was characterized by flow cytometry, polymerase chain reaction, and sequence analysis. Immune complexes containing shed tumor antigen and anti-shed tumor antigen Ab cross-linked FcγRl-expressing tumor cells, which resulted in an induction of tumor cell proliferation and of shed tumor antigen production. Use of selective tyrosine kinase inhibitors demonstrated that tumor cell proliferation induced by immune complex cross-linking of FcγRl is dependent on the tyrosine kinase signal transduction pathway. A selective inhibitor of phosphatidylinositol-3 kinase also inhibited this induction of tumor cell proliferation. These findings support a role for immune complexes and FcγRl expression by tumor cells in augmentation of tumor growth and a metastatic phenotype.

  9. Tumor-altered dendritic cell function: implications for anti-tumor immunity

    Directory of Open Access Journals (Sweden)

    Kristian Michael Hargadon

    2013-07-01

    Full Text Available Dendritic cells are key regulators of both innate and adaptive immunity, and the array of immunoregulatory functions exhibited by these cells is dictated by their differentiation, maturation, and activation status. Although a major role for these cells in the induction of immunity to pathogens has long been appreciated, data accumulated over the last several years has demonstrated that DC are also critical regulators of anti-tumor immune responses. However, despite the potential for stimulation of robust anti-tumor immunity by DC, tumor-altered DC function has been observed in many cancer patients and tumor-bearing animals and is often associated with tumor immune escape. Such dysfunction has significant implications for both the induction of natural anti-tumor immune responses as well as the efficacy of immunotherapeutic strategies that target endogenous DC in situ or that employ exogenous DC as part of anti-cancer immunization maneuvers. In this review, the major types of tumor-altered DC function will be described, with emphasis on recent insights into the mechanistic bases for the inhibition of DC differentiation from hematopoietic precursors, the altered programming of DC precursors to differentiate into myeloid-derived suppressor cells or tumor-associated macrophages, the suppression of DC maturation and activation, and the induction of immunoregulatory DC by tumors, tumor-derived factors, and tumor-associated cells within the milieu of the tumor microenvironment. The impact of these tumor-altered cells on the quality of the overall anti-tumor immune response will also be discussed. Finally, this review will also highlight questions concerning tumor-altered DC function that remain unanswered, and it will address factors that have limited advances in the study of this phenomenon in order to focus future research efforts in the field on identifying strategies for interfering with tumor-associated DC dysfunction and improving DC-mediated anti-tumor

  10. Shift of microRNA profile upon glioma cell migration using patient-derived spheroids and serum-free conditions

    DEFF Research Database (Denmark)

    Munthe, Sune; Halle, Bo; Boldt, Henning B

    2017-01-01

    Glioblastoma multiforme (GBM) is the most frequent malignant primary brain tumor. A major reason for the overall median survival being only 14.6 months is migrating tumor cells left behind after surgery. Another major reason is tumor cells having a so-called cancer stem cell phenotype being...... therefore resistant towards traditional chemo- and radiotherapy. A group of novel molecular targets are microRNAs (miRNAs). MiRNAs are small non-coding RNAs exerting post-transcriptional regulation of gene expression. The aim of this study was to identify differentially expressed miRNAs in migrating GBM...... cells using serum-free stem cell conditions. We used patient-derived GBM spheroid cultures for a novel serum-free migration assay. MiRNA expression of migrating tumor cells isolated at maximum migration speed was compared with corresponding spheroids using an OpenArray Real-Time PCR System. The mi...

  11. Characterization of biological features of a rat F98 GBM model: A PET-MRI study with [18F]FAZA and [18F]FDG

    International Nuclear Information System (INIS)

    Belloli, Sara; Brioschi, Andrea; Politi, Letterio Salvatore; Ronchetti, Francesca; Calderoni, Sara; Raccagni, Isabella; Pagani, Antonella; Monterisi, Cristina; Zenga, Francesco; Zara, Gianpaolo; Fazio, Ferruccio; Mauro, Alessandro

    2013-01-01

    Introduction: The prognosis of malignant gliomas remains largely unsatisfactory for the intrinsic characteristics of the pathology and for the delayed diagnosis. Multimodal imaging based on PET and MRI may assess the dynamics of disease onset and progression allowing the validation of preclinical models of glioblastoma multiforme (GBM). The aim of this study was the characterization of a syngeneic rat model of GBM using combined in vivo imaging and immunohistochemistry. Methods: Four groups of Fischer rats were implanted in a subcortical region with increasing concentration of rat glioma F98 cells and weekly monitored with Gd-MR, [ 18 F]FDG- and [ 18 F]FAZA-PET starting one week after surgery. Different targets were evaluated on post mortem brain specimens using immunohistochemistry: VEGF, GFAP, HIF-1α, Ki-67 and nestin. Results: Imaging results indicated that tumor onset but not progression was related to the number of F98 cells. Hypoxic regions identified with [ 18 F]FAZA and high-glucose metabolism regions recognized with [ 18 F]FDG were located respectively in the core and in external areas of the tumor, with partial overlap and remodeling during disease progression. Histological and immunohistochemical analysis confirmed PET/MRI results and revealed that our model resumes biological characteristics of human GBM. IHC and PET studies showed that necrotic regions, defined on the basis of [ 18 F]FDG uptake reduction, may include hypoxic clusters of vital tumor tissue identified with [ 18 F]FAZA. This last information is particularly relevant for the identification of the target volume during image-guided radiotherapy. Conclusions: In conclusion, the combined use of PET and MRI allows in vivo monitoring of the biological modification of F98 lesions during tumor progression

  12. Invasive Glioblastoma Cells Acquire Stemness and Increased Akt Activation

    Directory of Open Access Journals (Sweden)

    Jennifer R. Molina

    2010-06-01

    Full Text Available Glioblastoma multiforme (GBM is the most frequent and most aggressive brain tumor in adults. The dismal prognosis is due to postsurgery recurrences arising from escaped invasive tumor cells. The signaling pathways activated in invasive cells are under investigation, and models are currently designed in search for therapeutic targets. We developed here an in vivo model of human invasive GBM in mouse brain from a GBM cell line with moderate tumorigenicity that allowed simultaneous primary tumor growth and dispersal of tumor cells in the brain parenchyma. This strategy allowed for the first time the isolation and characterization of matched sets of tumor mass (Core and invasive (Inv cells. Both cell populations, but more markedly Inv cells, acquired stem cell markers, neurosphere renewal ability, and resistance to rapamycin-induced apoptosis relative to parental cells. The comparative phenotypic analysis between Inv and Core cells showed significantly increased tumorigenicity in vivo and increased invasion with decreased proliferation in vitro for Inv cells. Examination of a large array of signaling pathways revealed extracellular signal-regulated kinase (Erk down-modulation and Akt activation in Inv cells and an opposite profile in Core cells. Akt activation correlated with the increased tumorigenicity, stemness, and invasiveness, whereas Erk activation correlated with the proliferation of the cells. These results underscore complementary roles of the Erk and Akt pathways for GBM proliferation and dispersal and raise important implications for a concurrent inhibitory therapy.

  13. Childhood Central Nervous System Germ Cell Tumors Treatment

    Science.gov (United States)

    ... make hormones. Yolk sac tumors make the hormone alpha-fetoprotein (AFP). Mixed germ cell tumors are made of ... used to diagnose some CNS germ cell tumors: Alpha-fetoprotein (AFP). Beta-human chorionic gonadotropin (β-hCG). Blood ...

  14. Radiocolloid Uptake in the Pancreas Islet Cell Tumor: Case Report

    Energy Technology Data Exchange (ETDEWEB)

    Yang, W. J.; Chung, S. K.; Yeon, S. K.; Shinn, K. S.; Bahk, Y. W. [Catholic University College of Medicine, Seoul (Korea, Republic of)

    1994-03-15

    Colloid uptake in various hepatic conditions such as focal nodular hyperplasia, regenerating nodular in the cirrhotic liver, hamartoma, hemangioma and rarely hepatoma has been documented. Extrahepatic tumors may show colloid uptake and they include splenic hemangioma, malignant fibrous histiocytoma, breast carcinoma and Kaposi's sarcoma. The mechanism of colloid uptake in those lesions is associated with phagocytic activity in or around the tumors. We report a pancreas islet cell tumor that showed colloid uptake on {sup 99m}Tc-phytate liver scan without histologic evidence of phagocytosis by tumor cells or infiltration of phagocytes in the tumor. Microscopically the tumor was highly vascular and showed diffuse hemorrhage throughout the tumor. We postulated that extravasation of the colloid into the tumor interstitium caused nonspecific colloid uptake in this tumor. It is expected that hemorrhagic tumor may show nonspecific colloid uptake without phagocytosis in or about the lesion.

  15. Radiocolloid Uptake in the Pancreas Islet Cell Tumor: Case Report

    International Nuclear Information System (INIS)

    Yang, W. J.; Chung, S. K.; Yeon, S. K.; Shinn, K. S.; Bahk, Y. W.

    1994-01-01

    Colloid uptake in various hepatic conditions such as focal nodular hyperplasia, regenerating nodular in the cirrhotic liver, hamartoma, hemangioma and rarely hepatoma has been documented. Extrahepatic tumors may show colloid uptake and they include splenic hemangioma, malignant fibrous histiocytoma, breast carcinoma and Kaposi's sarcoma. The mechanism of colloid uptake in those lesions is associated with phagocytic activity in or around the tumors. We report a pancreas islet cell tumor that showed colloid uptake on 99m Tc-phytate liver scan without histologic evidence of phagocytosis by tumor cells or infiltration of phagocytes in the tumor. Microscopically the tumor was highly vascular and showed diffuse hemorrhage throughout the tumor. We postulated that extravasation of the colloid into the tumor interstitium caused nonspecific colloid uptake in this tumor. It is expected that hemorrhagic tumor may show nonspecific colloid uptake without phagocytosis in or about the lesion.

  16. Cancer stem cells in solid tumors: elusive or illusive?

    Directory of Open Access Journals (Sweden)

    Lehrach Hans R

    2010-05-01

    Full Text Available Abstract During the past years in vivo transplantation experiments and in vitro colony-forming assays indicated that tumors arise only from rare cells. These cells were shown to bear self-renewal capacities and the ability to recapitulate all cell types within an individual tumor. Due to their phenotypic resemblance to normal stem cells, the term "cancer stem cells" is used. However, some pieces of the puzzle are missing: (a a stringent definition of cancer stem cells in solid tumors (b specific markers that only target cells that meet the criteria for a cancer stem cell in a certain type of tumor. These missing parts started an ongoing debate about which is the best method to identify and characterize cancer stem cells, or even if their mere existence is just an artifact caused by the experimental procedures. Recent findings query the cancer stem cell hypothesis for solid tumors itself since it was shown in xenograft transplantation experiments that under appropriate conditions tumor-initiating cells are not rare. In this review we critically discuss the challenges and prospects of the currently used major methods to identify cancer stem cells. Further on, we reflect the present discussion about the existence of cancer stem cells in solid tumors as well as the amount and characteristics of tumor-initiating cells and finally provide new perspectives like the correlation of cancer stem cells and induced pluripotent cells.

  17. Circulating tumor cells in melanoma patients.

    Directory of Open Access Journals (Sweden)

    Gary A Clawson

    Full Text Available Circulating tumor cells (CTCs are of recognized importance for diagnosis and prognosis of cancer patients. With melanoma, most studies do not show any clear relationship between CTC levels and stage of disease. Here, CTCs were enriched (∼400X from blood of melanoma patients using a simple centrifugation device (OncoQuick, and 4 melanocyte target RNAs (TYR, MLANA, MITF, and MIF were quantified using QPCR. Approximately one-third of melanoma patients had elevated MIF and MLANA transcripts (p<0.0001 and p<0.001, respectively compared with healthy controls. In contrast, healthy controls had uniformly higher levels of TYR and MITF than melanoma patients (p<0.0001. There was a marked shift of leukocytes into the CTC-enriched fractions (a 430% increase in RNA recovery, p<0.001, and no relationship between CTC levels and stage of disease was found. CTCs were captured on microfabricated filters and cultured. Captured melanoma CTCs were large cells, and consisted of 2 subpopulations, based on immunoreactivity. One subpopulation (∼50% stained for both pan-cytokeratin (KRT markers and the common leukocyte marker CD-45, whereas the second subpopulation stained for only KRT. Since similar cells are described in many cancers, we also examined blood from colorectal and pancreatic cancer patients. We observed analogous results, with most captured CTCs staining for both CD-45/KRT markers (and for the monocyte differentiation marker CD-14. Our results suggest that immature melanocyte-related cells (expressing TYR and MITF RNA may circulate in healthy controls, although they are not readily detectable without considerable enrichment. Further, as early-stage melanomas develop, immature melanocyte migration into the blood is somehow curtailed, whereas a significant proportion of patients develop elevated CTC levels (based on MIF and MLANA RNAs. The nature of the captured CTCs is consistent with literature describing leukocyte/macrophage-tumor cell fusion hybrids

  18. Small cell glioblastoma or small cell carcinoma

    DEFF Research Database (Denmark)

    Hilbrandt, Christine; Sathyadas, Sathya; Dahlrot, Rikke H

    2013-01-01

    was admitted to the hospital with left-sided loss of motor function. A MRI revealed a 6 cm tumor in the right temporoparietal area. The histology was consistent with both glioblastoma multiforme (GBM) and small cell lung carcinoma (SCLC) but IHC was suggestive of a SCLC metastasis. PET-CT revealed...

  19. Granular cell tumor of the esophagus. Report of three cases.

    Science.gov (United States)

    Cohle, S D; McKechnie, J C; Truong, L; Jurco, S

    1981-06-01

    Granular cell tumors, (formerly called myoblastomas) involving the esophagus were encountered in three patients. In all three the tumors were asymptomatic and in two they were multiple. The first published endoscopic photographs of such a tumor are presented. The successful total removal of this neoplasm using the endoscope is described. The pathologic, radiologic and therapeutic aspects of previously reported cases of granular cell tumor of the esophagus are reviewed and compared with the three reported herein.

  20. Tumor cell culture on collagen–chitosan scaffolds as three-dimensional tumor model: A suitable model for tumor studies

    Directory of Open Access Journals (Sweden)

    Aziz Mahmoudzadeh

    2016-07-01

    Full Text Available Tumor cells naturally live in three-dimensional (3D microenvironments, while common laboratory tests and evaluations are done in two-dimensional (2D plates. This study examined the impact of cultured 4T1 cancer cells in a 3D collagen–chitosan scaffold compared with 2D plate cultures. Collagen–chitosan scaffolds were provided and passed confirmatory tests. 4T1 tumor cells were cultured on scaffolds and then tumor cells growth rate, resistance to X-ray radiation, and cyclophosphamide as a chemotherapy drug were analyzed. Furthermore, 4T1 cells were extracted from the scaffold model and were injected into the mice. Tumor growth rate, survival rate, and systemic immune responses were evaluated. Our results showed that 4T1 cells infiltrated the scaffolds pores and constructed a 3D microenvironment. Furthermore, 3D cultured tumor cells showed a slower proliferation rate, increased levels of survival to the X-ray irradiation, and enhanced resistance to chemotherapy drugs in comparison with 2D plate cultures. Transfer of extracted cells to the mice caused enhanced tumor volume and decreased life span. This study indicated that collagen–chitosan nanoscaffolds provide a suitable model of tumor that would be appropriate for tumor studies.

  1. Tumor cell culture on collagen-chitosan scaffolds as three-dimensional tumor model: A suitable model for tumor studies.

    Science.gov (United States)

    Mahmoudzadeh, Aziz; Mohammadpour, Hemn

    2016-07-01

    Tumor cells naturally live in three-dimensional (3D) microenvironments, while common laboratory tests and evaluations are done in two-dimensional (2D) plates. This study examined the impact of cultured 4T1 cancer cells in a 3D collagen-chitosan scaffold compared with 2D plate cultures. Collagen-chitosan scaffolds were provided and passed confirmatory tests. 4T1 tumor cells were cultured on scaffolds and then tumor cells growth rate, resistance to X-ray radiation, and cyclophosphamide as a chemotherapy drug were analyzed. Furthermore, 4T1 cells were extracted from the scaffold model and were injected into the mice. Tumor growth rate, survival rate, and systemic immune responses were evaluated. Our results showed that 4T1 cells infiltrated the scaffolds pores and constructed a 3D microenvironment. Furthermore, 3D cultured tumor cells showed a slower proliferation rate, increased levels of survival to the X-ray irradiation, and enhanced resistance to chemotherapy drugs in comparison with 2D plate cultures. Transfer of extracted cells to the mice caused enhanced tumor volume and decreased life span. This study indicated that collagen-chitosan nanoscaffolds provide a suitable model of tumor that would be appropriate for tumor studies. Copyright © 2016. Published by Elsevier B.V.

  2. d,l-Sulforaphane Induces ROS-Dependent Apoptosis in Human Gliomablastoma Cells by Inactivating STAT3 Signaling Pathway

    Directory of Open Access Journals (Sweden)

    Ziwei Miao

    2017-01-01

    Full Text Available d,l-Sulforaphane (SFN, a synthetic analogue of broccoli-derived isomer l-SFN, exerts cytotoxic effects on multiple tumor cell types through different mechanisms and is more potent than the l-isomer at inhibiting cancer growth. However, the means by which SFN impairs glioblastoma (GBM cells remains poorly understood. In this study, we investigated the anti-cancer effect of SFN in GBM cells and determined the underlying molecular mechanisms. Cell viability assays, flow cytometry, immunofluorescence, and Western blot results revealed that SFN could induced apoptosis of GBM cells in a dose- and time-dependent manner, via up-regulation of caspase-3 and Bax, and down-regulation of Bcl-2. Mechanistically, SFN treatment led to increase the intracellular reactive oxygen species (ROS level in GBM cells. Meanwhile, SFN also suppressed both constitutive and IL-6-induced phosphorylation of STAT3, and the activation of upstream JAK2 and Src tyrosine kinases, dose- and time-dependently. Moreover, blockage of ROS production by using the ROS inhibitor N-acetyl-l-cysteine totally reversed SFN-mediated down-regulation of JAK2/Src-STAT3 signaling activation and the subsequent effects on apoptosis by blocking the induction of apoptosis-related genes in GBM cells. Taken together, our data suggests that SFN induces apoptosis in GBM cells via ROS-dependent inactivation of STAT3 phosphorylation. These findings motivate further evaluation of SFN as a cancer chemopreventive agent in GBM treatment.

  3. Sox2, a stemness gene, regulates tumor-initiating and drug-resistant properties in CD133-positive glioblastoma stem cells

    Directory of Open Access Journals (Sweden)

    Wen-Shin Song

    2016-10-01

    Conclusion: SOX2 plays a crucial role in regulating tumorigenicity in CD133+ GBM cells. Our results not only revealed the genetic plasticity contributing to drug resistance and stemness but also demonstrated the dominant role of SOX2 in maintenance of GBM CSCs, which may provide a novel therapeutic target to overcome the conundrum of poor survival of brain cancers.

  4. Magnetar Observations with Fermi/GBM

    Science.gov (United States)

    Kouveliotou, Chryssa

    2009-01-01

    NASA's Fermi Observatory was launched June 11, 2009; the Fermi Gamma Ray Burst Monitor (GBM) began normal operations on July 14, about a month after launch, when the trigger algorithms were enabled. In the first year of operations we recorded emission from four magnetar sources; of these, only one was an old magnetar: SGR 1806+20. The other three detections were: SGR J0501+4516, newly discovered with Swift and extensively monitored with both Swift and GBM, SGR J1550-5418, a source originally classified as an Anomalous X-ray Pulsar (AXP) and a very recently discovered new source, SGR 0418+5729. I report below on the current status of the analyses efforts of the GBM data.

  5. Non-cell autonomous or secretory tumor suppression.

    Science.gov (United States)

    Chua, Christelle En Lin; Chan, Shu Ning; Tang, Bor Luen

    2014-10-01

    Many malignancies result from deletions or loss-of-function mutations in one or more tumor suppressor genes, the products of which curb unrestrained growth or induce cell death in those with dysregulated proliferative capacities. Most tumor suppressors act in a cell autonomous manner, and only very few proteins are shown to exert a non-cell autonomous tumor suppressor function on other cells. Examples of these include members of the secreted frizzled-related protein (SFRP) family and the secreted protein acidic and rich in cysteine (SPARC)-related proteins. Very recent findings have, however, considerably expanded our appreciation of non-cell autonomous tumor suppressor functions. Broadly, this may occur in two ways. Intracellular tumor suppressor proteins within cells could in principle inhibit aberrant growth of neighboring cells by conditioning an antitumor microenvironment through secreted factors. This is demonstrated by an apparent non-cell autonomous tumor suppressing property of p53. On the other hand, a tumor suppressor produced by a cell may be secreted extracellularly, and taken up by another cell with its activity intact. Intriguingly, this has been recently shown to occur for the phosphatase and tensin homolog (PTEN) by both conventional and unconventional modes of secretion. These recent findings would aid the development of therapeutic strategies that seek to reinstate tumor suppression activity in therapeutically recalcitrant tumor cells, which have lost it in the first place. © 2014 Wiley Periodicals, Inc.

  6. Studies on cross-immunity among syngeneic tumors by immunization with gamma-irradiated tumor cells

    International Nuclear Information System (INIS)

    Ito, Izumi

    1977-01-01

    In order to clarify whether cross-immunity among 3-methyl-cholanthrene (MCA)-induced sarcomas in C3H/He mice can be established or not, transplantations of syngeneic tumors were carried out in mice immunized with gamma-irradiated (13,000 rad 60 Co) tumor cells and in those immunized with living tumor cells thereafter. The following results were obtained. By using immunizing procedure with only gamma-irradiated tumor cells, a pair of tumors originating from one and the same mouse showed cross-resistance to each other. However, no such evidence was seen among tumors originating from different mice. Cross-immunity among syngeneic tumors originating from different mice could be clearly observed, when immunizing procedure using living tumor cells was added after the treatment with gamma-irradiated tumor cells. It was considered that common antigenicity among MCA-induced sarcoma cells was decreased by gamma-irradiation and that individual differences of tumor antigenecity were shown distinctly under such conditions. (auth.)

  7. Current status and future therapeutic perspectives of glioblastoma multiforme (GBM) therapy: A review.

    Science.gov (United States)

    Anjum, Komal; Shagufta, Bibi Ibtesam; Abbas, Syed Qamar; Patel, Seema; Khan, Ishrat; Shah, Sayed Asmat Ali; Akhter, Najeeb; Hassan, Syed Shams Ul

    2017-08-01

    Glioblastoma multiforme (GBM) is the deadliest form of heterogeneous brain cancer. It affects an enormous number of patients every year and the survival is approximately 8 to 15 months. GBM has driven by complex signaling pathways and considered as a most challenging to treat. Standard treatment of GBM includes surgery, radiation therapy, chemotherapy and also the combined treatment. This review article described inter and intra- tumor heterogeneity of GMB. In addition, recent chemotherapeutic agents, with their mechanism of action have been defined. FDA-approved drugs also been focused over here and most importantly highlighting some natural and synthetic and novel anti- glioma agents, that are the main focus of researchers nowadays. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  8. Fermi GBM Observations of Terrestrial Gamma Flashes

    Science.gov (United States)

    Wilson-Hodge, Colleen A.; Briggs, M. S.; Connaughton, V.; Fishman, G. J.; Bhat, P. N.; Paciesas, W. S.; Preece, R. D.; Kippen, R. M.; vonKienlin, A.; Dwyer, J. R.; hide

    2010-01-01

    In its first two years of operation, the Fermi Gamma Ray Burst Monitor (GBM) has observed 79 Terrestrial Gamma Flashes (TGFs). The thick Bismuth Germanate (BGO) detectors are excellent for TGF spectroscopy, having a high probability of recording the full energy of an incident photon, spanning a broad energy range from 150 keV to 40 MeV, and recording a large number of photons per TGF. Correlations between GBM TGF triggers and lightning sferics detected with the World-Wide Lightning Location Network indicate that TGFs and lightning are simultaneous to within tens of microseconds.

  9. Ovarian granulosa cell tumors : histopathology, immunopathology and prognosis

    NARCIS (Netherlands)

    S. Chadha-Ajwani (Savi)

    1987-01-01

    textabstractGranulosa cell tumors (GCT) of the ovary account for 2% of all ovarian tumors. As the name indicates, they are composed of granulosa cells but may also contain an admixture of theca cells. They are potentially malignant but, except for extraovarian spread, which is generally agreed

  10. Antitumor action of 3-bromopyruvate implicates reorganized tumor growth regulatory components of tumor milieu, cell cycle arrest and induction of mitochondria-dependent tumor cell death.

    Science.gov (United States)

    Yadav, Saveg; Kujur, Praveen Kumar; Pandey, Shrish Kumar; Goel, Yugal; Maurya, Babu Nandan; Verma, Ashish; Kumar, Ajay; Singh, Rana Pratap; Singh, Sukh Mahendra

    2018-01-15

    Evidences demonstrate that metabolic inhibitor 3-bromopyruvate (3-BP) exerts a potent antitumor action against a wide range of malignancies. However, the effect of 3-BP on progression of the tumors of thymic origin remains unexplored. Although, constituents of tumor microenvironment (TME) plays a pivotal role in regulation of tumor progression, it remains unclear if 3-BP can alter the composition of the crucial tumor growth regulatory components of the external surrounding of tumor cells. Thus, the present investigation attempts to understand the effect of 3-BP administration to a host bearing a progressively growing tumor of thymic origin on tumor growth regulatory soluble, cellular and biophysical components of tumor milieu vis-à-vis understanding its association with tumor progression, accompanying cell cycle events and mode of cell death. Further, the expression of cell survival regulatory molecules and hemodynamic characteristics of the tumor milieu were analysed to decipher mechanisms underlying the antitumor action of 3-BP. Administration of 3-BP to tumor-bearing hosts retarded tumor progression accompanied by induction of tumor cell death, cell cycle arrest, declined metabolism, inhibited mitochondrial membrane potential, elevated release of cytochrome c and altered hemodynamics. Moreover, 3-BP reconstituted the external milieu, in concurrence with deregulated glucose and pH homeostasis and increased tumor infiltration by NK cells, macrophages, and T lymphocytes. Further, 3-BP administration altered the expression of key regulatory molecules involved in glucose uptake, intracellular pH and tumor cell survival. The outcomes of this study will help in optimizing the therapeutic application of 3-BP by targeting crucial tumor growth regulatory components of tumor milieu. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. RasGRP3 regulates the migration of glioma cells via interaction with Arp3

    Science.gov (United States)

    Lee, Hae Kyung; Finniss, Susan; Cazacu, Simona; Xiang, Cunli; Poisson, Laila M.; Blumberg, Peter M.; Brodie, Chaya

    2015-01-01

    Glioblastoma (GBM), the most aggressive primary brain tumors, are highly infiltrative. Although GBM express high Ras activity and Ras proteins have been implicated in gliomagenesis, Ras-activating mutations are not frequent in these tumors. RasGRP3, an important signaling protein responsive to diacylglycerol (DAG), increases Ras activation. Here, we examined the expression and functions of RasGRP3 in GBM and glioma cells. RasGRP3 expression was upregulated in GBM specimens and glioma stem cells compared with normal brains and neural stem cells, respectively. RasGRP3 activated Ras and Rap1 in glioma cells and increased cell migration and invasion partially via Ras activation. Using pull-down assay and mass spectroscopy we identified the actin-related protein, Arp3, as a novel interacting protein of RasGRP3. The interaction of RasGRP3 and Arp3 was validated by immunofluorescence staining and co-immunoprecipitation, and PMA, which activates RasGRP3 and induces its translocation to the peri-nuclear region, increased the association of Arp3 and RasGRP3. Arp3 was upregulated in GBM, regulated cell spreading and migration and its silencing partially decreased these effects of RasGRP3 in glioma cells. In summary, RasGRP3 acts as an important integrating signaling protein of the DAG and Ras signaling pathways and actin polymerization and represents an important therapeutic target in GBM. PMID:25682201

  12. Solid KHT tumor dispersal for flow cytometric cell kinetic analysis

    International Nuclear Information System (INIS)

    Pallavicini, M.G.; Folstad, L.J.; Dunbar, C.

    1981-01-01

    A bacterial neutral protease was used to disperse KHT solid tumors into single cell suspensions suitable for routine cell kinetic analysis by flow cytometry and for clonogenic cell survival. Neutral protease disaggregation under conditions which would be suitable for routine tumor dispersal was compared with a trypsin/DNase procedure. Cell yield, clonogenic cell survival, DNA distributions of untreated and drug-perturbed tumors, rates of radioactive precursor incorporation during the cell cycle, and preferential cell cycle phase-specific cell loss were investigated. Tumors dispersed with neutral protease yielded approximately four times more cells than those dispersed with trypsin/DNase and approximately a 1.5-fold higher plating efficiency in a semisolid agar system. Quantitative analysis of DNA distributions obtained from untreated and cytosine-arabinoside-perturbed tumors produced similar results with both dispersal procedures. The rates of incorporation of tritiated thymidine during the cell cycle were also similar with neutral protease and trypsin/DNase dispersal. Preferential phase-specific cell loss was not obseved with either technique. We find that neutral protease provides good single cell suspensions of the KHT tumor for cell survival measurements and for cell kinetic analysis of drug-induced perturbations by flow cytometry. In addition, the high cell yields facilitate electronic cell sorting where large numbers of cells are often required

  13. Clinical relevance and biology of circulating tumor cells

    Science.gov (United States)

    2011-01-01

    Most breast cancer patients die due to metastases, and the early onset of this multistep process is usually missed by current tumor staging modalities. Therefore, ultrasensitive techniques have been developed to enable the enrichment, detection, isolation and characterization of disseminated tumor cells in bone marrow and circulating tumor cells in the peripheral blood of cancer patients. There is increasing evidence that the presence of these cells is associated with an unfavorable prognosis related to metastatic progression in the bone and other organs. This review focuses on investigations regarding the biology and clinical relevance of circulating tumor cells in breast cancer. PMID:22114869

  14. Tumor-derived circulating endothelial cell clusters in colorectal cancer.

    KAUST Repository

    Cima, Igor; Kong, Say Li; Sengupta, Debarka; Tan, Iain B; Phyo, Wai Min; Lee, Daniel; Hu, Min; Iliescu, Ciprian; Alexander, Irina; Goh, Wei Lin; Rahmani, Mehran; Suhaimi, Nur-Afidah Mohamed; Vo, Jess H; Tai, Joyce A; Tan, Joanna H; Chua, Clarinda; Ten, Rachel; Lim, Wan Jun; Chew, Min Hoe; Hauser, Charlotte; van Dam, Rob M; Lim, Wei-Yen; Prabhakar, Shyam; Lim, Bing; Koh, Poh Koon; Robson, Paul; Ying, Jackie Y; Hillmer, Axel M; Tan, Min-Han

    2016-01-01

    Clusters of tumor cells are often observed in the blood of cancer patients. These structures have been described as malignant entities for more than 50 years, although their comprehensive characterization is lacking. Contrary to current consensus, we demonstrate that a discrete population of circulating cell clusters isolated from the blood of colorectal cancer patients are not cancerous but consist of tumor-derived endothelial cells. These clusters express both epithelial and mesenchymal markers, consistent with previous reports on circulating tumor cell (CTC) phenotyping. However, unlike CTCs, they do not mirror the genetic variations of matched tumors. Transcriptomic analysis of single clusters revealed that these structures exhibit an endothelial phenotype and can be traced back to the tumor endothelium. Further results show that tumor-derived endothelial clusters do not form by coagulation or by outgrowth of single circulating endothelial cells, supporting a direct release of clusters from the tumor vasculature. The isolation and enumeration of these benign clusters distinguished healthy volunteers from treatment-naïve as well as pathological early-stage (≤IIA) colorectal cancer patients with high accuracy, suggesting that tumor-derived circulating endothelial cell clusters could be used as a means of noninvasive screening for colorectal cancer. In contrast to CTCs, tumor-derived endothelial cell clusters may also provide important information about the underlying tumor vasculature at the time of diagnosis, during treatment, and throughout the course of the disease.

  15. Tumor-derived circulating endothelial cell clusters in colorectal cancer.

    KAUST Repository

    Cima, Igor

    2016-06-29

    Clusters of tumor cells are often observed in the blood of cancer patients. These structures have been described as malignant entities for more than 50 years, although their comprehensive characterization is lacking. Contrary to current consensus, we demonstrate that a discrete population of circulating cell clusters isolated from the blood of colorectal cancer patients are not cancerous but consist of tumor-derived endothelial cells. These clusters express both epithelial and mesenchymal markers, consistent with previous reports on circulating tumor cell (CTC) phenotyping. However, unlike CTCs, they do not mirror the genetic variations of matched tumors. Transcriptomic analysis of single clusters revealed that these structures exhibit an endothelial phenotype and can be traced back to the tumor endothelium. Further results show that tumor-derived endothelial clusters do not form by coagulation or by outgrowth of single circulating endothelial cells, supporting a direct release of clusters from the tumor vasculature. The isolation and enumeration of these benign clusters distinguished healthy volunteers from treatment-naïve as well as pathological early-stage (≤IIA) colorectal cancer patients with high accuracy, suggesting that tumor-derived circulating endothelial cell clusters could be used as a means of noninvasive screening for colorectal cancer. In contrast to CTCs, tumor-derived endothelial cell clusters may also provide important information about the underlying tumor vasculature at the time of diagnosis, during treatment, and throughout the course of the disease.

  16. The use of bispecific antibodies in tumor cell and tumor vasculature directed immunotherapy

    NARCIS (Netherlands)

    Molema, G; Kroesen, BJ; Helfrich, W; Meijer, DKF; de Leij, LFMH

    2000-01-01

    To overcome dose limiting toxicities and to increase efficacy of immunotherapy of cancer, a number of strategies are under development for selectively redirecting effector cells/molecules towards tumor cells. Many of these strategies exploit the specificity of tumor associated antigen recognition by

  17. Treatment Options for Childhood Extracranial Germ Cell Tumors

    Science.gov (United States)

    ... tumors: Yolk sac tumors make a hormone called alpha-fetoprotein (AFP). They can form in the ovary, testicle, ... are used to detect extracranial germ cell tumors: Alpha-fetoprotein (AFP). Beta-human chorionic gonadotropin (β-hCG). For ...

  18. General Information about Childhood Extracranial Germ Cell Tumors

    Science.gov (United States)

    ... tumors: Yolk sac tumors make a hormone called alpha-fetoprotein (AFP). They can form in the ovary, testicle, ... are used to detect extracranial germ cell tumors: Alpha-fetoprotein (AFP). Beta-human chorionic gonadotropin (β-hCG). For ...

  19. Flow cytometric DNA ploidy analysis of ovarian granulosa cell tumors

    NARCIS (Netherlands)

    D. Chadha; C.J. Cornelisse; A. Schabert (A.)

    1990-01-01

    textabstractAbstract The nuclear DNA content of 50 ovarian tumors initially diagnosed as granulosa cell tumors was measured by flow cytometry using paraffin-embedded archival material. The follow-up period of the patients ranged from 4 months to 19 years. Thirty-eight tumors were diploid or

  20. TCGA Workshop: Genomics and Biology of Glioblastoma Multiforme (GBM) - TCGA

    Science.gov (United States)

    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.

  1. Adult, embryonic and fetal hemoglobin are expressed in human glioblastoma cells.

    Science.gov (United States)

    Emara, Marwan; Turner, A Robert; Allalunis-Turner, Joan

    2014-02-01

    Hemoglobin is a hemoprotein, produced mainly in erythrocytes circulating in the blood. However, non-erythroid hemoglobins have been previously reported in other cell types including human and rodent neurons of embryonic and adult brain, but not astrocytes and oligodendrocytes. Human glioblastoma multiforme (GBM) is the most aggressive tumor among gliomas. However, despite extensive basic and clinical research studies on GBM cells, little is known about glial defence mechanisms that allow these cells to survive and resist various types of treatment. We have shown previously that the newest members of vertebrate globin family, neuroglobin (Ngb) and cytoglobin (Cygb), are expressed in human GBM cells. In this study, we sought to determine whether hemoglobin is also expressed in GBM cells. Conventional RT-PCR, DNA sequencing, western blot analysis, mass spectrometry and fluorescence microscopy were used to investigate globin expression in GBM cell lines (M006x, M059J, M059K, M010b, U87R and U87T) that have unique characteristics in terms of tumor invasion and response to radiotherapy and hypoxia. The data showed that α, β, γ, δ, ζ and ε globins are expressed in all tested GBM cell lines. To our knowledge, we are the first to report expression of fetal, embryonic and adult hemoglobin in GBM cells under normal physiological conditions that may suggest an undefined function of those expressed hemoglobins. Together with our previous reports on globins (Ngb and Cygb) expression in GBM cells, the expression of different hemoglobins may constitute a part of series of active defence mechanisms supporting these cells to resist various types of treatments including chemotherapy and radiotherapy.

  2. Tumor cells and memory T cells converge at glycolysis

    Science.gov (United States)

    Karthikeyan, Swathi; Geschwind, Jean-Francois; Ganapathy-Kanniappan, Shanmugasundaram

    2014-01-01

    In the immune system, activation of naïve T (Tn) cells into effector T cells (Teff) involves a metabolic switch to glycolysis to promote rapid proliferation and differentiation. In the October issue of The Journal of Clinical Investigation, Sukumar et al. have demonstrated that in CD8+ memory T (Tems) cells glycolytic phenotype contributes to the shortened lifespan of Tems. Conversely, inhibition of glycolysis in Tems not only extended their viability but also augmented desirable properties. Notably, they also demonstrate that glycolytic inhibition during the ex vivo clonal expansion of tumor-specific Tems enhanced their antitumor function. Overall, the data suggest that an antiglycolytic strategy targeting the Tems could enhance antitumor immune response. On the other hand, cancer cells have long been known to exhibit metabolic reprogramming which involves a shift toward glycolysis (the conversion of glucose into lactate) to facilitate uninterrupted growth. Interestingly, antiglycolytic treatment of cancer cells has been known to trigger antitumor immune response as well. Taken together, it is probable that a strategy involving concurrent inhibition of glycolysis in tumor cells and Tems could promote a dual attack on cancer by inducing an effective antitumor immune response and an immunogenic chemotherapy. PMID:24556820

  3. Glycan Markers as Potential Immunological Targets in Circulating Tumor Cells.

    Science.gov (United States)

    Wang, Denong; Wu, Lisa; Liu, Xiaohe

    2017-01-01

    We present here an experimental approach for exploring a new class of tumor biomarkers that are overexpressed by circulating tumor cells (CTCs) and are likely targetable in immunotherapy against tumor metastasis. Using carbohydrate microarrays, anti-tumor monoclonal antibodies (mAbs) were scanned against a large panel of carbohydrate antigens to identify potential tumor glycan markers. Subsequently, flow cytometry and fiber-optic array scanning technology (FAST) were applied to determine whether the identified targets are tumor-specific cell-surface markers and are, therefore, likely suitable for targeted immunotherapy. Finally, the tumor glycan-specific antibodies identified were validated using cancer patients' blood samples for their performance in CTC-detection and immunotyping analysis. In this article, identifying breast CTC-specific glycan markers and targeting mAbs serve as examples to illustrate this tumor biomarker discovery strategy.

  4. Three years of Transients with Fermi GBM

    Science.gov (United States)

    Wilson-Hodge, Colleen A.

    2012-01-01

    The Gamma-ray Burst Monitor (GBM) is an all-sky monitoring instrument, sensitive between 8 keV and 40 MeV, with a primary objective of supporting the Large Area Telescope (LAT) in observations of Gamma-Ray Bursts (GRBs). Both instruments are part of the Fermi Gamma-ray Space Telescope. Together, the GBM and LAT instruments have provided ground-breaking measurements of GRBs that have, after 10 years of focus on GRB afterglows, inspired renewed interest in the prompt emission phase of GRBs and the physical mechanisms that fuel them. In addition to GRB science, GBM has made significant contributions to the astrophysics of galactic transient sources including long-term variations in the Crab nebula, spin state transitions in accretion powered pulsars, state transitions in black hole X-ray binaries, and unprecedented time-resolved spectral studies of soft gamma-ray repeater bursts. Closer to home, GBM also contributes to solar flare and terrestrial gamma flash science.

  5. Dielectrophoretic capture and genetic analysis of single neuroblastoma tumor cells

    Directory of Open Access Journals (Sweden)

    Erica L Carpenter

    2014-07-01

    Full Text Available Our understanding of the diversity of cells that escape the primary tumor and seed micrometastases remains rudimentary, and approaches for studying circulating and disseminated tumor cells have been limited by low throughput and sensitivity, reliance on single parameter sorting, and a focus on enumeration rather than phenotypic and genetic characterization. Here we utilize a highly sensitive microfluidic and dielectrophoretic approach for the isolation and genetic analysis of individual tumor cells. We employed fluorescence labeling to isolate 208 single cells from spiking experiments conducted with 11 cell lines, including 8 neuroblastoma cell lines, and achieved a capture sensitivity of 1 tumor cell per 106 white blood cells. Sample fixation or freezing had no detectable effect on cell capture. Point mutations were accurately detected in the whole genome amplification product of captured single tumor cells but not in negative control white blood cells. We applied this approach to capture 144 single tumor cells from 10 bone marrow samples from patients suffering from neuroblastoma. In this pediatric malignancy, high-risk patients often exhibit wide-spread hematogenous metastasis, but access to primary tumor can be difficult or impossible. Here we used flow-based sorting to pre-enrich samples with tumor involvement below 0.02%. For all patients for whom a mutation in the Anaplastic Lymphoma Kinase gene had already been detected in their primary tumor, the same mutation was detected in single cells from their marrow. These findings demonstrate a novel, non-invasive, and adaptable method for the capture and genetic analysis of single tumor cells from cancer patients.

  6. Tumor-associated macrophages in glioblastoma multiforme-a suitable target for somatostatin receptor-based imaging and therapy?

    Directory of Open Access Journals (Sweden)

    Constantin Lapa

    Full Text Available Glioblastoma multiforme (GBM is the most common primary brain tumor in adults. Tumor-associated macrophages (TAM have been shown to promote malignant growth and to correlate with poor prognosis. [1,4,7,10-tetraazacyclododecane-NN',N″,N'″-tetraacetic acid]-d-Phe1,Tyr3-octreotate (DOTATATE labeled with Gallium-68 selectively binds to somatostatin receptor 2A (SSTR2A which is specifically expressed and up-regulated in activated macrophages. On the other hand, the role of SSTR2A expression on the cell surface of glioma cells has not been fully elucidated yet. The aim of this study was to non-invasively assess SSTR2A expression of both glioma cells as well as macrophages in GBM.15 samples of patient-derived GBM were stained immunohistochemically for macrophage infiltration (CD68, proliferative activity (Ki67 as well as expression of SSTR2A. Anti-CD45 staining was performed to distinguish between resident microglia and tumor-infiltrating macrophages. In a subcohort, positron emission tomography (PET imaging using 68Ga-DOTATATE was performed and the semiquantitatively evaluated tracer uptake was compared to the results of immunohistochemistry.The amount of microglia/macrophages ranged from 50% in the tumor samples with the vast majority being resident microglial cells. A strong SSTR2A immunostaining was observed in endothelial cells of proliferating vessels, in neurons and neuropile. Only faint immunostaining was identified on isolated microglial and tumor cells. Somatostatin receptor imaging revealed areas of increased tracer accumulation in every patient. However, retention of the tracer did not correlate with immunohistochemical staining patterns.SSTR2A seems not to be overexpressed in GBM samples tested, neither on the cell surface of resident microglia or infiltrating macrophages, nor on the surface of tumor cells. These data suggest that somatostatin receptor directed imaging and treatment strategies are less promising in GBM.

  7. Opposite regulation of type II and III receptors for immunoglobulin G in mouse glomerular mesangial cells and in the induction of anti-glomerular basement membrane (GBM) nephritis

    NARCIS (Netherlands)

    Radeke, HH; Janssen-Graalfs, [No Value; Sowa, EN; Chouchakova, N; Skokowa, J; Loscher, F; Schmidt, RE; Heeringa, P; Gessner, JE

    2002-01-01

    We examined the capacity of mouse glomerular mesangial cells (MC) to express and function through two different low affinity FcgammaRs, the activating FcgammaRIII and the inhibitory FcgammaRII. Immunohistochemistry identified FcgammaRII as the prominent FcgammaR in the kidney, and low levels of

  8. Farewell to GBM-O: Genomic and transcriptomic profiling of glioblastoma with oligodendroglioma component reveals distinct molecular subgroups.

    Science.gov (United States)

    Hinrichs, Benjamin H; Newman, Scott; Appin, Christina L; Dunn, William; Cooper, Lee; Pauly, Rini; Kowalski, Jeanne; Rossi, Michael R; Brat, Daniel J

    2016-01-13

    Glioblastoma with oligodendroglioma component (GBM-O) was recognized as a histologic pattern of glioblastoma (GBM) by the World Health Organization (WHO) in 2007 and is distinguished by the presence of oligodendroglioma-like differentiation. To better understand the genetic underpinnings of this morphologic entity, we performed a genome-wide, integrated copy number, mutational and transcriptomic analysis of eight (seven primary, primary secondary) cases. Three GBM-O samples had IDH1 (p.R132H) mutations; two of these also demonstrated 1p/19q co-deletion and had a proneural transcriptional profile, a molecular signature characteristic of oligodendroglioma. The additional IDH1 mutant tumor lacked 1p/19q co-deletion, harbored a TP53 mutation, and overall, demonstrated features most consistent with IDH mutant (secondary) GBM. Finally, five tumors were IDH wild-type (IDHwt) and had chromosome seven gains, chromosome 10 losses, and homozygous 9p deletions (CDKN2A), alterations typical of IDHwt (primary) GBM. IDHwt GBM-Os also demonstrated EGFR and PDGFRA amplifications, which correlated with classical and proneural expression subtypes, respectively. Our findings demonstrate that GBM-O is composed of three discrete molecular subgroups with characteristic mutations, copy number alterations and gene expression patterns. Despite displaying areas that morphologically resemble oligodendroglioma, the current results indicate that morphologically defined GBM-O does not correspond to a particular genetic signature, but rather represents a collection of genetically dissimilar entities. Ancillary testing, especially for IDH and 1p/19q, should be used for determining these molecular subtypes.

  9. STI571 (Gleevec) improves tumor growth delay and survival in irradiated mouse models of glioblastoma

    International Nuclear Information System (INIS)

    Geng Ling; Shinohara, Eric T.; Kim, Dong; Tan Jiahuai; Osusky, Kate; Shyr, Yu; Hallahan, Dennis E.

    2006-01-01

    Purpose: Glioblastoma multiforme (GBM) is a devastating brain neoplasm that is essentially incurable. Although radiation therapy prolongs survival, GBMs progress within areas of irradiation. Recent studies in invertebrates have shown that STI571 (Gleevec; Novartis, East Hanover, NJ) enhances the cytotoxicity of ionizing radiation. In the present study, the effectiveness of STI571 in combination with radiation was studied in mouse models of GBM. Methods and Materials: Murine GL261 and human D54 GBM cell lines formed tumors in brains and hind limbs of C57BL6 and nude mice, respectively. GL261 and D54 cells were treated with 5 μmol/L of STI571 for 1 h and/or irradiated with 3 Gy. Protein was analyzed by Western immunoblots probed with antibodies to caspase 3, cleaved caspase 3, phospho-Akt, Akt, and platelet-derived growth factor receptor (PDGFR) α and β. Tumor volumes were assessed in mice bearing GL261 or D54 tumors treated with 21 Gy administered in seven fractionated doses. Histologic sections from STI571-treated mice were stained with phospho-Akt and phospho-PDGFR β antibodies. Kaplan-Meier survival curves were used to study the response of mice bearing intracranial implants of GL261. Results: STI571 penetrated the blood-brain barrier, which resulted in a reduction in phospho-PDGFR in GBM. STI571-induced apoptosis in GBM was significantly enhanced by irradiation. STI571 combined with irradiation induced caspase 3 cleavage in GBM cells. Glioblastoma multiforme response to therapy correlated with an increase in tumor growth delay and survival when STI571 was administered in conjunction with daily irradiation. Conclusion: These findings suggest that STI571 has the potential to augment radiotherapy and thereby improve median survival

  10. CT and MRI of germ-cell tumors with metastasis or multi-located tumors

    International Nuclear Information System (INIS)

    Miyagami, Mitsusuke; Tazoe, Makoto; Tsubokawa, Takashi

    1989-01-01

    Twenty-seven cases of germ-cell tumors were examined with a CT scan in our clinic. In the 11 cases of metastasis or multi-localized tumors, the CT findings were studied in connection with the MRI findings. There were 6 cases of germ-cell tumors which had broad infiltrating tumors with multiple lesions on first admission. Their tumor sites were different from that in cases of malignant glioma, being frequently localized in the pineal and/or the suprasellar region, on the wall of the third and/or lateral ventricle, and in the region of the basal ganglia. Five of the cases of germ-cell tumors had metastasis with various patterns connected to a remote area - that is, to spinal cords, to the ventricular wall and basal cistern of the brain stem by CSF dissemination, to a lung by hematogeneous metastasis, and to the peritoneal wall or organs by a V-P shunt. The CT findings of germ-cell tumors were correlated mainly with the results of the histological diagnosis; they were found not to differ with the tumor site. The germinoma in the suprasellar region had less calcification than in the pineal region. Cysts, calcification, and an enlargement of the lateral ventricle on the tumor side were frequently seen in the germinoma of the basal ganglia. On the MRI of 5 cases of germinoma, the T 1 -weighted image revealed a slightly low or iso signal intensity, while the T 2 -weighted image showed a high signal intensity. In the case of multiple tumor lesions, some cases demonstrated different CT findings and radiosensitivities for each tumor. The possibility of a multicentric origin for the tumors is thus suggested in some cases of germ-cell tumors. (author)

  11. SuperQuant-assisted comparative proteome analysis of glioblastoma subpopulations allows for identification of potential novel therapeutic targets and cell markers

    DEFF Research Database (Denmark)

    Verano-Braga, Thiago; Gorshkov, Vladimir; Munthe, Sune

    2018-01-01

    Glioblastoma (GBM) is a highly aggressive brain cancer with poor prognosis and low survival rate. Invasive cancer stem-like cells (CSCs) are responsible for tumor recurrence because they escape current treatments. Our main goal was to study the proteome of three GBM subpopulations to identify key...... molecules behind GBM cell phenotypes and potential cell markers for migrating cells. We used SuperQuant-an enhanced quantitative proteome approach-to increase proteome coverage. We found 148 proteins differentially regulated in migrating CSCs and 199 proteins differentially regulated in differentiated cells...... migration. Moreover, our data suggested that microRNA-122 (miR-122) is a potential upstream regulator of GBM phenotypes as miR-122 activation was predicted for differentiated cells while its inhibition was predicted for migrating CSCs. Finally, we validated transferrin (TF) and procollagen-lysine 2...

  12. Andrographolide suppresses the migratory ability of human glioblastoma multiforme cells by targeting ERK1/2-mediated matrix metalloproteinase-2 expression.

    Science.gov (United States)

    Yang, Shih-Liang; Kuo, Fu-Hsuan; Chen, Pei-Ni; Hsieh, Yi-Hsien; Yu, Nuo-Yi; Yang, Wei-En; Hsieh, Ming-Ju; Yang, Shun-Fa

    2017-12-01

    Glioblastoma multiforme (GBM) can be a fatal tumor because of difficulties in treating the related metastasis. Andrographolide is the bioactive component of the Andrographis paniculata . Andrographolide possesses the anti-inflammatory activity and inhibits the growth of various cancers; however, its effect on GBM cancer motility remains largely unknown. In this study, we examined the antimetastatic properties of andrographolide in human GBM cells. Our results revealed that andrographolide inhibited the invasion and migration abilities of GBM8401 and U251 cells. Furthermore, andrographolide inhibited matrix metalloproteinase (MMP)-2 activity and expression. Real-time PCR and promoter activity assays indicated that andrographolide inhibited MMP-2 expression at the transcriptional level. Such inhibitory effects were associated with the suppression of CREB DNA-binding activity and CREB expression. Mechanistically, andrographolide inhibited the cell motility of GBM8401 cells through the extracellular-regulated kinase (ERK) 1/2 pathway, and the blocking of the ERK 1/2 pathway could reverse MMP-2-mediated cell motility. In conclusion, CREB is a crucial target of andrographolide for suppressing MMP-2-mediated cell motility in GBM cells. Therefore, a combination of andrographolide and an ERK inhibitor might be a good strategy for preventing GBM metastasis.

  13. Anti-tumor therapy with macroencapsulated endostatin producer cells.

    Science.gov (United States)

    Rodrigues, Danielle B; Chammas, Roger; Malavasi, Natália V; da Costa, Patrícia L N; Chura-Chambi, Rosa M; Balduino, Keli N; Morganti, Ligia

    2010-03-02

    Theracyte is a polytetrafluoroethylene membrane macroencapsulation system designed to induce neovascularization at the tissue interface, protecting the cells from host's immune rejection, thereby circumventing the problem of limited half-life and variation in circulating levels. Endostatin is a potent inhibitor of angiogenesis and tumor growth. Continuous delivery of endostatin improves the efficacy and potency of the antitumoral therapy. The purpose of this study was to determine whether recombinant fibroblasts expressing endostatin encapsulated in Theracyte immunoisolation devices can be used for delivery of this therapeutic protein for treatment of mice bearing B16F10 melanoma and Ehrlich tumors. Mice were inoculated subcutaneously with melanoma (B16F10 cells) or Ehrlich tumor cells at the foot pads. Treatment began when tumor thickness had reached 0.5 mm, by subcutaneous implantation of 107 recombinant encapsulated or non-encapsulated endostatin producer cells. Similar melanoma growth inhibition was obtained for mice treated with encapsulated or non-encapsulated endostatin-expressing cells. The treatment of mice bearing melanoma tumor with encapsulated endostatin-expressing cells was decreased by 50.0%, whereas a decrease of 56.7% in tumor thickness was obtained for mice treated with non-encapsulated cells. Treatment of Ehrlich tumor-bearing mice with non-encapsulated endostatin-expressing cells reduced tumor thickness by 52.4%, whereas lower tumor growth inhibition was obtained for mice treated with encapsulated endostatin-expressing cells: 24.2%. Encapsulated endostatin-secreting fibroblasts failed to survive until the end of the treatment. However, endostatin release from the devices to the surrounding tissues was confirmed by immunostaining. Decrease in vascular structures, functional vessels and extension of the vascular area were observed in melanoma microenvironments. This study indicates that immunoisolation devices containing endostatin

  14. Blood Outgrowth Endothelial Cells Increase Tumor Growth Rates and Modify Tumor Physiology: Relevance for Therapeutic Targeting

    Energy Technology Data Exchange (ETDEWEB)

    Pagan, Jonathan, E-mail: jdpagan@uams.edu; Przybyla, Beata; Jamshidi-Parsian, Azemat [Department of Radiation Oncology, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205 (United States); Gupta, Kalpna [Vascular Biology Center and Division of Hematology-Oncology Transplantation, Department of Medicine, University of Minnesota Medical School, MN 72223 (United States); Griffin, Robert J. [Department of Radiation Oncology, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205 (United States)

    2013-02-18

    Endothelial cell precursors from human peripheral blood have been shown to home to areas of neovascularization and may assist tumor growth by increasing or fortifying blood vessel growth. In the present study, the influence of these cells on tumor growth and physiology was investigated and the role of these cells as a therapeutic target or in determining treatment sensitivity was tested. After isolation from human blood and expansion in vitro, actively growing cells with verified endothelial phenotype (Blood Outgrowth Endothelial Cell, BOEC) were injected i.v. into tumor bearing mice for three consecutive days. The growth rate was significantly enhanced in relatively small RERF human lung tumors (i.e., less than 150 mm{sup 3}) grown in immunocompromised mice by an average of 1.5-fold while it had no effect when injections were given to animals bearing larger tumors. There were no signs of toxicity or unwanted systemic effects. We also observed evidence of increased perfusion, vessel number, response to 15 Gy radiation and oxygenation in RERF tumors of animals injected with BOECs compared to control tumors. In addition, FSaII murine fibrosarcoma tumors were found to grow faster upon injection of BOECs. When FSaII tumors were subjected to a partial thermal ablation treatment using high intensity focused ultrasound (HIFU) there was consistently elevated detection of fluorescently labeled and i.v. injected endothelial precursors in the tumor when analyzed with optical imaging and/or histological preparations. Importantly, we also observed that BOECs treated with the novel anti-angiogenic peptide anginex in-vitro, show decreased proliferation and increased sensitivity to radiation. In vivo, the normal increase in FSaII tumor growth induced by injected BOECs was blunted by the addition of anginex treatment. It appears that endothelial precursors may significantly contribute to tumor vessel growth, tumor progression and/or repair of tumor damage and may improve the

  15. Blood Outgrowth Endothelial Cells Increase Tumor Growth Rates and Modify Tumor Physiology: Relevance for Therapeutic Targeting

    International Nuclear Information System (INIS)

    Pagan, Jonathan; Przybyla, Beata; Jamshidi-Parsian, Azemat; Gupta, Kalpna; Griffin, Robert J.

    2013-01-01

    Endothelial cell precursors from human peripheral blood have been shown to home to areas of neovascularization and may assist tumor growth by increasing or fortifying blood vessel growth. In the present study, the influence of these cells on tumor growth and physiology was investigated and the role of these cells as a therapeutic target or in determining treatment sensitivity was tested. After isolation from human blood and expansion in vitro, actively growing cells with verified endothelial phenotype (Blood Outgrowth Endothelial Cell, BOEC) were injected i.v. into tumor bearing mice for three consecutive days. The growth rate was significantly enhanced in relatively small RERF human lung tumors (i.e., less than 150 mm 3 ) grown in immunocompromised mice by an average of 1.5-fold while it had no effect when injections were given to animals bearing larger tumors. There were no signs of toxicity or unwanted systemic effects. We also observed evidence of increased perfusion, vessel number, response to 15 Gy radiation and oxygenation in RERF tumors of animals injected with BOECs compared to control tumors. In addition, FSaII murine fibrosarcoma tumors were found to grow faster upon injection of BOECs. When FSaII tumors were subjected to a partial thermal ablation treatment using high intensity focused ultrasound (HIFU) there was consistently elevated detection of fluorescently labeled and i.v. injected endothelial precursors in the tumor when analyzed with optical imaging and/or histological preparations. Importantly, we also observed that BOECs treated with the novel anti-angiogenic peptide anginex in-vitro, show decreased proliferation and increased sensitivity to radiation. In vivo, the normal increase in FSaII tumor growth induced by injected BOECs was blunted by the addition of anginex treatment. It appears that endothelial precursors may significantly contribute to tumor vessel growth, tumor progression and/or repair of tumor damage and may improve the

  16. Malignant primary germ-cell tumor of the brain

    International Nuclear Information System (INIS)

    Yamamoto, Toyoshiro; Sato, Shinichi; Nakao, Satoshi; Ban, Sadahiko; Namba, Koh

    1983-01-01

    The unusual case of a 15 year old boy with three discrete paraventricular germ-cell tumors is reported.FThe first tumor was located just lateral to the left thalamus and included a massive cystic part around it, the second tumor in the paraventricular region above the head of the left caudate nucleus and the third tumor in the medial part of the left parietal lobe.FTotal removal of all tumors was successfully accomplished in stages at four separate operations, namely, the first tumor was removed through the left transsylvian approach, the second tumor via left superior frontal gyrus and the third tumor via left superior frontal gyrus and left superior parietal lobule.FHistological examination revealed that the first tumor was teratoma, the second was choriocarcinoma and the third was germinoma.FPrimary germ-cell tumors of the brain can be divided into 5 groups: 1) germinoma; 2) embryonal carcinoma; 3) choriocarcinoma; 4) yolk-sac tumor; or 5) teratoma.FIn this case, a combination of three different histological patterns was seen. If malignant germ-cell tumor is supected on CT, aggressive extirpation should be done, not only to determine the exact diagnosis, but also to provide the basis for subsequent adjunctive therapy. (author)

  17. Migratory neighbors and distant invaders: tumor-associated niche cells

    Science.gov (United States)

    Wels, Jared; Kaplan, Rosandra N.; Rafii, Shahin; Lyden, David

    2008-01-01

    The cancer environment is comprised of tumor cells as well as a wide network of stromal and vascular cells participating in the cellular and molecular events necessary for invasion and metastasis. Tumor secretory factors can activate the migration of host cells, both near to and far from the primary tumor site, as well as promote the exodus of cells to distant tissues. Thus, the migration of stromal cells and tumor cells among specialized microenvironments takes place throughout tumor and metastatic progression, providing evidence for the systemic nature of a malignancy. Investigations of the tumor–stromal and stromal–stromal cross-talk involved in cellular migration in cancer may lead to the design of novel therapeutic strategies. PMID:18316475

  18. Human CD34+ cells engineered to express membrane-bound tumor necrosis factor-related apoptosis-inducing ligand target both tumor cells and tumor vasculature.

    Science.gov (United States)

    Lavazza, Cristiana; Carlo-Stella, Carmelo; Giacomini, Arianna; Cleris, Loredana; Righi, Marco; Sia, Daniela; Di Nicola, Massimo; Magni, Michele; Longoni, Paolo; Milanesi, Marco; Francolini, Maura; Gloghini, Annunziata; Carbone, Antonino; Formelli, Franca; Gianni, Alessandro M

    2010-03-18

    Adenovirus-transduced CD34+ cells expressing membrane-bound tumor necrosis factor-related apoptosis-inducing ligand (CD34-TRAIL+ cells) exert potent antitumor activity. To further investigate the mechanism(s) of action of CD34-TRAIL+ cells, we analyzed their homing properties as well as antitumor and antivascular effects using a subcutaneous myeloma model in immunodeficient mice. After intravenous injection, transduced cells homed in the tumor peaking at 48 hours when 188 plus or minus 25 CD45+ cells per 10(5) tumor cells were detected. Inhibition experiments showed that tumor homing of CD34-TRAIL+ cells was largely mediated by vascular cell adhesion molecule-1 and stromal cell-derived factor-1. Both CD34-TRAIL+ cells and soluble (s)TRAIL significantly reduced tumor volume by 40% and 29%, respectively. Computer-aided analysis of TdT-mediated dUTP nick end-labeling-stained tumor sections demonstrated significantly greater effectiveness for CD34-TRAIL+ cells in increasing tumor cell apoptosis and necrosis over sTRAIL. Proteome array analysis indicated that CD34-TRAIL+ cells and sTRAIL activate similar apoptotic machinery. In vivo staining of tumor vasculature with sulfosuccinimidyl-6-(biotinamido) hexanoate-biotin revealed that CD34-TRAIL+ cells but not sTRAIL significantly damaged tumor vasculature, as shown by TdT-mediated dUTP nick end-labeling+ endothelial cells, appearance of hemorrhagic areas, and marked reduction of endothelial area. These results demonstrate that tumor homing of CD34-TRAIL+ cells induces early vascular disruption, resulting in hemorrhagic necrosis and tumor destruction.

  19. Tumor Cells and Tumor-Associated Macrophages: Secreted Proteins as Potential Targets for Therapy

    Science.gov (United States)

    Baay, Marc; Brouwer, Anja; Pauwels, Patrick; Peeters, Marc; Lardon, Filip

    2011-01-01

    Inflammatory pathways, meant to defend the organism against infection and injury, as a byproduct, can promote an environment which favors tumor growth and metastasis. Tumor-associated macrophages (TAMs), which constitute a significant part of the tumor-infiltrating immune cells, have been linked to the growth, angiogenesis, and metastasis of a variety of cancers, most likely through polarization of TAMs to the M2 (alternative) phenotype. The interaction between tumor cells and macrophages provides opportunities for therapy. This paper will discuss secreted proteins as targets for intervention. PMID:22162712

  20. Tumor Cells and Tumor-Associated Macrophages: Secreted Proteins as Potential Targets for Therapy

    Directory of Open Access Journals (Sweden)

    Marc Baay

    2011-01-01

    Full Text Available Inflammatory pathways, meant to defend the organism against infection and injury, as a byproduct, can promote an environment which favors tumor growth and metastasis. Tumor-associated macrophages (TAMs, which constitute a significant part of the tumor-infiltrating immune cells, have been linked to the growth, angiogenesis, and metastasis of a variety of cancers, most likely through polarization of TAMs to the M2 (alternative phenotype. The interaction between tumor cells and macrophages provides opportunities for therapy. This paper will discuss secreted proteins as targets for intervention.

  1. Residual tumor cells that drive disease relapse after chemotherapy do not have enhanced tumor initiating capacity.

    Directory of Open Access Journals (Sweden)

    Ganapati V Hegde

    Full Text Available Although chemotherapy is used to treat most advanced solid tumors, recurrent disease is still the major cause of cancer-related mortality. Cancer stem cells (CSCs have been the focus of intense research in recent years because they provide a possible explanation for disease relapse. However, the precise role of CSCs in recurrent disease remains poorly understood and surprisingly little attention has been focused on studying the cells responsible for re-initiating tumor growth within the original host after chemotherapy treatment. We utilized both xenograft and genetically engineered mouse models of non-small cell lung cancer (NSCLC to characterize the residual tumor cells that survive chemotherapy treatment and go on to cause tumor regrowth, which we refer to as tumor re-initiating cells (TRICs. We set out to determine whether TRICs display characteristics of CSCs, and whether assays used to define CSCs also provide an accurate readout of a cell's ability to cause tumor recurrence. We did not find consistent enrichment of CSC marker positive cells or enhanced tumor initiating potential in TRICs. However, TRICs from all models do appear to be in EMT, a state that has been linked to chemoresistance in numerous types of cancer. Thus, the standard CSC assays may not accurately reflect a cell's ability to drive disease recurrence.

  2. An Effective Approach for Immunotherapy Using Irradiated Tumor Cells

    International Nuclear Information System (INIS)

    Mostafa, D.M.B.

    2011-01-01

    This study has been aimed to investigate the effect of injection of Irradiated Ehrlich tumor cells alone or concurrent with immunomodulator in mice before and after challenge with viable Ehrlich tumor cells for enhancement of immune system. This study includes the estimation of survival, tumor size, lymphocyte count, LDH, MTT, granzyme B, and DNA fragmentation. In order to fulfill the target of this study, a total of 120 female swiss albino mice were used. They were divided into two classes vaccinated (injection of vaccine before challenge) and therapeutic class (injection of vaccine after challenge). Each class was divided into four groups, group (1) mice injected with viable Ehrlich tumor cells (G1), group (2) mice injected with irradiated tumor cells (G2), group (3) mice injected with immunomodulator (G3), and group (4) mice injected with irradiated tumor cells + immunomodulator (G4). Results obtained from this study demonstrated that, the lymphocyte count and granzyme B activity were increased in both the vaccinated and therapeutic classes compared with control group. LDH activity was decreased in all groups of vaccinated class and also in G2 and G4 groups of therapeutic class compared with control group. There was a significant increase in percent apoptosis of tumor cells cultured with spleenocytes of the groups of vaccinated class as compared with control group. Cellular DNA from Ehrlich tumor cell line cultured with spleenocytes of immunized groups was fragmented into discrete bands of approximate multiples of 200 bp. Revealing significant apoptosis in tumor cells due to vaccination. It is concluded that, vaccination with irradiated tumor cells is an effective approach in stimulation of immune system against viable tumor cells.

  3. Nanoparticle-mediated knockdown of DNA repair sensitizes cells to radiotherapy and extends survival in a genetic mouse model of glioblastoma.

    Science.gov (United States)

    Kievit, Forrest M; Wang, Kui; Ozawa, Tatsuya; Tarudji, Aria W; Silber, John R; Holland, Eric C; Ellenbogen, Richard G; Zhang, Miqin

    2017-10-01

    Glioblastoma (GBM) remains incurable, and recurrent tumors rarely respond to standard-of-care radiation and chemo-therapies. Therefore, strategies that enhance the effects of these therapies should provide significant benefits to GBM patients. We have developed a nanoparticle delivery vehicle that can stably bind and protect nucleic acids for specific delivery into brain tumor cells. These nanoparticles can deliver therapeutic siRNAs to sensitize GBM cells to radiotherapy and improve GBM treatment via systemic administration. We show that nanoparticle-mediated knockdown of the DNA repair protein apurinic endonuclease 1 (Ape1) sensitizes GBM cells to radiotherapy and extend survival in a genetic mouse model of GBM. Specific knockdown of Ape1 activity by 30% in brain tumor tissue doubled the extended survival achieved with radiotherapy alone. Ape1 is a promising target for increasing the effectiveness of radiotherapy, and nanoparticle-mediated delivery of siRNA is a promising strategy for tumor specific knockdown of Ape1. Copyright © 2017. Published by Elsevier Inc.

  4. Variant allele frequency enrichment analysis in vitro reveals sonic hedgehog pathway to impede sustained temozolomide response in GBM.

    Science.gov (United States)

    Biswas, Nidhan K; Chandra, Vikas; Sarkar-Roy, Neeta; Das, Tapojyoti; Bhattacharya, Rabindra N; Tripathy, Laxmi N; Basu, Sunandan K; Kumar, Shantanu; Das, Subrata; Chatterjee, Ankita; Mukherjee, Ankur; Basu, Pryiadarshi; Maitra, Arindam; Chattopadhyay, Ansuman; Basu, Analabha; Dhara, Surajit

    2015-01-21

    Neoplastic cells of Glioblastoma multiforme (GBM) may or may not show sustained response to temozolomide (TMZ) chemotherapy. We hypothesize that TMZ chemotherapy response in GBM is predetermined in its neoplastic clones via a specific set of mutations that alter relevant pathways. We describe exome-wide enrichment of variant allele frequencies (VAFs) in neurospheres displaying contrasting phenotypes of sustained versus reversible TMZ-responses in vitro. Enrichment of VAFs was found on genes ST5, RP6KA1 and PRKDC in cells showing sustained TMZ-effect whereas on genes FREM2, AASDH and STK36, in cells showing reversible TMZ-effect. Ingenuity pathway analysis (IPA) revealed that these genes alter cell-cycle, G2/M-checkpoint-regulation and NHEJ pathways in sustained TMZ-effect cells whereas the lysine-II&V/phenylalanine degradation and sonic hedgehog (Hh) pathways in reversible TMZ-effect cells. Next, we validated the likely involvement of the Hh-pathway in TMZ-response on additional GBM neurospheres as well as on GBM patients, by extracting RNA-sequencing-based gene expression data from the TCGA-GBM database. Finally, we demonstrated TMZ-sensitization of a TMZ non-responder neurosphere in vitro by treating them with the FDA-approved pharmacological Hh-pathway inhibitor vismodegib. Altogether, our results indicate that the Hh-pathway impedes sustained TMZ-response in GBM and could be a potential therapeutic target to enhance TMZ-response in this malignancy.

  5. Antigen localization controls T cell-mediated tumor immunity.

    Science.gov (United States)

    Zeelenberg, Ingrid S; van Maren, Wendy W C; Boissonnas, Alexandre; Van Hout-Kuijer, Maaike A; Den Brok, Martijn H M G M; Wagenaars, Jori A L; van der Schaaf, Alie; Jansen, Eric J R; Amigorena, Sebastian; Théry, Clotilde; Figdor, Carl G; Adema, Gosse J

    2011-08-01

    Effective antitumor immunotherapy requires the identification of suitable target Ags. Interestingly, many of the tumor Ags used in clinical trials are present in preparations of secreted tumor vesicles (exosomes). In this study, we compared T cell responses elicited by murine MCA101 fibrosarcoma tumors expressing a model Ag at different localizations within the tumor cell in association with secreted vesicles (exosomes), as a nonsecreted cell-associated protein, or as secreted soluble protein. Remarkably, we demonstrated that only the tumor-secreting vesicle-bound Ag elicited a strong Ag-specific CD8(+) T cell response, CD4(+) T cell help, Ag-specific Abs, and a decrease in the percentage of immunosuppressive regulatory T cells in the tumor. Moreover, in a therapeutic tumor model of cryoablation, only in tumors secreting vesicle-bound Ag could Ag-specific CD8(+) T cells still be detected up to 16 d after therapy. We concluded that the localization of an Ag within the tumor codetermines whether a robust immunostimulatory response is elicited. In vivo, vesicle-bound Ag clearly skews toward a more immunogenic phenotype, whereas soluble or cell-associated Ag expression cannot prevent or even delay outgrowth and results in tumor tolerance. This may explain why particular immunotherapies based on these vesicle-bound tumor Ags are potentially successful. Therefore, we conclude that this study may have significant implications in the discovery of new tumor Ags suitable for immunotherapy and that their location should be taken into account to ensure a strong antitumor immune response.

  6. A Rare Cause of Prepubertal Gynecomastia: Sertoli Cell Tumor

    Directory of Open Access Journals (Sweden)

    Fatma Dursun

    2015-01-01

    Full Text Available Prepubertal gynecomastia due to testis tumors is a very rare condition. Nearly 5% of the patients with testicular mass present with gynecomastia. Sertoli cell tumors are sporadic in 60% of the reported cases, while the remaining is a component of multiple neoplasia syndromes such as Peutz-Jeghers syndrome and Carney complex. We present a 4-year-old boy with gynecomastia due to Sertoli cell tumor with no evidence of Peutz-Jeghers syndrome or Carney complex.

  7. Treatment Options By Stage (Ovarian Germ Cell Tumors)

    Science.gov (United States)

    ... Germ Cell Tumors Treatment (PDQ®)–Patient Version Treatment Option Overview Go to Health Professional Version Key Points ... and restore) the body’s blood cells. New treatment options Combination chemotherapy (the use of more than one ...

  8. Selective Killing of Prostate Tumor Cells by Cytocidal Viruses

    National Research Council Canada - National Science Library

    Lyles, Douglas

    2003-01-01

    .... The novelty in our approach is our ability to enhance the selectivity of killing of tumor cells versus normal cells by manipulating the viral genes that control the antiviral interferon response...

  9. Selective Killing of Prostate Tumor Cells by Cytocidal Viruses

    National Research Council Canada - National Science Library

    Lyles, Douglas

    2004-01-01

    .... The novelty in our approach is our ability to enhance the selectivity of killing of tumor cells versus normal cells by manipulating the viral genes that control the antiviral interferon response...

  10. Selective Killing of Prostate Tumor Cells by Cytocidal Viruses

    National Research Council Canada - National Science Library

    Lyles, Douglas S

    2005-01-01

    ...). The novelty in our approach is our ability to enhance the selectivity of VSV-induced killing of tumor cells versus normal cells by manipulating the viral genes that control the antiviral interferon response...

  11. Large mid-esophageal granular cell tumor: benign versus malignant

    Directory of Open Access Journals (Sweden)

    Prarthana Roselil Christopher

    2015-06-01

    Full Text Available Granular cell tumors are rare soft tissue neoplasms, among which only 2% are malignant, arising from nervous tissue. Here we present a case of a large esophageal granular cell tumor with benign histopathological features which metastasized to the liver, but showing on positron emission tomography-computerized tomography standardized uptake value suggestive of a benign lesion.

  12. Establishment, maintenance and in vitro and in vivo applications of primary human glioblastoma multiforme (GBM) xenograft models for translational biology studies and drug discovery.

    Science.gov (United States)

    Carlson, Brett L; Pokorny, Jenny L; Schroeder, Mark A; Sarkaria, Jann N

    2011-03-01

    Development of clinically relevant tumor model systems for glioblastoma multiforme (GBM) is important for advancement of basic and translational biology. One model that has gained wide acceptance in the neuro-oncology community is the primary xenograft model. This model entails the engraftment of patient tumor specimens into the flank of nude mice and subsequent serial passage of these tumors in the flank of mice. These tumors are then used to establish short-term explant cultures or intracranial xenografts. This unit describes detailed procedures for establishment, maintenance, and utilization of a primary GBM xenograft panel for the purpose of using them as tumor models for basic or translational studies.

  13. Maternal smoking and testicular germ cell tumors.

    Science.gov (United States)

    McGlynn, Katherine A; Zhang, Yawei; Sakoda, Lori C; Rubertone, Mark V; Erickson, Ralph L; Graubard, Barry I

    2006-10-01

    Testicular germ cell tumors (TGCT) are the most common cancer among men ages 15 to 35 years in the United States. The well-established TGCT risk factors cryptorchism, prior diagnosis of TGCT, and family history of testicular cancer indicate that exposures in early life and/or in the familial setting may be critical to determining risk. Previous reports of familial clustering of lung cancer in mothers and testicular cancers in sons suggest that passive smoking in childhood may be such an exposure. To clarify the relationship of passive smoking exposure to TGCT risk, data from 754 cases and 928 controls enrolled in the Servicemen's Testicular Tumor Environmental and Endocrine Determinants study were analyzed. Data from 1,086 mothers of the cases and controls were also examined. Overall, there was no relationship between maternal [odds ratio (OR), 1.1; 95% confidence interval (95% CI), 0.9-1.3] or paternal smoking (OR, 1.0; 95% CI, 0.8-1.3) and TGCT risk. Although living with a non-parent smoker was marginally related to risk (OR, 1.4; 95% CI, 1.0-2.1), there was no relationship with number of smokers, amount smoked, or duration of smoking. Responses from both case-control participants and mothers also revealed no relationship between either maternal smoking while pregnant or while breast-feeding. Results did not differ by TGCT histology (seminoma, non-seminoma). These results do not support the hypothesis that passive smoking, either in utero or in childhood, is related to risk of TGCT. Other early life exposures, however, may explain the familial clustering of lung cancer in mothers and TGCT in sons.

  14. Targeted Proteomics to Assess the Response to Anti-Angiogenic Treatment in Human Glioblastoma (GBM).

    Science.gov (United States)

    Demeure, Kevin; Fack, Fred; Duriez, Elodie; Tiemann, Katja; Bernard, Amandine; Golebiewska, Anna; Bougnaud, Sébastien; Bjerkvig, Rolf; Domon, Bruno; Niclou, Simone P

    2016-02-01

    Glioblastoma (GBM) is a highly aggressive primary brain tumor with dismal outcome for affected patients. Because of the significant neo-angiogenesis exhibited by GBMs, anti-angiogenic therapies have been intensively evaluated during the past years. Recent clinical studies were however disappointing, although a subpopulation of patients may benefit from such treatment. We have previously shown that anti-angiogenic targeting in GBM increases hypoxia and leads to a metabolic adaptation toward glycolysis, suggesting that combination treatments also targeting the glycolytic phenotype may be effective in GBM patients. The aim of this study was to identify marker proteins that are altered by treatment and may serve as a short term readout of anti-angiogenic therapy. Ultimately such proteins could be tested as markers of efficacy able to identify patient subpopulations responsive to the treatment. We applied a proteomics approach based on selected reaction monitoring (SRM) to precisely quantify targeted protein candidates, selected from pathways related to metabolism, apoptosis and angiogenesis. The workflow was developed in the context of patient-derived intracranial GBM xenografts developed in rodents and ensured the specific identification of human tumor versus rodent stroma-derived proteins. Quality control experiments were applied to assess sample heterogeneity and reproducibility of SRM assays at different levels. The data demonstrate that tumor specific proteins can be precisely quantified within complex biological samples, reliably identifying small concentration differences induced by the treatment. In line with previous work, we identified decreased levels of TCA cycle enzymes, including isocitrate dehydrogenase, whereas malectin, calnexin, and lactate dehydrogenase A were augmented after treatment. We propose the most responsive proteins of our subset as potential novel biomarkers to assess treatment response after anti-angiogenic therapy that warrant future

  15. Effect of misonidazole on radiosensitivity of Ehrlich ascites tumor cells

    International Nuclear Information System (INIS)

    Takeuchi, Hiroshi

    1986-01-01

    The effect of Misonidazole on radiosensitivity of Ehrlich ascites tumor cells was studied in vivo. Ehrlich ascites tumor cells growing intraperitoneally (ICR/SIC mice) for either 1, 4, 6 or 10 days were irradiated in vivo (whole body irradiation) with or without Misonidazole. Immediately after irradiation tumor cells were transplanted intraperitoneally into new animals. Four days later, the propagated surviving cells were removed and counted for analyses. Enhancement ratio of Misonidazole at the surviving fraction of 0.1 were 1.0 (for 1-day-old), 1.3 (for 4-day-old), 1.9 (for 6-day-old), 1.9 (for 10-day-old) and 2.8 (for anoxic cells) respectively. The gradual increase of the enhancement ratio of the ascites tumore cells during intraperitoneal growth from 1 through 10 days might be attributed to an increase of hypoxic tumor cells. Cytotoxicity was not observed at 0.1 mg per gram body weight of Misonidazole but was at 1 mg per gram body weight of Misonidazole in 6-day-old and 10-day-old Ehrlich ascites tumor cells which were supposed to contain hypoxic cells. These results suggest that Misonidazole may prove an effective radiosensitizer for hypoxic tumor cells. (author)

  16. Targeting Mitochondrial Function to Treat Quiescent Tumor Cells in Solid Tumors

    Directory of Open Access Journals (Sweden)

    Xiaonan Zhang

    2015-11-01

    Full Text Available The disorganized nature of tumor vasculature results in the generation of microenvironments characterized by nutrient starvation, hypoxia and accumulation of acidic metabolites. Tumor cell populations in such areas are often slowly proliferating and thus refractory to chemotherapeutical drugs that are dependent on an active cell cycle. There is an urgent need for alternative therapeutic interventions that circumvent growth dependency. The screening of drug libraries using multicellular tumor spheroids (MCTS or glucose-starved tumor cells has led to the identification of several compounds with promising therapeutic potential and that display activity on quiescent tumor cells. Interestingly, a common theme of these drug screens is the recurrent identification of agents that affect mitochondrial function. Such data suggest that, contrary to the classical Warburg view, tumor cells in nutritionally-compromised microenvironments are dependent on mitochondrial function for energy metabolism and survival. These findings suggest that mitochondria may represent an “Achilles heel” for the survival of slowly-proliferating tumor cells and suggest strategies for the development of therapy to target these cell populations.

  17. Radiation induction of drug resistance in RIF-1 tumors and tumor cells

    International Nuclear Information System (INIS)

    Hopwood, L.E.; Moulder, J.E.

    1989-01-01

    The RIF-1 tumor cell line contains a small number of cells (1-20 per 10(6) cells) that are resistant to various single antineoplastic drugs, including 5-fluorouracil (5FU), methotrexate (MTX), and adriamycin (ADR). For 5FU the frequency of drug resistance is lower for tumor-derived cells than for cells from cell culture; for MTX the reverse is true, and for ADR there is no difference. In vitro irradiation at 5 Gy significantly increased the frequency of drug-resistant cells for 5FU, MTX, and ADR. In vivo irradiation at 3 Gy significantly increased the frequency of drug-resistant cells for 5FU and MTX, but not for ADR. The absolute risk for in vitro induction of MTX, 5FU, and ADR resistance, and for in vivo induction of 5FU resistance, was 1-3 per 10(6) cells per Gy; but the absolute risk for in vivo induction of MTX resistance was 54 per 10(6) cells per Gy. The frequency of drug-resistant cells among individual untreated tumors was highly variable; among individual irradiated tumors the frequency of drug-resistant cells was significantly less variable. These studies provide supporting data for models of the development of tumor drug resistance, and imply that some of the drug resistance seen when chemotherapy follows radiotherapy may be due to radiation-induced drug resistance

  18. Tumor Response to Radiotherapy Regulated by Endothelial Cell Apoptosis

    Science.gov (United States)

    Garcia-Barros, Monica; Paris, Francois; Cordon-Cardo, Carlos; Lyden, David; Rafii, Shahin; Haimovitz-Friedman, Adriana; Fuks, Zvi; Kolesnick, Richard

    2003-05-01

    About 50% of cancer patients receive radiation therapy. Here we investigated the hypothesis that tumor response to radiation is determined not only by tumor cell phenotype but also by microvascular sensitivity. MCA/129 fibrosarcomas and B16F1 melanomas grown in apoptosis-resistant acid sphingomyelinase (asmase)-deficient or Bax-deficient mice displayed markedly reduced baseline microvascular endothelial apoptosis and grew 200 to 400% faster than tumors on wild-type microvasculature. Thus, endothelial apoptosis is a homeostatic factor regulating angiogenesis-dependent tumor growth. Moreover, these tumors exhibited reduced endothelial apoptosis upon irradiation and, unlike tumors in wild-type mice, they were resistant to single-dose radiation up to 20 grays (Gy). These studies indicate that microvascular damage regulates tumor cell response to radiation at the clinically relevant dose range.

  19. A functional study of EGFR and Notch signaling in brain cancer stem-like cells from glioblastoma multiforme (Ph.d.)

    DEFF Research Database (Denmark)

    Kristoffersen, Karina

    2013-01-01

    Glioblastoma Multiforme (GBM) is the most common and aggressive brain tumor in adults with a median survival for newly diagnosed GBM patients at less than 1.5 year. Despite intense treatment efforts the vast majority of patients will experience relapse and much research today is therefore searching...... for new molecular and cellular targets that can improve the prognosis for GBM patients. One such target is the brain cancer stem-like cells (bCSC) that are believed to be responsible for tumor initiation, progression, treatment resistance and ultimately relapse. bCSC are identified based...... on their resemblance to normal neural stem cells (NSC) and their tumorigenic potential. Like for NSC, the epidermal growth factor receptor (EGFR) and Notch receptor signaling pathways are believed to be important for the maintenance of bCSC. These pathways as such present promising targets in a future anti-bCSC GBM...

  20. Tumor-Induced Generation of Splenic Erythroblast-like Ter-Cells Promotes Tumor Progression.

    Science.gov (United States)

    Han, Yanmei; Liu, Qiuyan; Hou, Jin; Gu, Yan; Zhang, Yi; Chen, Zhubo; Fan, Jia; Zhou, Weiping; Qiu, Shuangjian; Zhang, Yonghong; Dong, Tao; Li, Ning; Jiang, Zhengping; Zhu, Ha; Zhang, Qian; Ma, Yuanwu; Zhang, Lianfeng; Wang, Qingqing; Yu, Yizhi; Li, Nan; Cao, Xuetao

    2018-04-19

    Identifying tumor-induced leukocyte subsets and their derived circulating factors has been instrumental in understanding cancer as a systemic disease. Nevertheless, how primary tumor-induced non-leukocyte populations in distal organs contribute to systemic spread remains poorly defined. Here, we report one population of tumor-inducible, erythroblast-like cells (Ter-cells) deriving from megakaryocyte-erythroid progenitor cells with a unique Ter-119 + CD45 - CD71 + phenotype. Ter-cells are enriched in the enlarged spleen of hosts bearing advanced tumors and facilitate tumor progression by secreting neurotrophic factor artemin into the blood. Transforming growth factor β (TGF-β) and Smad3 activation are important in Ter-cell generation. In vivo blockade of Ter-cell-derived artemin inhibits hepatocellular carcinoma (HCC) growth, and artemin deficiency abolishes Ter-cells' tumor-promoting ability. We confirm the presence of splenic artemin-positive Ter-cells in human HCC patients and show that significantly elevated serum artemin correlates with poor prognosis. We propose that Ter-cells and the secreted artemin play important roles in cancer progression with prognostic and therapeutic implications. Copyright © 2018 Elsevier Inc. All rights reserved.

  1. [Isolation and identification of brain tumor stem cells from human brain neuroepithelial tumors].

    Science.gov (United States)

    Fang, Jia-sheng; Deng, Yong-wen; Li, Ming-chu; Chen, Feng-Hua; Wang, Yan-jin; Lu, Ming; Fang, Fang; Wu, Jun; Yang, Zhuan-yi; Zhou, Xang-yang; Wang, Fei; Chen, Cheng

    2007-01-30

    To establish a simplified culture system for the isolation of brain tumor stem cells (BTSCs) from the tumors of human neuroepithelial tissue, to observe the growth and differentiation pattern of BTSCs, and to investigate their expression of the specific markers. Twenty-six patients with brain neuroepithelial tumors underwent tumor resection. Two pieces of tumor tissues were taken from each tumor to be dissociated, triturated into single cells in sterile DMEM-F12 medium, and then filtered. The tumor cells were seeded at a concentration of 200,000 viable cells per mL into serum-free DMEM-F12 medium simply supplemented with B27, human basic fibroblast growth factor (20 microg/L), human epidermal growth factor (20 microg /L), insulin (4 U/L), L-glutamine, penicillin and streptomycin. After the primary brain tumor spheres (BTSs) were generated, they were triturated again and passed in fresh medium. Limiting dilution assay was performed to observe the monoclone formation. 5-bromodeoxyuridine (BrdU) incorporation test was performed to observe the proliferation of the BTS. The BTSCs were cultured in mitogen-free DMEM-F12 medium supplemented with 10% fetal bovine serum to observe their differentiation. Immunocytochemistry was used to examine the expression of CD133 and nestin, specific markers of BTSC, and the rate of CD133 positive cells. Only a minority of subsets of cells from the tumors of neuroepithelial tissue had the capacity to survive, proliferate, and generate free-floating neurosphere-like BTSs in the simplified serum-free medium. These cells attached to the poly-L-lysine coated coverslips in the serum-supplemented medium and differentiated. The BTSCs were CD133 and nestin positive. The rate of CD133 positive cells in the tumor specimens was (21 +/- 6.2)% - (38 +/- 7.0)%. A new simplified culture system for the isolation of BTSCs is established. The tumors of human neuroepithelial tissue contain CD133 and nestin positive tumor stem cells which can be isolated

  2. A novel pre-clinical in vivo mouse model for malignant brain tumor growth and invasion.

    Science.gov (United States)

    Shelton, Laura M; Mukherjee, Purna; Huysentruyt, Leanne C; Urits, Ivan; Rosenberg, Joshua A; Seyfried, Thomas N

    2010-09-01

    Glioblastoma multiforme (GBM) is a rapidly progressive disease of morbidity and mortality and is the most common form of primary brain cancer in adults. Lack of appropriate in vivo models has been a major roadblock to developing effective therapies for GBM. A new highly invasive in vivo GBM model is described that was derived from a spontaneous brain tumor (VM-M3) in the VM mouse strain. Highly invasive tumor cells could be identified histologically on the hemisphere contralateral to the hemisphere implanted with tumor cells or tissue. Tumor cells were highly expressive for the chemokine receptor CXCR4 and the proliferation marker Ki-67 and could be identified invading through the pia mater, the vascular system, the ventricular system, around neurons, and over white matter tracts including the corpus callosum. In addition, the brain tumor cells were labeled with the firefly luciferase gene, allowing for non-invasive detection and quantitation through bioluminescent imaging. The VM-M3 tumor has a short incubation time with mortality occurring in 100% of the animals within approximately 15 days. The VM-M3 brain tumor model therefore can be used in a pre-clinical setting for the rapid evaluation of novel anti-invasive therapies.

  3. Cancer stem cells and the tumor microenvironment: interplay in tumor heterogeneity.

    Science.gov (United States)

    Albini, Adriana; Bruno, Antonino; Gallo, Cristina; Pajardi, Giorgio; Noonan, Douglas M; Dallaglio, Katiuscia

    2015-01-01

    Tumor cells able to recapitulate tumor heterogeneity have been tracked, isolated and characterized in different tumor types, and are commonly named Cancer Stem Cells or Cancer Initiating Cells (CSC/CIC). CSC/CIC are disseminated in the tumor mass and are resistant to anti-cancer therapies and adverse conditions. They are able to divide into another stem cell and a "proliferating" cancer cell. They appear to be responsible for disease recurrence and metastatic dissemination even after apparent eradication of the primary tumor. The modulation of CSC/CIC activities by the tumor microenvironment (TUMIC) is still poorly known. CSC/CIC may mutually interact with the TUMIC in a special and unique manner depending on the TUMIC cells or proteins encountered. The TUMIC consists of extracellular matrix components as well as cellular players among which endothelial, stromal and immune cells, providing and responding to signals to/from the CSC/CIC. This interplay can contribute to the mechanisms through which CSC/CIC may reside in a dormant state in a tissue for years, later giving rise to tumor recurrence or metastasis in patients. Different TUMIC components, including the connective tissue, can differentially activate CIC/CSC in different areas of a tumor and contribute to the generation of cancer heterogeneity. Here, we review possible networking activities between the different components of the tumor microenvironment and CSC/CIC, with a focus on its role in tumor heterogeneity and progression. We also summarize novel therapeutic options that could target both CSC/CIC and the microenvironment to elude resistance mechanisms activated by CSC/CIC, responsible for disease recurrence and metastases.

  4. Tumor-specific CD4+ T cells develop cytotoxic activity and eliminate virus-induced tumor cells in the absence of regulatory T cells.

    Science.gov (United States)

    Akhmetzyanova, Ilseyar; Zelinskyy, Gennadiy; Schimmer, Simone; Brandau, Sven; Altenhoff, Petra; Sparwasser, Tim; Dittmer, Ulf

    2013-02-01

    The important role of tumor-specific cytotoxic CD8(+) T cells is well defined in the immune control of the tumors, but the role of effector CD4(+) T cells is poorly understood. In the current research, we have used a murine retrovirus-induced tumor cell line of C57BL/6 mouse origin, namely FBL-3 cells, as a model to study basic mechanisms of immunological control and escape during tumor formation. This study shows that tumor-specific CD4(+) T cells are able to protect against virus-induced tumor cells. We show here that there is an expansion of tumor-specific CD4(+) T cells producing cytokines and cytotoxic molecule granzyme B (GzmB) in the early phase of tumor growth. Importantly, we demonstrate that in vivo depletion of regulatory T cells (Tregs) and CD8(+) T cells in FBL-3-bearing DEREG transgenic mice augments IL-2 and GzmB production by CD4(+) T cells and increases FV-specific CD4(+) T-cell effector and cytotoxic responses leading to the complete tumor regression. Therefore, the capacity to reject tumor acquired by tumor-reactive CD4(+) T cells largely depends on the direct suppressive activity of Tregs. We suggest that a cytotoxic CD4(+) T-cell immune response may be induced to enhance resistance against oncovirus-associated tumors.

  5. General Information about Pancreatic Neuroendocrine Tumors (Islet Cell Tumors)

    Science.gov (United States)

    ... Common Cancer Types Recurrent Cancer Common Cancer Types Bladder Cancer Breast Cancer Colorectal Cancer Kidney (Renal Cell) Cancer ... also called nuclear magnetic resonance imaging (NMRI). Somatostatin receptor scintigraphy : A type of radionuclide scan that may ...

  6. Treatment Option Overview (Pancreatic Neuroendocrine Tumors / Islet Cell Tumors)

    Science.gov (United States)

    ... Common Cancer Types Recurrent Cancer Common Cancer Types Bladder Cancer Breast Cancer Colorectal Cancer Kidney (Renal Cell) Cancer ... also called nuclear magnetic resonance imaging (NMRI). Somatostatin receptor scintigraphy : A type of radionuclide scan that may ...

  7. NKT cells as an ideal anti-tumor immunotherapeutic.

    Science.gov (United States)

    Fujii, Shin-Ichiro; Shimizu, Kanako; Okamoto, Yoshitaka; Kunii, Naoki; Nakayama, Toshinori; Motohashi, Shinichiro; Taniguchi, Masaru

    2013-12-02

    Human natural killer T (NKT) cells are characterized by their expression of an invariant T cell antigen receptor α chain variable region encoded by a Vα24Jα18 rearrangement. These NKT cells recognize α-galactosylceramide (α-GalCer) in conjunction with the MHC class I-like CD1d molecule and bridge the innate and acquired immune systems to mediate efficient and augmented immune responses. A prime example of one such function is adjuvant activity: NKT cells augment anti-tumor responses because they can rapidly produce large amounts of IFN-γ, which acts on NK cells to eliminate MHC negative tumors and also on CD8 cytotoxic T cells to kill MHC positive tumors. Thus, upon administration of α-GalCer-pulsed DCs, both MHC negative and positive tumor cells can be effectively eliminated, resulting in complete tumor eradication without tumor recurrence. Clinical trials have been completed in a cohort of 17 patients with advanced non-small cell lung cancers and 10 cases of head and neck tumors. Sixty percent of advanced lung cancer patients with high IFN-γ production had significantly prolonged median survival times of 29.3 months with only the primary treatment. In the case of head and neck tumors, 10 patients who completed the trial all had stable disease or partial responses 5 weeks after the combination therapy of α-GalCer-DCs and activated NKT cells. We now focus on two potential powerful treatment options for the future. One is to establish artificial adjuvant vector cells containing tumor mRNA and α-GalCer/CD1d. This stimulates host NKT cells followed by DC maturation and NK cell activation but also induces tumor-specific long-term memory CD8 killer T cell responses, suppressing tumor metastasis even 1 year after the initial single injection. The other approach is to establish induced pluripotent stem (iPS) cells that can generate unlimited numbers of NKT cells with adjuvant activity. Such iPS-derived NKT cells produce IFN-γ in vitro and in vivo upon

  8. X-ray sensitivity of human tumor cells in vitro

    International Nuclear Information System (INIS)

    Weichselbaum, R.R.; Nove, J.; Little, J.B.

    1980-01-01

    Clonally-derived cells from ten human malignant tumors considered radiocurable (breast, neuroblastoma, medulloblastoma) or non-radiocurable (osteosarcoma, hypernephroma, glioblastoma, melanoma) were studied in cell culture and their in vitro x-ray survival curve parameters determined (anti n, D 0 ). There were no significant differences among the tumor cell lines suggesting that survival parameters in vitro do not explain differences in clinical radiocurability. Preliminary investigation with density inhibited human tumor cells indicate that such an approach may yield information regarding inherent cellular differences in radiocurability

  9. Reduction of irradiated tumor cells viability under effect of hyperglycemia

    International Nuclear Information System (INIS)

    Meshcherikova, V.V.; Voloshina, E.A.

    1983-01-01

    On Ehrlich carcinoma cells adapted to growth in vivo and in vitro, cellular mechanisms of short-term hyperglycemia effect have been studied. It has been found that SH by itself leads to the loss of viability of a part of cells of ELD solid tumors manifesting during the first 24 hours upon irradiation according to the interphase death type. Tumor cell radiation injuries arising under the effect of irradiation, usually non realized up to the first division, under SH conditions potentiate its injury effect. The phenomena observed explain partially selective injury of tumoral cells in the course of irradiation under SH conditions which testifies to the prospects of its use in clinics

  10. CAR T Cells Targeting Podoplanin Reduce Orthotopic Glioblastomas in Mouse Brains.

    Science.gov (United States)

    Shiina, Satoshi; Ohno, Masasuke; Ohka, Fumiharu; Kuramitsu, Shunichiro; Yamamichi, Akane; Kato, Akira; Motomura, Kazuya; Tanahashi, Kuniaki; Yamamoto, Takashi; Watanabe, Reiko; Ito, Ichiro; Senga, Takeshi; Hamaguchi, Michinari; Wakabayashi, Toshihiko; Kaneko, Mika K; Kato, Yukinari; Chandramohan, Vidyalakshmi; Bigner, Darell D; Natsume, Atsushi

    2016-03-01

    Glioblastoma (GBM) is the most common and lethal primary malignant brain tumor in adults with a 5-year overall survival rate of less than 10%. Podoplanin (PDPN) is a type I transmembrane mucin-like glycoprotein, expressed in the lymphatic endothelium. Several solid tumors overexpress PDPN, including the mesenchymal type of GBM, which has been reported to present the worst prognosis among GBM subtypes. Chimeric antigen receptor (CAR)-transduced T cells can recognize predefined tumor surface antigens independent of MHC restriction, which is often downregulated in gliomas. We constructed a lentiviral vector expressing a third-generation CAR comprising a PDPN-specific antibody (NZ-1-based single-chain variable fragment) with CD28, 4-1BB, and CD3ζ intracellular domains. CAR-transduced peripheral blood monocytes were immunologically evaluated by calcein-mediated cytotoxic assay, ELISA, tumor size, and overall survival. The generated CAR T cells were specific and effective against PDPN-positive GBM cells in vitro. Systemic injection of the CAR T cells into an immunodeficient mouse model inhibited the growth of intracranial glioma xenografts in vivo. CAR T-cell therapy that targets PDPN would be a promising adoptive immunotherapy to treat mesenchymal GBM. ©2016 American Association for Cancer Research.

  11. Hypoxic cell turnover in different solid tumor lines

    International Nuclear Information System (INIS)

    Ljungkvist, Anna S.E.; Bussink, Johan; Kaanders, Johannes H.A.M.; Rijken, Paulus F.J.W.; Begg, Adrian C.; Raleigh, James A.; Kogel, Albert J. van der

    2005-01-01

    Purpose: Most solid tumors contain hypoxic cells, and the amount of tumor hypoxia has been shown to have a negative impact on the outcome of radiotherapy. The efficacy of combined modality treatments depends both on the sequence and timing of the treatments. Hypoxic cell turnover in tumors may be important for optimal scheduling of combined modality treatments, especially when hypoxic cell targeting is involved. Methods and Materials: Previously we have shown that a double bioreductive hypoxic marker assay could be used to detect changes of tumor hypoxia in relation to the tumor vasculature after carbogen and hydralazine treatments. This assay was used in the current study to establish the turnover rate of hypoxic cells in three different tumor models. The first hypoxic marker, pimonidazole, was administered at variable times before tumor harvest, and the second hypoxic marker, CCI-103F, was injected at a fixed time before harvest. Hypoxic cell turnover was defined as loss of pimonidazole (first marker) relative to CCI-103F (second marker). Results: The half-life of hypoxic cell turnover was 17 h in the murine C38 colon carcinoma line, 23 h and 49 h in the human xenograft lines MEC82 and SCCNij3, respectively. Within 24 h, loss of pimonidazole-stained areas in C38 and MEC82 occurred concurrent with the appearance of pimonidazole positive cell debris in necrotic regions. In C38 and MEC82, most of the hypoxic cells had disappeared after 48 h, whereas in SCCNij3, viable cells that had been labeled with pimonidazole were still observed after 5 days. Conclusions: The present study demonstrates that the double hypoxia marker assay can be used to study changes in both the proportion of hypoxic tumor cells and their lifespan at the same time. The present study shows that large differences in hypoxic cell turnover rates may exist among tumor lines, with half-lives ranging from 17-49 h

  12. Baldness, acne and testicular germ cell tumors

    Science.gov (United States)

    Trabert, Britton; Sigurdson, Alice J.; Sweeney, Anne M.; Amato, Robert J.; Strom, Sara S.; McGlynn, Katherine A.

    2013-01-01

    Androgen levels during critical periods of testicular development may be involved in the etiology of testicular germ cell tumors (TGCT). We evaluated the roles of adolescent and early adult life correlates of androgen exposure and TGCT in a hospital-based case control study. TGCT cases (n=187) and controls (n=148), matched on age, race and state of residence, participated in the study. Unconditional logistic regression was used to estimate associations between TGCT and male pattern baldness, severe acne, markers of puberty onset and body size. Cases were significantly less likely to report hair loss than controls (OR, 0.6; 95% CI, 0.4, 1.0). Amount of hair loss, increasing age at onset and increasing rate of loss were all inversely associated with TGCT (rate of hair loss: p-trend=0.03; age at onset: p-trend=0.03; amount of hair loss: p-trend=0.01). History of severe acne was inversely associated with TGCT (OR, 0.5; 95% CI, 0.3, 0.9) and height was positively associated with TGCT (p-trend=0.02). Increased endogenous androgen levels during puberty and early adulthood may be associated with decreased risk of TGCT. Additional studies of endogenous hormone levels during puberty and early adult life are warranted, especially studies evaluating the role of androgen synthesis, metabolism and uptake. PMID:21128977

  13. Circulating tumor cells in lung cancer.

    Science.gov (United States)

    Young, Rachel; Pailler, Emma; Billiot, Fanny; Drusch, Françoise; Barthelemy, Amélie; Oulhen, Marianne; Besse, Benjamin; Soria, Jean-Charles; Farace, Françoise; Vielh, Philippe

    2012-01-01

    Circulating tumor cells (CTCs) have emerged as potential biomarkers in several cancers such as colon, prostate, and breast carcinomas, with a correlation between CTC number and patient prognosis being established by independent research groups. The detection and enumeration of CTCs, however, is still a developing field, with no universal method of detection suitable for all types of cancer. CTC detection in lung cancer in particular has proven difficult to perform, as CTCs in this type of cancer often present with nonepithelial characteristics. Moreover, as many detection methods rely on the use of epithelial markers to identify CTCs, the loss of these markers during epithelial-to-mesenchymal transition in certain metastatic cancers can render these methods ineffective. The development of personalized medicine has led to an increase in the advancement of molecular characterization of CTCs. The application of techniques such as FISH and RT-PCR to detect EGFR, HER2, and KRAS abnormalities in lung, breast, and colon cancer, for example, could be used to characterize CTCs in real time. The use of CTCs as a 'liquid biopsy' is therefore an exciting possibility providing information on patient prognosis and treatment efficacy. This review summarizes the state of CTC detection today, with particular emphasis on lung cancer, and discusses the future applications of CTCs in helping the clinician to develop new strategies in patient treatment. Copyright © 2012 S. Karger AG, Basel.

  14. Desmoplastic Small Round Cell Tumor of Stomach

    Directory of Open Access Journals (Sweden)

    Ahmed Abu-Zaid

    2013-01-01

    Full Text Available Desmoplastic small round cell tumor (DSRCT is an extremely uncommon, highly aggressive, and malignant mesenchymal neoplasm of undetermined histogenesis. Less than 200 case reports have been documented in literature so far. Herein, we report a 26-year-old otherwise healthy female patient who presented with a 1-month history of epigastric pain. On physical examination, a palpable, slightly mobile, and tender epigastric mass was detected. All laboratory tests were normal. A chest, abdominal, and pelvic contrast-enhanced computed tomography (CT scans showed a 3.8 × 7.2 × 8.7 cm ill-defined mass, involving gastric fundus and extending into gastric cardia and lower gastroesophageal junction. It was associated with multiple enlarged gastrohepatic lymph nodes; the largest measured 1.2 cm. There was no evidence of ascites or retroperitoneal or mesenteric lymphatic metastases. Patient underwent total gastrectomy with D2 lymphadenectomy, splenectomy, and antecolic Roux-en-Y esophagojejunal anastomosis. Histopathological examination revealed coexpression of mesenchymal, epithelial, and neural markers. The characteristic chromosomal translocation (t(11; 22(p13; q12 was demonstrated on fluorescence in situ hybridization (FISH technique. Diagnosis of DSRCT of stomach was confirmed. Patient received no postoperative radiotherapy or chemotherapy. A postoperative 3-month followup failed to show any recurrence. In addition, a literature review on DSRCT is included.

  15. Vulnerability of cultured canine lung tumor cells to NK cell-mediated cytolysis

    International Nuclear Information System (INIS)

    Haley, P.J.; Kohr, J.M.; Kelly, G.; Muggenburg, B.A.; Guilmette, B.A.

    1988-01-01

    Five cell lines, designated as canine lung epithelial cell (CLEP), derived from radiation induced canine lung tumors and canine thyroid adeno-carcinoma (CTAC) cells were compared for their susceptibility to NK cell-mediated cytolysis using peripheral blood lymphocytes from normal, healthy Beagle dogs as effector cells. Effector cells and chromium 51 radiolabeled target cells were incubated for 16 h at ratios of 12.5:1, 25:1, 50:1, and 100:1. Increasing cytolysis was observed for all cell lines as the effector-to-target-cell ratios increased from 12.5:1 to 100:1. The percent cytotoxicity was significantly less for all lung tumor cell lines as compared to CTAC at the 100:1 ratio. One lung tumor cell line, CLEP-9, had 85% of the lytic vulnerability of the CTAC cell line and significantly greater susceptibility to NK cell-mediated lysis than all of the other lung tumor cell lines. Susceptibility to NK cell cytolysis did not correlate with in vivo malignant behavior of the original tumor. These data suggest that cultured canine lung tumor cells are susceptible to NK cell cytolytic activity in vitro and that at least one of these cell lines (CLEP-9) is a candidate for substitution of the standard canine NK cell target, CTAC, in NK cell assays. The use of lung tumor cells in NK cell assays may provide greater insight into the control of lung tumors by immune mechanisms. (author)

  16. Radiologic findings of granulosa cell tumor of the ovary

    Energy Technology Data Exchange (ETDEWEB)

    Sohn, Jung Eun; Kim, Kie Hwan; Yoo, Ji Young; Lee, Eun Chun; Lee, Tae Hyun; Chin, Soo Il [Korea Cancer Center Hospital, Seoul (Korea, Republic of)

    1997-08-01

    To evaluate the radiologic findings of granulosa cell tumor of the ovary. Fourteen cases(fifteen tumors) of pathologically confirmed ovarian granulosa cell tumor were retrospectively analyzed on the basis of CT(n=10), MR imaging(n=4), and ultrasound(n=7) findings. The patients' mean age was 44.3(range, 5-71)years. The mean diameter of the tumors was 12.1(range, 5-26.5)cm. Thirteen cases were unilateral, and one was bilateral. Eleven tumors(ten cases) were mainly solid and eight of these had focal cystic components. Multilocular cysts accounted for three cases, and in two of these, mural nodules were present. One case was a unilocular cyst with no mural nodule. Ten cases were well demarcated. All the solid tumors were enhanced on postcontrast CT and MR imaging. Endometrial thickening was seen in five cases, ascites in six, and peritoneal implants or omental fat infiltration in five. One was associated with lymph node metastasis. All the postmenopausal patients had solid tumors, whereas 66.7%(4 of 6 cases) of young adults and children had cystic tumors. Granulosa cell tumors of the ovary were solid or cystic;the former were more common. There were no characteristic findings which permitted definitive differentiation from other ovarian tumors.

  17. Glioblastoma: Molecular Pathways, Stem Cells and Therapeutic Targets

    International Nuclear Information System (INIS)

    Jhanwar-Uniyal, Meena; Labagnara, Michael; Friedman, Marissa; Kwasnicki, Amanda; Murali, Raj

    2015-01-01

    Glioblastoma (GBM), a WHO-defined Grade IV astrocytoma, is the most common and aggressive CNS malignancy. Despite current treatment modalities, the survival time remains dismal. The main cause of mortality in patients with this disease is reoccurrence of the malignancy, which is attributed to treatment-resistant cancer stem cells within and surrounding the primary tumor. Inclusion of novel therapies, such as immuno- and DNA-based therapy, may provide better means of treating GBM. Furthermore, manipulation of recently discovered non-coding microRNAs, some of which regulate tumor growth through the development and maintenance of GBM stem cells, could provide new prospective therapies. Studies conducted by The Cancer Genome Atlas (TCGA) also demonstrate the role of molecular pathways, specifically the activated PI3K/AKT/mTOR pathway, in GBM tumorigenesis. Inhibition of the aforementioned pathway may provide a more direct and targeted method to GBM treatment. The combination of these treatment modalities may provide an innovative therapeutic approach for the management of GBM

  18. Glioblastoma: Molecular Pathways, Stem Cells and Therapeutic Targets

    Energy Technology Data Exchange (ETDEWEB)

    Jhanwar-Uniyal, Meena, E-mail: meena_jhanwar@nymc.edu; Labagnara, Michael; Friedman, Marissa; Kwasnicki, Amanda; Murali, Raj [Department of Neurosurgery, New York Medical College, Valhalla, NY 10595 (United States)

    2015-03-25

    Glioblastoma (GBM), a WHO-defined Grade IV astrocytoma, is the most common and aggressive CNS malignancy. Despite current treatment modalities, the survival time remains dismal. The main cause of mortality in patients with this disease is reoccurrence of the malignancy, which is attributed to treatment-resistant cancer stem cells within and surrounding the primary tumor. Inclusion of novel therapies, such as immuno- and DNA-based therapy, may provide better means of treating GBM. Furthermore, manipulation of recently discovered non-coding microRNAs, some of which regulate tumor growth through the development and maintenance of GBM stem cells, could provide new prospective therapies. Studies conducted by The Cancer Genome Atlas (TCGA) also demonstrate the role of molecular pathways, specifically the activated PI3K/AKT/mTOR pathway, in GBM tumorigenesis. Inhibition of the aforementioned pathway may provide a more direct and targeted method to GBM treatment. The combination of these treatment modalities may provide an innovative therapeutic approach for the management of GBM.

  19. Human tumor cell proliferation evaluated using manganese-enhanced MRI.

    Directory of Open Access Journals (Sweden)

    Rod D Braun

    Full Text Available Tumor cell proliferation can depend on calcium entry across the cell membrane. As a first step toward the development of a non-invasive test of the extent of tumor cell proliferation in vivo, we tested the hypothesis that tumor cell uptake of a calcium surrogate, Mn(2+ [measured with manganese-enhanced MRI (MEMRI], is linked to proliferation rate in vitro.Proliferation rates were determined in vitro in three different human tumor cell lines: C918 and OCM-1 human uveal melanomas and PC-3 prostate carcinoma. Cells growing at different average proliferation rates were exposed to 1 mM MnCl(2 for one hour and then thoroughly washed. MEMRI R(1 values (longitudinal relaxation rates, which have a positive linear relationship with Mn(2+ concentration, were then determined from cell pellets. Cell cycle distributions were determined using propidium iodide staining and flow cytometry. All three lines showed Mn(2+-induced increases in R(1 compared to cells not exposed to Mn(2+. C918 and PC-3 cells each showed a significant, positive correlation between MEMRI R(1 values and proliferation rate (p≤0.005, while OCM-1 cells showed no significant correlation. Preliminary, general modeling of these positive relationships suggested that pellet R(1 for the PC-3 cells, but not for the C918 cells, could be adequately described by simply accounting for changes in the distribution of the cell cycle-dependent subpopulations in the pellet.These data clearly demonstrate the tumor-cell dependent nature of the relationship between proliferation and calcium influx, and underscore the usefulness of MEMRI as a non-invasive method for investigating this link. MEMRI is applicable to study tumors in vivo, and the present results raise the possibility of evaluating proliferation parameters of some tumor types in vivo using MEMRI.

  20. Fermi/GBM Results of Magnetars

    Science.gov (United States)

    Kouveliotou, chryssa

    2011-01-01

    Magnetars are magnetically powered rotating neutron stars with extreme magnetic fields (over 10(exp 14) Gauss). They were discovered in the X- and gamma-rays where they predominantly emit their radiation. Very few sources (roughly 18) have been found since their discovery in 1987. NASA's Fermi Gamma-ray Space Telescope was launched June 11,2009; since then the Fermi Gamma-ray Burst Monitor (GBM) recorded emission from four magnetar sources. Two of these were brand new sources, SGR J0501 +4516, discovered with Swift and extensively monitored with Swift and GBM, SGR J0418+5729, discovered with GBM and the Interplanetary Network (IPN). A third was SGR Jl550-5418, a source originally classified as an Anomalous X-ray Pulsar (AXP IEI547.0-5408), but exhibiting a very prolific outburst with over 400 events recorded in January 2009. In my talk I will give a short history of magnetars and describe how this, once relatively esoteric field, has emerged as a link between several astrophysical areas including Gamma-Ray Bursts. Finally, I will describe the exciting new results of Fermi in this field and the current status of our knowledge of the magnetar population properties and magnetic fields.

  1. Enhanced Radiosensitivity of Tumor Cells Treated with Vanadate in Vitro

    International Nuclear Information System (INIS)

    Lee, Myung Za; Lee, Won Young

    1994-01-01

    Intracellular ions which have a major role in cellular function have been reported to affect repair of radiation damage. Recently it has been reported that ouabain sensitizes A549 tumor cells hut not CCL-120 normal cells to radiation. Ouabain inhibits the Na+-K+-pump rapidly thus it increases intracellular Na concentration. Vanadate which is distributed extensively in almost all living organisms in known to be a Na+-K+-ATPase inhibitors. This study was performed to see any change in radiosensitivity of tumor cell by vanadate and any role of Na+-K+-ATPase in radiosensitization. Experiments have been carried out by pretreatment with vanadate in human cell line(A549, JMG) and mouse cell line(L1210, spleen). For the cell survival MTT assay was performed for A549 and JMG cell and trypan blue dye exclusion test for L120, and spleen cells. Measurements of Na+-K+-ATPase activity in control, vanadate treated cell, radiation treated cell (9 Gy for A549 and JMG, 2 Gy for L1201, spleen), and combined 10-6 M vanadate and radiation treated cells were done. The results were summarized as follows. 1. L1210 cell was most radiosensitive, and spleen cell and JMG cell were intermediate, and A549 cell was least radiosensitive. 2. Minimum or cytotoxicity was seen with vanadate below concentration of 10-6 M. 3. In A549 cells there was a little change in radiosensitivity with treatment of vanadate. However radiation sensitization was shown in low dose level of radiation i. E. 2-Gy. In JMG cells no change in radiosensitivity was noted. Both L1210 and spleen cell had radiosensitization but change was greater in tumor cell. 4. Na+-K+-ATPase activity was inhibited significantly in tumor cell by treatment of vanadate. 5. Radiation itself inhibited Na+-K+-ATPase activity of tumor cell with high Na+- K+-ATPase concention. Increase in radiosensitivity by vanadate was closely associated with original Na+-K+-ATPase contents. From the above results vanadate had little cytotoxicity and it sensitized

  2. Dual inhibition of Ang-2 and VEGF receptors normalizes tumor vasculature and prolongs survival in glioblastoma by altering macrophages

    Science.gov (United States)

    Peterson, Teresa E.; Kirkpatrick, Nathaniel D.; Huang, Yuhui; Farrar, Christian T.; Marijt, Koen A.; Kloepper, Jonas; Datta, Meenal; Amoozgar, Zohreh; Seano, Giorgio; Jung, Keehoon; Kamoun, Walid S.; Vardam, Trupti; Snuderl, Matija; Goveia, Jermaine; Chatterjee, Sampurna; Batista, Ana; Muzikansky, Alona; Leow, Ching Ching; Xu, Lei; Batchelor, Tracy T.; Duda, Dan G.; Fukumura, Dai; Jain, Rakesh K.

    2016-01-01

    Glioblastomas (GBMs) rapidly become refractory to anti-VEGF therapies. We previously demonstrated that ectopic overexpression of angiopoietin-2 (Ang-2) compromises the benefits of anti-VEGF receptor (VEGFR) treatment in murine GBM models and that circulating Ang-2 levels in GBM patients rebound after an initial decrease following cediranib (a pan-VEGFR tyrosine kinase inhibitor) administration. Here we tested whether dual inhibition of VEGFR/Ang-2 could improve survival in two orthotopic models of GBM, Gl261 and U87. Dual therapy using cediranib and MEDI3617 (an anti–Ang-2–neutralizing antibody) improved survival over each therapy alone by delaying Gl261 growth and increasing U87 necrosis, effectively reducing viable tumor burden. Consistent with their vascular-modulating function, the dual therapies enhanced morphological normalization of vessels. Dual therapy also led to changes in tumor-associated macrophages (TAMs). Inhibition of TAM recruitment using an anti–colony-stimulating factor-1 antibody compromised the survival benefit of dual therapy. Thus, dual inhibition of VEGFR/Ang-2 prolongs survival in preclinical GBM models by reducing tumor burden, improving normalization, and altering TAMs. This approach may represent a potential therapeutic strategy to overcome the limitations of anti-VEGFR monotherapy in GBM patients by integrating the complementary effects of anti-Ang2 treatment on vessels and immune cells. PMID:27044097

  3. Cell Competition Drives the Formation of Metastatic Tumors in a Drosophila Model of Epithelial Tumor Formation

    DEFF Research Database (Denmark)

    Eichenlaub, Teresa; Cohen, Stephen M; Herranz, Héctor

    2016-01-01

    . The mechanisms that allow for ongoing cell competition during adult life could, in principle, contribute to tumorigenesis. However, direct evidence supporting this hypothesis has been lacking. Here, we provide evidence that cell competition drives tumor formation in a Drosophila model of epithelial cancer. Cells...

  4. Targeting Tumor Oct4 to Deplete Prostate Tumor and Metastasis Initiating Cells

    Science.gov (United States)

    2017-12-01

    is associated with androgen receptor (AR). We detected Oct4 protein expression in prostate cancer cells as well as in tumor tissue specimens...unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT Identification of genes driving prostate carcinogenesis will lead to new cancer treatment. The human...a pseudogene of embryonic Oct4 (POU5F1). A recent study found that tumor Oct4 found in prostate cancer cells is due to the gene expression of POU5F1B

  5.  An Uncommon Presentation of Giant Cell Tumor

    Directory of Open Access Journals (Sweden)

    Gopal Malhotra

    2011-09-01

    Full Text Available  Giant Cell Tumors commonly occur at the ends of long bones. However in rare cases, they can occur in the bones of the hands and feet. Tumors in these locations occur in younger patients; in addition, these tumors are more commonly multifocal and are associated with a higher risk for local recurrence than tumors at the ends of long bones. Since lesions in the small bones may be multifocal, a patient with a giant cell tumor of the small bones should undergo a skeletal survey to exclude similar lesions elsewhere. Primary surgical treatment ranges from curettage or excision with or without bone grafting to amputation. The success of surgical treatment depends on the completeness with which the tumor was removed. We are presenting a case report of a 34 year old female, who presented with a swelling in the right hand, following trauma. X-ray of the hand showed an osteolytic expansile lesion at the base of the 1st metacarpal bone. The lesion was initially curetted and then treated by local resection with bone grafting. Histological examination revealed a typical benign giant cell tumor composed of closely packed stromal cells with a variable admixture of giant cells. Follow up at the end of one year did not reveal any recurrence of the tumor.

  6. Overexpression of the duffy antigen receptor for chemokines (DARC) by NSCLC tumor cells results in increased tumor necrosis

    International Nuclear Information System (INIS)

    Addison, Christina L; Belperio, John A; Burdick, Marie D; Strieter, Robert M

    2004-01-01

    The Duffy antigen receptor for chemokines (DARC) is known to be a promiscuous chemokine receptor that binds a variety of CXC and CC chemokines in the absence of any detectable signal transduction events. Within the CXC group of chemokines, DARC binds the angiogenic CXC chemokines including IL-8 (CXCL8), GROα (CXCL1) and ENA-78 (CXCL5), all of which have previously been shown to be important in non-small cell lung carcinoma (NSCLC) tumor growth. We hypothesized that overexpression of DARC by a NSCLC tumor cell line would result in the binding of the angiogenic ELR+ CXC chemokines by the tumor cells themselves, and thus interfere with the stimulation of endothelial cells and induction of angiogenesis by the tumor cell-derived angiogenic chemokines. NSCLC tumor cells that constitutively expressed DARC were generated and their growth characteristics were compared to control transfected cells in vitro and in vivo in SCID animals. We found that tumors derived from DARC-expressing cells were significantly larger in size than tumors derived from control-transfected cells. However, upon histological examination we found that DARC-expressing tumors had significantly more necrosis and decreased tumor cellularity, as compared to control tumors. Expression of DARC by NSCLC cells was also associated with a decrease in tumor-associated vasculature and a reduction in metastatic potential. The expression of DARC in the context of NSCLC tumors may act as a chemokine decoy receptor and interferes with normal tumor growth and chemokine-induced tumor neovascularization

  7. Apoptosis and tumor cell death in response to HAMLET (human alpha-lactalbumin made lethal to tumor cells).

    Science.gov (United States)

    Hallgren, Oskar; Aits, Sonja; Brest, Patrick; Gustafsson, Lotta; Mossberg, Ann-Kristin; Wullt, Björn; Svanborg, Catharina

    2008-01-01

    HAMLET (human alpha-lactalbumin made lethal to tumor cells) is a molecular complex derived from human milk that kills tumor cells by a process resembling programmed cell death. The complex consists of partially unfolded alpha-lactalbumin and oleic acid, and both the protein and the fatty acid are required for cell death. HAMLET has broad antitumor activity in vitro, and its therapeutic effect has been confirmed in vivo in a human glioblastoma rat xenograft model, in patients with skin papillomas and in patients with bladder cancer. The mechanisms of tumor cell death remain unclear, however. Immediately after the encounter with tumor cells, HAMLET invades the cells and causes mitochondrial membrane depolarization, cytochrome c release, phosphatidyl serine exposure, and a low caspase response. A fraction of the cells undergoes morphological changes characteristic of apoptosis, but caspase inhibition does not rescue the cells and Bcl-2 overexpression or altered p53 status does not influence the sensitivity of tumor cells to HAMLET. HAMLET also creates a state of unfolded protein overload and activates 20S proteasomes, which contributes to cell death. In parallel, HAMLET translocates to tumor cell nuclei, where high-affinity interactions with histones cause chromatin disruption, loss of transcription, and nuclear condensation. The dying cells also show morphological changes compatible with macroautophagy, and recent studies indicate that macroautophagy is involved in the cell death response to HAMLET. The results suggest that HAMLET, like a hydra with many heads, may interact with several crucial cellular organelles, thereby activating several forms of cell death, in parallel. This complexity might underlie the rapid death response of tumor cells and the broad antitumor activity of HAMLET.

  8. Exosome-Based Cell-Cell Communication in the Tumor Microenvironment

    Directory of Open Access Journals (Sweden)

    Joana Maia

    2018-02-01

    Full Text Available Tumors are not isolated entities, but complex systemic networks involving cell-cell communication between transformed and non-transformed cells. The milieu created by tumor-associated cells may either support or halt tumor progression. In addition to cell-cell contact, cells communicate through secreted factors via a highly complex system involving characteristics such as ligand concentration, receptor expression and integration of diverse signaling pathways. Of these, extracellular vesicles, such as exosomes, are emerging as novel cell-cell communication mediators in physiological and pathological scenarios. Exosomes, membrane vesicles of endocytic origin released by all cells (both healthy and diseased, ranging in size from 30 to 150 nm, transport all the main biomolecules, including lipids, proteins, DNAs, messenger RNAs and microRNA, and perform intercellular transfer of components, locally and systemically. By acting not only in tumor cells, but also in tumor-associated cells such as fibroblasts, endothelium, leukocytes and progenitor cells, tumor- and non-tumor cells-derived exosomes have emerged as new players in tumor growth and invasion, tumor-associated angiogenesis, tissue inflammation and immunologic remodeling. In addition, due to their property of carrying molecules from their cell of origin to the peripheral circulation, exosomes have been increasingly studied as sources of tumor biomarkers in liquid biopsies. Here we review the current literature on the participation of exosomes in the communication between tumor and tumor-associated cells, highlighting the role of this process in the setup of tumor microenvironments that modulate tumor initiation and metastasis.

  9. The expression and regulation of glucose transporters in tumor cells

    Directory of Open Access Journals (Sweden)

    Pengfei Zhao

    2016-12-01

    Full Text Available Glucose transporter proteins are involved in many physiological and biochemical processes. In particular, the high expressions of sodium-glucose cotransporter and glucose transporter proteins in tumor cells show that these two transporters play a key role in tumor cell metabolism. Studying the crystal structure and conformation of human glucose transporter proteins has enabled the development of drugs based on specific binding sites, opening up a new path towards more effective cancer treatments. This mini review serves to summarize our existing understanding of the metabolic pathways of tumor cells, focusing on the roles of glucose transporter proteins.

  10. Contribution to Tumor Angiogenesis From Innate Immune Cells Within the Tumor Microenvironment: Implications for Immunotherapy

    Directory of Open Access Journals (Sweden)

    Adriana Albini

    2018-04-01

    Full Text Available The critical role of angiogenesis in promoting tumor growth and metastasis is strongly established. However, tumors show considerable variation in angiogenic characteristics and in their sensitivity to antiangiogenic therapy. Tumor angiogenesis involves not only cancer cells but also various tumor-associated leukocytes (TALs and stromal cells. TALs produce chemokines, cytokines, proteases, structural proteins, and microvescicles. Vascular endothelial growth factor (VEGF and inflammatory chemokines are not only major proangiogenic factors but are also immune modulators, which increase angiogenesis and lead to immune suppression. In our review, we discuss the regulation of angiogenesis by innate immune cells in the tumor microenvironment, specific features, and roles of major players: macrophages, neutrophils, myeloid-derived suppressor and dendritic cells, mast cells, γδT cells, innate lymphoid cells, and natural killer cells. Anti-VEGF or anti-inflammatory drugs could balance an immunosuppressive microenvironment to an immune permissive one. Anti-VEGF as well as anti-inflammatory drugs could therefore represent partners for combinations with immune checkpoint inhibitors, enhancing the effects of immune therapy.

  11. T cells enhance gold nanoparticle delivery to tumors in vivo

    Science.gov (United States)

    Kennedy, Laura C.; Bear, Adham S.; Young, Joseph K.; Lewinski, Nastassja A.; Kim, Jean; Foster, Aaron E.; Drezek, Rebekah A.

    2011-12-01

    Gold nanoparticle-mediated photothermal therapy (PTT) has shown great potential for the treatment of cancer in mouse studies and is now being evaluated in clinical trials. For this therapy, gold nanoparticles (AuNPs) are injected intravenously and are allowed to accumulate within the tumor via the enhanced permeability and retention (EPR) effect. The tumor is then irradiated with a near infrared laser, whose energy is absorbed by the AuNPs and translated into heat. While reliance on the EPR effect for tumor targeting has proven adequate for vascularized tumors in small animal models, the efficiency and specificity of tumor delivery in vivo, particularly in tumors with poor blood supply, has proven challenging. In this study, we examine whether human T cells can be used as cellular delivery vehicles for AuNP transport into tumors. We first demonstrate that T cells can be efficiently loaded with 45 nm gold colloid nanoparticles without affecting viability or function (e.g. migration and cytokine production). Using a human tumor xenograft mouse model, we next demonstrate that AuNP-loaded T cells retain their capacity to migrate to tumor sites in vivo. In addition, the efficiency of AuNP delivery to tumors in vivo is increased by more than four-fold compared to injection of free PEGylated AuNPs and the use of the T cell delivery system also dramatically alters the overall nanoparticle biodistribution. Thus, the use of T cell chaperones for AuNP delivery could enhance the efficacy of nanoparticle-based therapies and imaging applications by increasing AuNP tumor accumulation.

  12. "Mixed germ cell testicular tumor" in an adult female

    Directory of Open Access Journals (Sweden)

    Udasimath Shivakumarswamy

    2012-01-01

    Full Text Available The androgen insensitivity (testicular feminization syndrome was described by Morris in phenotypic females with 46XY karyotype, presenting with primary amenorrhea, adequate breast development, and absent or scanty pubic or axillary hair. Gonads consist usually of seminiferous tubules without spermatogenesis. These patients have a 5-10% risk of developing germ cell tumors, usually after the complete development of secondary female sexual characteristics. We hereby report a case considered as a female with married life of 15 years, who was operated for severe abdominal pain. Phenotype characters were that of female. Microscopic examination of the tumor from the abdomen revealed germinoma and yolk sac tumor with adjacent seminiferous tubules. Karyotyping showed 46XY. Final diagnosis of malignant mixed germ cell tumor in androgen insensitivity syndrome was made. Surveillance may be the most appropriate option when these conditions are initially diagnosed in adulthood to prevent development of germ cell tumors.

  13. Bilateral giant cell tumor of tendon sheath of tendoachilles

    Directory of Open Access Journals (Sweden)

    Soma Datta

    2014-01-01

    Full Text Available Giant cell tumor of tendon sheath arises from the synovium of tendon sheaths, joints, or bursae, mostly affects adults between 30 and 50 years of age, and is slightly more common in females. We report the case of a 32-years-old male presenting with pain in both ankles without any history of trauma. On clinical examination, tenderness on both tendoachilles and local thickening were observed. Ultrasonography showed thickening of local tendinous area with increase in anteroposterior diameter, and Doppler demonstrated increased flow in peritendinous area. MRI findings showed that most of the tumor had intermediate signal intensity and portions of the tumor had low signal intensity. Fine needle aspiration cytology confirmed the diagnosis of giant cell tumor of tendon sheath. Excision biopsy was done with no recurrence on five month follow-up. Review of literature did not reveal any similar result; so, bilateral giant cell tumor of tendon sheath of tendoachilles is a rare presentation.

  14. Recent discoveries concerning the tumor - mesenchymal stem cell interactions.

    Science.gov (United States)

    Lazennec, Gwendal; Lam, Paula Y

    2016-12-01

    Tumor microenvironment plays a crucial role in coordination with cancer cells in the establishment, growth and dissemination of the tumor. Among cells of the microenvironment, mesenchymal stem cells (MSCs) and their ability to evolve into cancer associated fibroblasts (CAFs) have recently generated a major interest in the field. Numerous studies have described the potential pro- or anti-tumorigenic action of MSCs. The goal of this review is to synthesize recent and emerging discoveries concerning the mechanisms by which MSCs can be attracted to tumor sites, how they can generate CAFs and by which way MSCs are able to modulate the growth, response to treatments, angiogenesis, invasion and metastasis of tumors. The understanding of the role of MSCs in tumor development has potential and clinical applications in terms of cancer management. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  15. Molecular markers for tumor cell dissemination in female cancers

    International Nuclear Information System (INIS)

    Obermayr, E.

    2009-01-01

    In the fight against cancer many advances have been made in early detection and treatment of the disease during the last few decades. Nevertheless, many patients still die of cancer due to metastatic spreading of the disease. Tumor cell dissemination may occur very early and usually is not discovered at the time of initial diagnosis. In these cases, the mere excision of the primary tumor is an insufficient treatment. Microscopic tumor residues will remain in the blood, lymph nodes, or the bone marrow and will cause disease recurrence. To improve the patient's prognosis, a sensitive tool for the detection of single tumor cells supplementing conventional diagnostic procedures is required. As the blood is more easily accessible than the bone marrow or tissue biopsies, we intended to identify gene markers for the detection of circulating tumor cells in the blood of cancer patients. We focused on patients with breast, ovarian, endometrial or cervical cancer. Starting from a genome-wide gene expression analysis of tumor cells and blood cells, we found six genes higher expression levels in cancer patients compared to healthy women. These findings suggest that an increased expression of these genes in the blood indicates the presence of circulating tumor cells inducing future metastases and thus the need for adjuvant therapy assisting the primary treatment. Measuring the expression levels of these six genes in the blood may supplement conventional diagnostic tests and improve the patient's prognosis. (author) [de

  16. Immunogenicity of ascites tumor cells following in vitro hyperthermia

    International Nuclear Information System (INIS)

    Dickson, J.A.; Jasiewicz, M.L.; Simpson, A.C.

    1982-01-01

    The concept that host immunization may be achieved by heat-induced antigenic modifications of cancer cells and/or the release of immunogenic products by dead or dying tumor cells following in vitro heating was examined. Ehrlich ascites cells were used, inasmuch as it was claimed that in vitro hyperthermia increased the immunogenicity of these cells. Tumor cell populations of different viability were obtained by heating Ehrlich cells at 42.5 degrees, 45 degrees, or 60 degrees C. Viable and nonviable cells were separated by Ficoll-Hypaque density centrifugation; viable nonreplicating cells were obtained by treatment with mitomycin C. Cell populations of different viability after heating were left to die slowly over 3 days at 37 degrees C. Swiss TO mice were then given injections of the treated cells and/or medium. No survival benefit occurred in mice inoculated with any of these different components and then challenged with viable tumor cells. Injection of irradiated cells, however, did produce host immunity. Similarly, D23 rat hepatoma ascites cells produced host immunity after 15,000 rad but not after heating. The claim that in vitro hyperthermia increases the immunogenicity of tumor cells was not confirmed

  17. Biophysical force regulation in 3D tumor cell invasion

    Science.gov (United States)

    Wu, Mingming

    When embedded within 3D extracellular matrices (ECM), animal cells constantly probe and adapt to the ECM locally (at cell length scale) and exert forces and communicate with other cells globally (up to 10 times of cell length). It is now well accepted that mechanical crosstalk between animal cells and their microenvironment critically regulate cell function such as migration, proliferation and differentiation. Disruption of the cell-ECM crosstalk is implicated in a number of pathologic processes including tumor progression and fibrosis. Central to the problem of cell-ECM crosstalk is the physical force that cells generate. By measuring single cell generated force within 3D collagen matrices, we revealed a mechanical crosstalk mechanism between the tumor cells and the ECM. Cells generate sufficient force to stiffen collagen fiber network, and stiffer matrix, in return promotes larger cell force generation. Our work highlights the importance of fibrous nonlinear elasticity in regulating tumor cell-ECM interaction, and results may have implications in the rapid tissue stiffening commonly found in tumor progression and fibrosis. This work is partially supported by NIH Grants R21RR025801 and R21GM103388.

  18. Turnover rate of hypoxic cells in solid tumors

    International Nuclear Information System (INIS)

    Ljungkvist, A.S.E.; Bussink, J.; Rijken, P.F.J.W.; Van Der Kogel, A.J.

    2003-01-01

    Most solid tumors contain hypoxic cells, and both the amount and duration of tumor hypoxia has been shown to influence the effect of radiation treatment negatively. It is important to understand the dynamic processes within the hypoxic cell population in non-treated tumors, and the effect of different treatment modalities on the kinetics of hypoxic cells to be able to design optimal combined modality treatments. The turnover rate of hypoxic cells was analyzed in three different solid tumor models with a double bio-reductive hypoxic marker assay with sequential injection of the two hypoxic markers. Previously it was shown that this assay could be used to detect both a decrease and an increase of tumor hypoxia in relation to the tumor vasculature with high spatial resolution. In this study the first hypoxic marker, pimonidazole, was administered at variable times relative to tumor harvest, and the second hypoxic marker, CCI-103F, was injected at a fixed time before harvest. The hypoxic cell turnover rate was calculated as the loss of pimonidazole positive cells relative to CCI-103F. The murine C38 line had the fastest hypoxic turnover rate of 60% /24h and the human xenograft line SCCNij3 had the slowest hypoxic turnover rate of 30% /24 h. The hypoxic turnover rate was most heterogeneous in the SCCNij3 line that even contained viable groups of cells that had been hypoxic for at least 5 days. The human xenograft line MEC82 fell in between with a hypoxic turnover rate of 50% /24 h. The hypoxic cell turnover was related to the potential tumor volume doubling time (Tpot) with a Tpot of 26h in C38 and 103h in SCCNij3. The dynamics of hypoxic cells, quantified with a double hypoxic marker method, showed large differences in hypoxic cell turnover rate and were related to Tpot

  19. The effects of tumor treating fields and temozolomide in MGMT expressing and non-expressing patient-derived glioblastoma cells.

    Science.gov (United States)

    Clark, Paul A; Gaal, Jordan T; Strebe, Joslyn K; Pasch, Cheri A; Deming, Dustin A; Kuo, John S; Robins, H Ian

    2017-02-01

    A recent Phase 3 study of newly diagnosed glioblastoma (GBM) demonstrated the addition of tumor treating fields (TTFields) to temozolomide (TMZ) after combined radiation/TMZ significantly increased survival and progression free survival. Preliminary data suggested benefit with both methylated and unmethylated O-6-methylguanine-DNA methyl-transferase (MGMT) promoter status. To date, however, there have been no studies to address the potential interactions of TTFields and TMZ. Thus, the effects of TTFields and TMZ were studied in vitro using patient-derived GBM stem-like cells (GSCs) including MGMT expressing (TMZ resistant: 12.1 and 22GSC) and non-MGMT expressing (TMZ sensitive: 33 and 114GSC) lines. Dose-response curves were constructed using cell proliferation and sphere-forming assays. Results demonstrated a ⩾10-fold increase in TMZ resistance of MGMT-expressing (12.1GSCs: IC 50 =160μM; 22GSCs: IC 50 =44μM) compared to MGMT non-expressing (33GSCs: IC 50 =1.5μM; 114GSCs: IC 50 =5.2μM) lines. TTFields inhibited 12.1 GSC proliferation at all tested doses (50-500kHz) with an optimal frequency of 200kHz. At 200kHz, TTFields inhibited proliferation and tumor sphere formation of both MGMT GSC subtypes at comparable levels (12.1GSC: 74±2.9% and 38±3.2%, respectively; 22GSC: 61±11% and 38±2.6%, respectively; 33GSC: 56±9.5% and 60±7.1%, respectively; 114 GSC: 79±3.5% and 41±4.3%, respectively). In combination, TTFields (200kHz) and TMZ showed an additive anti-neoplastic effect with equal efficacy for TTFields in both cell types (i.e., ± MGMT expression) with no effect on TMZ resistance. This is the first demonstration of the effects of TTFields on cancer stem cells. The expansion of such studies may have clinical implications. Copyright © 2016 Elsevier Ltd. All rights reserved.

  20. Multifocal Abrikossoff's granular cell tumor of the oesophagus: Case report

    Directory of Open Access Journals (Sweden)

    Ranđelović Tomislav D.

    2008-01-01

    Full Text Available INTRODUCTION Granular cell tumors, relatively uncommon soft tissue tumors, have been a matter of debate among pathologists regarding histogenesis for a long time. Less common locations are in the aerodigestive tract including the oesophagus. CASE OUTLINE We have recently treated a rare case, a 37-year old male, who was admitted due to dysphagia and a painful swallow with occasional pharyngo-nasal regurgitation followed with a mild loss of weight. Standard clinical examination including X-ray chest, ECG and laboratory tests did not show pathological findings. Barium contrast oesophagography demonstrated multiple ovoid defects in the wall of the oesophagus. CT scan of the chest confirmed luminal narrowing owing to the tumor of the upper oesophagus. Upper endoscopy showed unusual multifocal nodular lesions alongside the oesophageal axis covered by smooth mucosa. A primary biopsy specimen taken from the largest nodules confirmed an unusual pathological finding of the granular cell tumor. Subtotal, transpleural oesophagectomy was performed and reconstruction was derived by long colon segment interposition through the posterior mediastinum. The postoperative course was uneventful. The operative specimen consisted of four ovoid tumors alongside the oesophagus (the greatest diameter 0.5-1.8, average 1.25. All verified tumors histologicaly consisted of a spindle-shaped or polygonal cells containing small and large eosinophilic granules and central nuclei. Most tumor cells showed strongly positive immunohistochemical staining for S-100 protein. These tumor cells were partially positive for p-53 and Ki-67. No lymph node metastases were detected histologically. CONCLUSION Multifocal granular cell tumor of the oesophagus is an unusual finding with low incidence, and rarely caused symptoms. Pathological features and multiplicity of such tumors emphasized malignant predisposition requiring surgical resection of the oesophagus.

  1. Multifocal Synchronous Granular Cell Tumors of the Gastrointestinal Tract

    OpenAIRE

    Lipkin-Moore, Zachary; Thomas, Rebecca M.; Rothstein, Robin D.

    2014-01-01

    Granular cell tumors (GCT) are rare and unusual tumors, which are usually benign and asymptomatic. Only 5?10% of cases involve the gastrointestinal tract, most commonly as singular, non-cancerous lesions in the esophagus. We report a rare case of symptomatic, multifocal, synchronous GCT involving the esophagus, stomach, and cecum.

  2. TANTIGEN: a comprehensive database of tumor T cell antigens

    DEFF Research Database (Denmark)

    Olsen, Lars Rønn; Tongchusak, Songsak; Lin, Honghuang

    2017-01-01

    Tumor T cell antigens are both diagnostically and therapeutically valuable molecules. A large number of new peptides are examined as potential tumor epitopes each year, yet there is no infrastructure for storing and accessing the results of these experiments. We have retroactively cataloged more ...

  3. Noninvasive Assessment of Tumor Cell Proliferation in Animal Models

    Directory of Open Access Journals (Sweden)

    Matthias Edinger

    1999-10-01

    Full Text Available Revealing the mechanisms of neoplastic disease and enhancing our ability to intervene in these processes requires an increased understanding of cellular and molecular changes as they occur in intact living animal models. We have begun to address these needs by developing a method of labeling tumor cells through constitutive expression of an optical reporter gene, noninvasively monitoring cellular proliferation in vivo using a sensitive photon detection system. A stable line of HeLa cells that expressed a modified firefly luciferase gene was generated, proliferation of these cells in irradiated severe combined immunodeficiency (SCID mice was monitored. Tumor cells were introduced into animals via subcutaneous, intraperitoneal and intravenous inoculation and whole body images, that revealed tumor location and growth kinetics, were obtained. The number of photons that were emitted from the labeled tumor cells and transmitted through murine tissues was sufficient to detect 1×103 cells in the peritoneal cavity, 1×104 cells at subcutaneous sites and 1×106 circulating cells immediately following injection. The kinetics of cell proliferation, as measured by photon emission, was exponential in the peritoneal cavity and at subcutaneous sites. Intravenous inoculation resulted in detectable colonies of tumor cells in animals receiving more than 1×103 cells. Our demonstrated ability to detect small numbers of tumor cells in living animals noninvasively suggests that therapies designed to treat minimal disease states, as occur early in the disease course and after elimination of the tumor mass, may be monitored using this approach. Moreover, it may be possible to monitor micrometastases and evaluate the molecular steps in the metastatic process. Spatiotemporal analyses of neoplasia will improve the predictability of animal models of human disease as study groups can be followed over time, this method will accelerate development of novel therapeutic

  4. Influence of the Tumor Microenvironment on Cancer Cells Metabolic Reprogramming

    Directory of Open Access Journals (Sweden)

    Victoire Gouirand

    2018-04-01

    Full Text Available As with castles, tumor cells are fortified by surrounding non-malignant cells, such as cancer-associated fibroblasts, immune cells, but also nerve fibers and extracellular matrix. In most cancers, this fortification creates a considerable solid pressure which limits oxygen and nutrient delivery to the tumor cells and causes a hypoxic and nutritional stress. Consequently, tumor cells have to adapt their metabolism to survive and proliferate in this harsh microenvironment. To satisfy their need in energy and biomass, tumor cells develop new capacities to benefit from metabolites of the microenvironment, either by their uptake through the macropinocytosis process or through metabolite transporters, or by a cross-talk with stromal cells and capture of extracellular vesicles that are released by the neighboring cells. However, the microenvironments of primary tumor and metastatic niches differ tremendously in their cellular/acellular components and available nutrients. Therefore, cancer cells must develop a metabolic flexibility conferring on them the ability to satisfy their biomass and energetic demands at both primary and metastasis sites. In this review, we propose a brief overview of how proliferating cancer cells take advantage of their surrounding microenvironment to satisfy their high metabolic demand at both primary and metastasis sites.

  5. In vivo imaging of tumor vascular endothelial cells

    Science.gov (United States)

    Zhao, Dawen; Stafford, Jason H.; Zhou, Heling; Thorpe, Philip E.

    2013-02-01

    Phosphatidylserine (PS), normally restricted to the inner leaflet of the plasma membrane, becomes exposed on the outer surface of viable (non-apoptotic) endothelial cells in tumor blood vessels, probably in response to oxidative stresses present in the tumor microenvironment. In the present study, we optically imaged exposed PS on tumor vasculature in vivo using PGN635, a novel human monoclonal antibody that targets PS. PGN635 F(ab')2 was labeled with the near infrared (NIR) dye, IRDye 800CW. Human glioma U87 cells or breast cancer MDA-MB-231 cells were implanted subcutaneously or orthotopically into nude mice. When the tumors reached ~5 mm in diameter, 800CW- PGN635 was injected via a tail vein and in vivo dynamic NIR imaging was performed. For U87 gliomas, NIR imaging allowed clear detection of tumors as early as 4 h later, which improved over time to give a maximal tumor/normal ratio (TNR = 2.9 +/- 0.5) 24 h later. Similar results were observed for orthotopic MDA-MB-231 breast tumors. Localization of 800CW-PGN635 to tumors was antigen specific since 800CW-Aurexis, a control probe of irrelevant specificity, did not localize to the tumors, and pre-administration of unlabeled PGN635 blocked the uptake of 800CW-PGN635. Fluorescence microscopy confirmed that 800CW-PGN635 was binding to PS-positive tumor vascular endothelium. Our studies suggest that tumor vasculature can be successfully imaged in vivo to provide sensitive tumor detection.

  6. Chimeric antigen receptor T-cell therapy for solid tumors

    Directory of Open Access Journals (Sweden)

    Kheng Newick

    2016-01-01

    Full Text Available Chimeric antigen receptor (CAR T cells are engineered constructs composed of synthetic receptors that direct T cells to surface antigens for subsequent elimination. Many CAR constructs are also manufactured with elements that augment T-cell persistence and activity. To date, CAR T cells have demonstrated tremendous success in eradicating hematological malignancies (e.g., CD19 CARs in leukemias. This success is not yet extrapolated to solid tumors, and the reasons for this are being actively investigated. Here in this mini-review, we discuss some of the key hurdles encountered by CAR T cells in the solid tumor microenvironment.

  7. EG-03EXPRESSION OF PRMT5 CORRELATES WITH MALIGNANT GRADE IN GLIOMAS AND PLAYS A PIVOTAL ROLE IN TUMOR GROWTH

    Science.gov (United States)

    Han, Xiaosi; Li, Rong; Zhang, Wenbin; Yang, Xiuhua; Fathallah-Shaykh, Hassan; Gillespie, Yancey; Nabors, Burt

    2014-01-01

    Protein arginine methyltransferase 5 (PRMT5) catalyzes the formation of ω-NG,N′G-symmetric dimethylarginine residues on histones as well as other proteins. The modification play an important role in cell differentiation and tumor cell growth. However, the role of PRMT5 in human glioma cells has not been characterized. In this study, we assessed protein expression profiles of PRMT5 in control brain, WHO grade II astrocytomas, anaplastic astrocytomas, and glioblastoma multiforme (GBM) by immunohistochemistry. PRMT5 was low in glial cells in control brain tissues and low grade astrocytomas. Its expression increased in parallel with malignant progression, and was highly expressed in GBM. Knockdown of PRMT5 by small hairpin RNA caused alterations of p-ERK1/2 and significantly repressed the clonogenic potential and viability of glioma cells. These findings indicate that PRMT5 is a marker of malignant progression in glioma tumors and plays a pivotal role in tumor growth.

  8. Androgen - secreting steroid cell tumor of the ovary

    Directory of Open Access Journals (Sweden)

    Paras Ratilal Udhreja

    2014-01-01

    Full Text Available Steroid cell tumors (SCTs, not otherwise specified of the ovary are rare subgroup of sex cord tumors, which account for less than 0.1% of all ovarian tumors and also that will present at any age. The majority of these tumors produce steroids with testosterone being the most common. A case of a 28-year-old woman who presented with symptoms of virilization is reported. Although SCTs are generally benign, there is a risk for malignant transformation. Surgery is the most important and hallmark treatment.

  9. Dutasteride and enzalutamide synergistically suppress prostate tumor cell proliferation

    NARCIS (Netherlands)

    Hamid, A.R.; Verhaegh, G.W.C.T.; Smit, F.P.; RIjt-van de Westerlo, C.; Armandari, I.; Brandt, A.; Sweep, F.C.; Sedelaar, J.P.M.; Schalken, J.A.

    2015-01-01

    PURPOSE: Dihydrotestosterone is the main active androgen in the prostate and it has a role in prostate cancer progression. After androgen deprivation therapy androgen receptor signaling is still active in tumor cells. Persistent intratumor steroidogenesis and androgen receptor changes are

  10. Quantitative Analysis of Signaling Networks across Differentially Embedded Tumors Highlights Interpatient Heterogeneity in Human Glioblastoma

    Science.gov (United States)

    2015-01-01

    Glioblastoma multiforme (GBM) is the most aggressive malignant primary brain tumor, with a dismal mean survival even with the current standard of care. Although in vitro cell systems can provide mechanistic insight into the regulatory networks governing GBM cell proliferation and migration, clinical samples provide a more physiologically relevant view of oncogenic signaling networks. However, clinical samples are not widely available and may be embedded for histopathologic analysis. With the goal of accurately identifying activated signaling networks in GBM tumor samples, we investigated the impact of embedding in optimal cutting temperature (OCT) compound followed by flash freezing in LN2 vs immediate flash freezing (iFF) in LN2 on protein expression and phosphorylation-mediated signaling networks. Quantitative proteomic and phosphoproteomic analysis of 8 pairs of tumor specimens revealed minimal impact of the different sample processing strategies and highlighted the large interpatient heterogeneity present in these tumors. Correlation analyses of the differentially processed tumor sections identified activated signaling networks present in selected tumors and revealed the differential expression of transcription, translation, and degradation associated proteins. This study demonstrates the capability of quantitative mass spectrometry for identification of in vivo oncogenic signaling networks from human tumor specimens that were either OCT-embedded or immediately flash-frozen. PMID:24927040

  11. Training stem cells for treatment of malignant brain tumors

    Institute of Scientific and Technical Information of China (English)

    Shengwen; Calvin; Li; Mustafa; H; Kabeer; Long; T; Vu; Vic; Keschrumrus; Hong; Zhen; Yin; Brent; A; Dethlefs; Jiang; F; Zhong; John; H; Weiss; William; G; Loudon

    2014-01-01

    The treatment of malignant brain tumors remains a challenge. Stem cell technology has been applied in the treatment of brain tumors largely because of the ability of some stem cells to infiltrate into regions within the brain where tumor cells migrate as shown in preclinical studies. However, not all of these efforts can translate in the effective treatment that improves the quality of life for pa-tients. Here, we perform a literature review to identify the problems in the field. Given the lack of efficacy of most stem cell-based agents used in the treatment of malignant brain tumors, we found that stem cell distribution(i.e., only a fraction of stem cells applied capable of targeting tumors) are among the limiting factors. We provide guidelines for potential improvements in stem cell distribution. Specifically, we use an engineered tissue graft platform that replicates the in vivo microenvironment, and provide our data to validate that this culture platform is viable for producing stem cells that have better stem cell distribution than with the Petri dish culture system.

  12. Anti-tumor therapy with macroencapsulated endostatin producer cells

    Directory of Open Access Journals (Sweden)

    Balduino Keli N

    2010-03-01

    Full Text Available Abstract Background Theracyte is a polytetrafluoroethylene membrane macroencapsulation system designed to induce neovascularization at the tissue interface, protecting the cells from host's immune rejection, thereby circumventing the problem of limited half-life and variation in circulating levels. Endostatin is a potent inhibitor of angiogenesis and tumor growth. Continuous delivery of endostatin improves the efficacy and potency of the antitumoral therapy. The purpose of this study was to determine whether recombinant fibroblasts expressing endostatin encapsulated in Theracyte immunoisolation devices can be used for delivery of this therapeutic protein for treatment of mice bearing B16F10 melanoma and Ehrlich tumors. Results Mice were inoculated subcutaneously with melanoma (B16F10 cells or Ehrlich tumor cells at the foot pads. Treatment began when tumor thickness had reached 0.5 mm, by subcutaneous implantation of 107 recombinant encapsulated or non-encapsulated endostatin producer cells. Similar melanoma growth inhibition was obtained for mice treated with encapsulated or non-encapsulated endostatin-expressing cells. The treatment of mice bearing melanoma tumor with encapsulated endostatin-expressing cells was decreased by 50.0%, whereas a decrease of 56.7% in tumor thickness was obtained for mice treated with non-encapsulated cells. Treatment of Ehrlich tumor-bearing mice with non-encapsulated endostatin-expressing cells reduced tumor thickness by 52.4%, whereas lower tumor growth inhibition was obtained for mice treated with encapsulated endostatin-expressing cells: 24.2%. Encapsulated endostatin-secreting fibroblasts failed to survive until the end of the treatment. However, endostatin release from the devices to the surrounding tissues was confirmed by immunostaining. Decrease in vascular structures, functional vessels and extension of the vascular area were observed in melanoma microenvironments. Conclusions This study indicates that

  13. SVD identifies transcript length distribution functions from DNA microarray data and reveals evolutionary forces globally affecting GBM metabolism.

    Directory of Open Access Journals (Sweden)

    Nicolas M Bertagnolli

    Full Text Available To search for evolutionary forces that might act upon transcript length, we use the singular value decomposition (SVD to identify the length distribution functions of sets and subsets of human and yeast transcripts from profiles of mRNA abundance levels across gel electrophoresis migration distances that were previously measured by DNA microarrays. We show that the SVD identifies the transcript length distribution functions as "asymmetric generalized coherent states" from the DNA microarray data and with no a-priori assumptions. Comparing subsets of human and yeast transcripts of the same gene ontology annotations, we find that in both disparate eukaryotes, transcripts involved in protein synthesis or mitochondrial metabolism are significantly shorter than typical, and in particular, significantly shorter than those involved in glucose metabolism. Comparing the subsets of human transcripts that are overexpressed in glioblastoma multiforme (GBM or normal brain tissue samples from The Cancer Genome Atlas, we find that GBM maintains normal brain overexpression of significantly short transcripts, enriched in transcripts that are involved in protein synthesis or mitochondrial metabolism, but suppresses normal overexpression of significantly longer transcripts, enriched in transcripts that are involved in glucose metabolism and brain activity. These global relations among transcript length, cellular metabolism and tumor development suggest a previously unrecognized physical mode for tumor and normal cells to differentially regulate metabolism in a transcript length-dependent manner. The identified distribution functions support a previous hypothesis from mathematical modeling of evolutionary forces that act upon transcript length in the manner of the restoring force of the harmonic oscillator.

  14. Localized tenosynovial giant cell tumor in both knee joints

    International Nuclear Information System (INIS)

    Kim, Hyun Su; Kwon, Jong Won; Ahn, Jin Hwan; Chang, Moon Jong; Cho, Eun Yoon

    2010-01-01

    Tenosynovial giant cell tumor, previously called pigmented villonodular synovitis (PVNS), is a rare benign neoplastic process that may involve the synovium of the joint. The disorder is usually monoarticular and only a few cases have been reported on polyarticular involvement. Herein, we present a case of localized intra-articular tenosynovial giant cell tumor in a 29-year-old man involving both knee joints with a description of the MR imaging and histological findings. (orig.)

  15. Ultrastructure and pathology of desmoplastic small round cell tumor

    International Nuclear Information System (INIS)

    Xu Bin; Wang Bo; Gu Junlian; Li Xin; Li Yang

    2010-01-01

    Objective: To observe the change of ultrastructure and pathology of desmoplastic small round cell tumor (DSRCT) and recognize the characteristics of DSRCT and improve the standard of diagnosis. Methods: One case of primary DSRCT in right leg was observed by light microscope, immunohistochemical method and electron microscope and analyzed with review of the literatures. Results: The size of tumor was 3.2 cm x 2.4 cm x 1.3 cm with gray-yellow on cross-section. Foci of hemorrhage and necrosis were noted. Under light microscope, the tumor was composed of sharply demarcated nests of small rounded or oval cells. The cellular aggregates were surrounded and separated by abundant fibrous connective tissue. The tumor cells were uniform in size and shape, and showed small to moderate amounts of pale cytoplasm with indistinct cell borders. The nuclei were round to oval, with clumped chromatin and marked hyperchromasia. Some cells had one or two indistinct nucleoli. Numerous mitotic figures and areas of necrosis were dentified. The immunohistochemical results showed that the tumor cells were strongly positive for CK, EMA and NSE. There was focal positive staining for desmin with a perinuclear dot-like pattern. However, the tumor cells were negative for CgA, Myogenin, Syn, LCA, SMA, S-100, NF, GFAP, HMB45, HHF-35, CD3, CD10, Actin, CD99, and CD20. Under electron microscope, the tumor cells showed paranuclear cytoplasmic intermediate filaments arranging in globular or whorl array. Conclusion: DSRCT occurs both in the abdomen and at other sites. The patients with DSRCT range widely in age. DSRCT has distinctive histopathologic and ultrastructural features. This tumor shows immunohistochemical feature of epithelial, mesenchymal as well as neural multidirectional differentiation. RT-PCR may be served as an important diagnostic adjunct for DSRAT. The prognosis of the patients with DSRCT is very poor. (authors)

  16. Colon cancer stem cells dictate tumor growth and resist cell death by production of interleukin-4

    NARCIS (Netherlands)

    Todaro, Matilde; Alea, Mileidys Perez; Di Stefano, Anna B.; Cammareri, Patrizia; Vermeulen, Louis; Iovino, Flora; Tripodo, Claudio; Russo, Antonio; Gulotta, Gaspare; Medema, Jan Paul; Stassi, Giorgio

    2007-01-01

    A novel paradigm in tumor biology suggests that cancer growth is driven by stem-like cells within a tumor. Here, we describe the identification and characterization of such cells from colon carcinomas using the stem cell marker CD133 that accounts around 2% of the cells in human colon cancer. The

  17. NK cell-released exosomes: Natural nanobullets against tumors.

    Science.gov (United States)

    Fais, Stefano

    2013-01-01

    We have recently reported that human natural killer (NK) cells release exosomes that express both NK-cell markers and cytotoxic molecules. Similar results were obtained with circulating exosomes from human healthy donors. Both NK-cell derived and circulating exosomes exerted a full functional activity and killed both tumor and activated immune cells. These findings indicate that NK-cell derived exosomes might constitute a new promising therapeutic tool.

  18. REST controls self-renewal and tumorigenic competence of human glioblastoma cells.

    Directory of Open Access Journals (Sweden)

    Luciano Conti

    Full Text Available The Repressor Element 1 Silencing Transcription factor (REST/NRSF is a master repressor of neuronal programs in non-neuronal lineages shown to function as a central regulator of developmental programs and stem cell physiology. Aberrant REST function has been associated with a number of pathological conditions. In cancer biology, REST has been shown to play a tumor suppressor activity in epithelial cancers but an oncogenic role in brain childhood malignancies such as neuroblastoma and medulloblastoma. Here we examined REST expression in human glioblastoma multiforme (GBM specimens and its role in GBM cells carrying self-renewal and tumorigenic competence. We found REST to be expressed in GBM specimens, its presence being particularly enriched in tumor cells in the perivascular compartment. Significantly, REST is highly expressed in self-renewing tumorigenic-competent GBM cells and its knock down strongly reduces their self-renewal in vitro and tumor-initiating capacity in vivo and affects levels of miR-124 and its downstream targets. These results indicate that REST contributes to GBM maintenance by affecting its self-renewing and tumorigenic cellular component and that, hence, a better understanding of these circuitries in these cells might lead to new exploitable therapeutic targets.

  19. BRE enhances in vivo growth of tumor cells

    International Nuclear Information System (INIS)

    Chan, Ben Chung-Lap; Li Qing; Chow, Stephanie Ka-Yee; Ching, Arthur Kar-Keung; Liew, Choong Tsek; Lim, Pak-Leong; Lee, Kenneth Ka-Ho; Chan, John Yeuk-Hon; Chui, Y.-L.

    2005-01-01

    Human BRE, a death receptor-associating intracellular protein, attenuates apoptotic response of human and mouse tumor cell lines to death receptor stimuli in vitro. In this report, we addressed whether the in vitro antiapoptotic effect of BRE could impact on tumor growth in vivo. We have shown that the mouse Lewis lung carcinoma D122 stable transfectants of human BRE expression vector developed into local tumor significantly faster than the stable transfectants of empty vector and parental D122, in both the syngeneic C57BL/6 host and nude mice. In vitro growth of the BRE stable transfectants was, however, not accelerated. No significant difference in metastasis between the transfectants and the parental D122 was detected. Thus, overexpression of BRE promotes local tumor growth but not metastasis. We conclude that the enhanced tumor growth is more likely due to the antiapoptotic activity of BRE than any direct effect of the protein on cell proliferation

  20. Frequency and distribution of Notch mutations in tumor cell lines

    International Nuclear Information System (INIS)

    Mutvei, Anders Peter; Fredlund, Erik; Lendahl, Urban

    2015-01-01

    Deregulated Notch signaling is linked to a variety of tumors and it is therefore important to learn more about the frequency and distribution of Notch mutations in a tumor context. In this report, we use data from the recently developed Cancer Cell Line Encyclopedia to assess the frequency and distribution of Notch mutations in a large panel of cancer cell lines in silico. Our results show that the mutation frequency of Notch receptor and ligand genes is at par with that for established oncogenes and higher than for a set of house-keeping genes. Mutations were found across all four Notch receptor genes, but with notable differences between protein domains, mutations were for example more prevalent in the regions encoding the LNR and PEST domains in the Notch intracellular domain. Furthermore, an in silico estimation of functional impact showed that deleterious mutations cluster to the ligand-binding and the intracellular domains of NOTCH1. For most cell line groups, the mutation frequency of Notch genes is higher than in associated primary tumors. Our results shed new light on the spectrum of Notch mutations after in vitro culturing of tumor cells. The higher mutation frequency in tumor cell lines indicates that Notch mutations are associated with a growth advantage in vitro, and thus may be considered to be driver mutations in a tumor cell line context. The online version of this article (doi:10.1186/s12885-015-1278-x) contains supplementary material, which is available to authorized users

  1. Efficacy of ONC201 in Desmoplastic Small Round Cell Tumor.

    Science.gov (United States)

    Hayes-Jordan, Andrea A; Ma, Xiao; Menegaz, Brian A; Lamhamedi-Cherradi, Salah-Eddine; Kingsley, Charles V; Benson, Jalen A; Camacho, Pamela E; Ludwig, Joseph A; Lockworth, Cynthia R; Garcia, Gloria E; Craig, Suzanne L

    2018-05-01

    Desmoplastic Small Round Cell Tumor (DSRCT) is a rare sarcoma tumor of adolescence and young adulthood, which harbors a recurrent chromosomal translocation between the Ewing's sarcoma gene (EWSR1) and the Wilms' tumor suppressor gene (WT1). Patients usually develop multiple abdominal tumors with liver and lymph node metastasis developing later. Survival is poor using a multimodal therapy that includes chemotherapy, radiation and surgical resection, new therapies are needed for better management of DSRCT. Triggering cell apoptosis is the scientific rationale of many cancer therapies. Here, we characterized for the first time the expression of pro-apoptotic receptors, tumor necrosis-related apoptosis-inducing ligand receptors (TRAILR1-4) within an established human DSRCT cell line and clinical samples. The molecular induction of TRAIL-mediated apoptosis using agonistic small molecule, ONC201 in vitro cell-based proliferation assay and in vivo novel orthotopic xenograft animal models of DSRCT, was able to inhibit cell proliferation that was associated with caspase activation, and tumor growth, indicating that a cell-based delivery of an apoptosis-inducing factor could be relevant therapeutic agent to control DSRCT. Copyright © 2018. Published by Elsevier Inc.

  2. Efficacy of ONC201 in Desmoplastic Small Round Cell Tumor

    Directory of Open Access Journals (Sweden)

    Andrea A. Hayes-Jordan

    2018-05-01

    Full Text Available Desmoplastic Small Round Cell Tumor (DSRCT is a rare sarcoma tumor of adolescence and young adulthood, which harbors a recurrent chromosomal translocation between the Ewing’s sarcoma gene (EWSR1 and the Wilms’ tumor suppressor gene (WT1. Patients usually develop multiple abdominal tumors with liver and lymph node metastasis developing later. Survival is poor using a multimodal therapy that includes chemotherapy, radiation and surgical resection, new therapies are needed for better management of DSRCT. Triggering cell apoptosis is the scientific rationale of many cancer therapies. Here, we characterized for the first time the expression of pro-apoptotic receptors, tumor necrosis-related apoptosis-inducing ligand receptors (TRAILR1-4 within an established human DSRCT cell line and clinical samples. The molecular induction of TRAIL-mediated apoptosis using agonistic small molecule, ONC201 in vitro cell-based proliferation assay and in vivo novel orthotopic xenograft animal models of DSRCT, was able to inhibit cell proliferation that was associated with caspase activation, and tumor growth, indicating that a cell-based delivery of an apoptosis-inducing factor could be relevant therapeutic agent to control DSRCT.

  3. The role of tumor cell-derived connective tissue growth factor (CTGF/CCN2) in pancreatic tumor growth.

    Science.gov (United States)

    Bennewith, Kevin L; Huang, Xin; Ham, Christine M; Graves, Edward E; Erler, Janine T; Kambham, Neeraja; Feazell, Jonathan; Yang, George P; Koong, Albert; Giaccia, Amato J

    2009-02-01

    Pancreatic cancer is highly aggressive and refractory to existing therapies. Connective tissue growth factor (CTGF/CCN2) is a fibrosis-related gene that is thought to play a role in pancreatic tumor progression. However, CCN2 can be expressed in a variety of cell types, and the contribution of CCN2 derived from either tumor cells or stromal cells as it affects the growth of pancreatic tumors is unknown. Using genetic inhibition of CCN2, we have discovered that CCN2 derived from tumor cells is a critical regulator of pancreatic tumor growth. Pancreatic tumor cells derived from CCN2 shRNA-expressing clones showed dramatically reduced growth in soft agar and when implanted s.c. We also observed a role for CCN2 in the growth of pancreatic tumors implanted orthotopically, with tumor volume measurements obtained by positron emission tomography imaging. Mechanistically, CCN2 protects cells from hypoxia-mediated apoptosis, providing an in vivo selection for tumor cells that express high levels of CCN2. We found that CCN2 expression and secretion was increased in hypoxic pancreatic tumor cells in vitro, and we observed colocalization of CCN2 and hypoxia in pancreatic tumor xenografts and clinical pancreatic adenocarcinomas. Furthermore, we found increased CCN2 staining in clinical pancreatic tumor tissue relative to stromal cells surrounding the tumor, supporting our assertion that tumor cell-derived CCN2 is important for pancreatic tumor growth. Taken together, these data improve our understanding of the mechanisms responsible for pancreatic tumor growth and progression, and also indicate that CCN2 produced by tumor cells represents a viable therapeutic target for the treatment of pancreatic cancer.

  4. Iatrogenic giant cell tumor at bone graft harvesting site

    Directory of Open Access Journals (Sweden)

    Zile S Kundu

    2013-01-01

    Full Text Available 30 year old female patient with giant cell tumor of the distal tibia initially treated at a peripheral nononcological center by curettage and autologous bone grafting from the ipsilateral iliac crest reported to us with local recurrence and an implantation giant cell tumor at the graft harvesting site which required extensive surgeries at both sites. The risk of iatrogenic direct implantation of tumor, often attributable to inadequate surgical planning or poor surgical techniques, and the steps to prevent such complication is reported here.

  5. Tumor-educated myeloid cells: impact the micro- and macroenvironment.

    Science.gov (United States)

    Becker, Jürgen C

    2014-03-01

    Immune escape mechanisms of cancers include some of the mechanisms normally used for immune homeostasis, particular those preventing autoimmunity; one of these is the polarisation of myeloid cells. Thereby, tumors, i.e. the cancerous and stromal cells, also condition distant sites like spleen and bone marrow via soluble factors and membrane vesicles such as exosomes in order to create a tumor-educated macroenvironment. Albeit these mechanisms are currently in the focus of (tumor-)immunologic research, the first evidence had been published almost 40 years ago. One of these early reports will be discussed here. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  6. Active targeting of tumor cells using light emitting bacteria

    International Nuclear Information System (INIS)

    Moon, Sung Min; Min, Jung Joon; Hong, Yeong Jin; Kim, Hyun Ju; Le, Uuenchi N.; Rhee, Joon Haeng; Song, Ho Chun; Heo, Young Jun; Bom, Hee Seung; Choy, Hyon E

    2004-01-01

    The presence of bacteria and viruses in human tumors has been recognized for more than 50 years. Today, with the discovery of bacterial strains that specifically target tumors, and aided by genomic sequencing and genetic engineering, there is new interest in the use of bacteria as tumor vectors. Here, we show that bacteria injected intravenously into live animals entered and replicated in solid tumors and metastases using the novel imaging technology of biophotonics. Bioluminescence operon (LuxCDABE) or fluorescence protein, GFP) has been cloned into pUC19 plasmid to engineer pUC19lux or pUC19gfp. Engineered plasmid was transformed into different kinds of wild type (MG1655) or mutant E. coli (DH5, ppGpp, fnr, purE, crpA, flagella, etc.) strains to construct light emitting bacteria. Xenograft tumor model has been established using CT26 colon cancer cell line. Light emitting bacteria was injected via tail vein into tumor bearing mouse. In vivo bioluminescence imaging has been done after 20 min to 14 days of bacterial injection. We observed localization of tumors by light-emitting E. coli in tumor (CT-26) bearing mice. We confirmed the presence of light-emitting bacteria under the fluorescence microscope with E. coli expressing GFP. Althoug varying mutants strain with deficient invading function has been found in tumor tissues, mutant strains of movement (flagella) couldn't show any light signal from the tumor tissue under the cooled CCD camera, indicating bacteria may actively target the tumor cells. Based on their 'tumor-finding' nature, bacteria may be designed to carry multiple genes or drugs for detection and treatment of cancer, such as prodrug-converting enzymes, toxins, angiogenesis inhibitors and cytokines

  7. Review of juxtaglomerular cell tumor with focus on pathobiological aspect

    Directory of Open Access Journals (Sweden)

    Pan Chin-Chen

    2011-08-01

    Full Text Available Abstract Juxtaglomerular cell tumor (JGCT generally affects adolescents and young adults. The patients experience symptoms related to hypertension and hypokalemia due to renin-secretion by the tumor. Grossly, the tumor is well circumscribed with fibrous capsule and the cut surface shows yellow or gray-tan color with frequent hemorrhage. Histologically, the tumor is composed of monotonous polygonal cells with entrapped normal tubules. Immunohistochemically, tumor cells exhibit a positive reactivity for renin, vimentin and CD34. Ultrastructurally, neoplastic cells contain rhomboid-shaped renin protogranules. Genetically, losses of chromosomes 9 and 11 were frequently observed. Clinically, the majority of tumors showed a benign course, but rare tumors with vascular invasion or metastasis were reported. JGCT is a curable cause of hypertensive disease if it is discovered early and surgically removed, but may cause a fatal outcome usually by a cerebrovascular attack or may cause fetal demise in pregnancy. Additionally, pathologists and urologists need to recognize that this neoplasm in most cases pursues a benign course, but aggressive forms may develop in some cases.

  8. Fermi GBM: Highlights from the First Year

    Science.gov (United States)

    Wilson-Hodge, Colleen A.

    2009-01-01

    The Fermi Gamma ray Burst Monitor is an all-sky instrument sensitive to photons from about 8 keV to 40 MeV. I will summarize highlights from the first year, including triggered observations of gamma ray bursts, soft gamma ray repeaters, and terrestrial gamma flashes, and observations in the continuous data of X-ray binaries and accreting X-ray pulsars. GBM provides complementary observations to Swift/BAT, observing many of the same sources, but over a wider energy range.

  9. A rare ovarian tumor, leydig stromal cell tumor, presenting with virilization: a case report

    Directory of Open Access Journals (Sweden)

    Soheila Aminimoghaddam

    2012-11-01

    Full Text Available  Abstract Leydig stromal cell tumor is a rare ovarian tumor that belongs to the group of sex-cord stromal tumors. They produce testosterone leading to hyperandrogenism. We present a 41yr old woman with symptoms of virilization and a mass of right adenex via ultra Sonography, and a rise of total and free serum testosterone. An ovarian source of androgen was suspected and a surgery performed. A diagnosis of leydig-stromal cell tumor was confirmed. Our report is a reminder that although idiopathic hirsutism and other benign androgen excess disorder like Polycystic Ovarian Syndrome (PCOs are common, ovarian mass should be considered in differential diagnosis. 

  10. Assessing the role of STAT3 in DC differentiation and autologous DC immunotherapy in mouse models of GBM.

    Directory of Open Access Journals (Sweden)

    Hikmat Assi

    Full Text Available Cellular microenvironments, particularly those found in tumors, elicit a tolerogenic DC phenotype which can attenuate immune responses. Central to this process is the STAT3-mediated signaling cascade. As a transcription factor and oncogene, STAT3 promotes the expression of genes which allow tumor cells to proliferate, migrate and evade apoptosis. More importantly, activation of STAT3 in tumor infiltrating immune cells has been shown to be responsible, in part, for their immune-suppressed phenotype. The ability of STAT3 to orchestrate a diverse set of immunosuppressive instructions has made it an attractive target for cancer vaccines. Using a conditional hematopoietic knockout mouse model of STAT3, we evaluated the impact of STAT3 gene ablation on the differentiation of dendritic cells from bone marrow precursors. We also assessed the impact of STAT3 deletion on phagocytosis, maturation, cytokine secretion and antigen presentation by GM-CSF derived DCs in vitro. In addition to in vitro studies, we compared the therapeutic efficacy of DC vaccination using STAT3 deficient DCs to wild type counterparts in an intracranial mouse model of GBM. Our results indicated the following pleiotropic functions of STAT3: hematopoietic cells which lacked STAT3 were unresponsive to Flt3L and failed to differentiate as DCs. In contrast, STAT3 was not required for GM-CSF induced DC differentiation as both wild type and STAT3 null bone marrow cells gave rise to similar number of DCs. STAT3 also appeared to regulate the response of GM-CSF derived DCs to CpG. STAT3 null DCs expressed high levels of MHC-II, secreted more IL-12p70, IL-10, and TNFα were better antigen presenters in vitro. Although STAT3 deficient DCs displayed an enhanced activated phenotype in culture, they elicited comparable therapeutic efficacy in vivo compared to their wild type counterparts when utilized in vaccination paradigms in mice bearing intracranial glioma tumors.

  11. Assessing the role of STAT3 in DC differentiation and autologous DC immunotherapy in mouse models of GBM.

    Science.gov (United States)

    Assi, Hikmat; Espinosa, Jaclyn; Suprise, Sarah; Sofroniew, Michael; Doherty, Robert; Zamler, Daniel; Lowenstein, Pedro R; Castro, Maria G

    2014-01-01

    Cellular microenvironments, particularly those found in tumors, elicit a tolerogenic DC phenotype which can attenuate immune responses. Central to this process is the STAT3-mediated signaling cascade. As a transcription factor and oncogene, STAT3 promotes the expression of genes which allow tumor cells to proliferate, migrate and evade apoptosis. More importantly, activation of STAT3 in tumor infiltrating immune cells has been shown to be responsible, in part, for their immune-suppressed phenotype. The ability of STAT3 to orchestrate a diverse set of immunosuppressive instructions has made it an attractive target for cancer vaccines. Using a conditional hematopoietic knockout mouse model of STAT3, we evaluated the impact of STAT3 gene ablation on the differentiation of dendritic cells from bone marrow precursors. We also assessed the impact of STAT3 deletion on phagocytosis, maturation, cytokine secretion and antigen presentation by GM-CSF derived DCs in vitro. In addition to in vitro studies, we compared the therapeutic efficacy of DC vaccination using STAT3 deficient DCs to wild type counterparts in an intracranial mouse model of GBM. Our results indicated the following pleiotropic functions of STAT3: hematopoietic cells which lacked STAT3 were unresponsive to Flt3L and failed to differentiate as DCs. In contrast, STAT3 was not required for GM-CSF induced DC differentiation as both wild type and STAT3 null bone marrow cells gave rise to similar number of DCs. STAT3 also appeared to regulate the response of GM-CSF derived DCs to CpG. STAT3 null DCs expressed high levels of MHC-II, secreted more IL-12p70, IL-10, and TNFα were better antigen presenters in vitro. Although STAT3 deficient DCs displayed an enhanced activated phenotype in culture, they elicited comparable therapeutic efficacy in vivo compared to their wild type counterparts when utilized in vaccination paradigms in mice bearing intracranial glioma tumors.

  12. Glycan Sulfation Modulates Dendritic Cell Biology and Tumor Growth

    Directory of Open Access Journals (Sweden)

    Roland El Ghazal

    2016-05-01

    Full Text Available In cancer, proteoglycans have been found to play roles in facilitating the actions of growth factors, and effecting matrix invasion and remodeling. However, little is known regarding the genetic and functional importance of glycan chains displayed by proteoglycans on dendritic cells (DCs in cancer immunity. In lung carcinoma, among other solid tumors, tumor-associated DCs play largely subversive/suppressive roles, promoting tumor growth and progression. Herein, we show that targeting of DC glycan sulfation through mutation in the heparan sulfate biosynthetic enzyme N-deacetylase/N-sulfotransferase-1 (Ndst1 in mice increased DC maturation and inhibited trafficking of DCs to draining lymph nodes. Lymphatic-driven DC migration and chemokine (CCL21-dependent activation of a major signaling pathway required for DC migration (as measured by phospho-Akt were sensitive to Ndst1 mutation in DCs. Lewis lung carcinoma tumors in mice deficient in Ndst1 were reduced in size. Purified CD11c+ cells from the tumors, which contain the tumor-infiltrating DC population, showed a similar phenotype in mutant cells. These features were replicated in mice deficient in syndecan-4, the major heparan sulfate proteoglycan expressed on the DC surface: Tumors were growth-impaired in syndecan-4–deficient mice and were characterized by increased infiltration by mature DCs. Tumors on the mutant background also showed greater infiltration by NK cells and NKT cells. These findings indicate the genetic importance of DC heparan sulfate proteoglycans in tumor growth and may guide therapeutic development of novel strategies to target syndecan-4 and heparan sulfate in cancer.

  13. HAMLET interacts with histones and chromatin in tumor cell nuclei.

    Science.gov (United States)

    Düringer, Caroline; Hamiche, Ali; Gustafsson, Lotta; Kimura, Hiroshi; Svanborg, Catharina

    2003-10-24

    HAMLET is a folding variant of human alpha-lactalbumin in an active complex with oleic acid. HAMLET selectively enters tumor cells, accumulates in their nuclei and induces apoptosis-like cell death. This study examined the interactions of HAMLET with nuclear constituents and identified histones as targets. HAMLET was found to bind histone H3 strongly and to lesser extent histones H4 and H2B. The specificity of these interactions was confirmed using BIAcore technology and chromatin assembly assays. In vivo in tumor cells, HAMLET co-localized with histones and perturbed the chromatin structure; HAMLET was found associated with chromatin in an insoluble nuclear fraction resistant to salt extraction. In vitro, HAMLET bound strongly to histones and impaired their deposition on DNA. We conclude that HAMLET interacts with histones and chromatin in tumor cell nuclei and propose that this interaction locks the cells into the death pathway by irreversibly disrupting chromatin organization.

  14. Cuprous oxide nanoparticles selectively induce apoptosis of tumor cells

    Science.gov (United States)

    Wang, Ye; Zi, Xiao-Yuan; Su, Juan; Zhang, Hong-Xia; Zhang, Xin-Rong; Zhu, Hai-Ying; Li, Jian-Xiu; Yin, Meng; Yang, Feng; Hu, Yi-Ping

    2012-01-01

    In the rapid development of nanoscience and nanotechnology, many researchers have discovered that metal oxide nanoparticles have very useful pharmacological effects. Cuprous oxide nanoparticles (CONPs) can selectively induce apoptosis and suppress the proliferation of tumor cells, showing great potential as a clinical cancer therapy. Treatment with CONPs caused a G1/G0 cell cycle arrest in tumor cells. Furthermore, CONPs enclosed in vesicles entered, or were taken up by mitochondria, which damaged their membranes, thereby inducing apoptosis. CONPs can also produce reactive oxygen species (ROS) and initiate lipid peroxidation of the liposomal membrane, thereby regulating many signaling pathways and influencing the vital movements of cells. Our results demonstrate that CONPs have selective cytotoxicity towards tumor cells, and indicate that CONPs might be a potential nanomedicine for cancer therapy. PMID:22679374

  15. Pre-Clinical Studies of Dendritic Cell-Tumor Cell Fusion Vaccines to Treat Breast Cancer

    National Research Council Canada - National Science Library

    Akporiaye, Emmanuel

    2002-01-01

    ...+ T-helper cells, CD8+ cytotoxic T lymphocytes (CTLs), NK and NKT cells (1,2). Because DC have the capacity to take up various types of molecules, the cells can be loaded with tumor-associated antigens (TAAs...

  16. Selective tumor cell targeting by the disaccharide moiety of bleomycin.

    Science.gov (United States)

    Yu, Zhiqiang; Schmaltz, Ryan M; Bozeman, Trevor C; Paul, Rakesh; Rishel, Michael J; Tsosie, Krystal S; Hecht, Sidney M

    2013-02-27

    In a recent study, the well-documented tumor targeting properties of the antitumor agent bleomycin (BLM) were studied in cell culture using microbubbles that had been derivatized with multiple copies of BLM. It was shown that BLM selectively targeted MCF-7 human breast carcinoma cells but not the "normal" breast cell line MCF-10A. Furthermore, it was found that the BLM analogue deglycobleomycin, which lacks the disaccharide moiety of BLM, did not target either cell line, indicating that the BLM disaccharide moiety is necessary for tumor selectivity. Not resolved in the earlier study were the issues of whether the BLM disaccharide moiety alone is sufficient for tumor cell targeting and the possible cellular uptake of the disaccharide. In the present study, we conjugated BLM, deglycoBLM, and BLM disaccharide to the cyanine dye Cy5**. It was found that the BLM and BLM disaccharide conjugates, but not the deglycoBLM conjugate, bound selectively to MCF-7 cells and were internalized. The same was also true for the prostate cancer cell line DU-145 (but not for normal PZ-HPV-7 prostate cells) and for the pancreatic cancer cell line BxPC-3 (but not for normal SVR A221a pancreas cells). The targeting efficiency of the disaccharide was only slightly less than that of BLM in MCF-7 and DU-145 cells and comparable to that of BLM in BxPC-3 cells. These results establish that the BLM disaccharide is both necessary and sufficient for tumor cell targeting, a finding with obvious implications for the design of novel tumor imaging and therapeutic agents.

  17. Immunotherapy with neuraminidase-treated tumor cells after radiotherapy

    International Nuclear Information System (INIS)

    Song, C.W.; Levitt, S.H.

    1975-01-01

    The effect of active immunotherapy with Vibrio cholerae neuraminidase-treated syngeneic tumor cells (VCN-cells) following radiotherapy has been studied with 3-methylcholanthrene-induced fibrosarcoma, M-79, transplanted to the thigh of C3H/HeJ mice. When the tumors reached 4 to 8 mm in diameter, various treatments were started. X-irradiation with 2000 rad in a single dose induced a complete regression of 24 out of 103 tumors (23.3 percent). The inoculation of 1 x 10 6 of VCN-cells to the tumor-bearing animals, every other day for a total of three doses, caused a complete regression of 6 out of 57 tumors (10.5 percent). Treatments of animals with the immunotherapy starting 1 day after X-irradiation of tumors with 2000 rad resulted in a complete regression of 22 out of 58 tumors (37.9 percent). The median survival time of animals that received combined radiotherapy and immunotherapy was longer than that observed after either treatment alone

  18. Antitumor Cell-Complex Vaccines Employing Genetically Modified Tumor Cells and Fibroblasts

    Directory of Open Access Journals (Sweden)

    Antonio Miguel

    2014-02-01

    Full Text Available The present study evaluates the immune response mediated by vaccination with cell complexes composed of irradiated B16 tumor cells and mouse fibroblasts genetically modified to produce GM-CSF. The animals were vaccinated with free B16 cells or cell complexes. We employed two gene plasmid constructions: one high producer (pMok and a low producer (p2F. Tumor transplant was performed by injection of B16 tumor cells. Plasma levels of total IgG and its subtypes were measured by ELISA. Tumor volumes were measured and survival curves were obtained. The study resulted in a cell complex vaccine able to stimulate the immune system to produce specific anti-tumor membrane proteins (TMP IgG. In the groups vaccinated with cells transfected with the low producer plasmid, IgG production was higher when we used free B16 cell rather than cell complexes. Nonspecific autoimmune response caused by cell complex was not greater than that induced by the tumor cells alone. Groups vaccinated with B16 transfected with low producer plasmid reached a tumor growth delay of 92% (p ≤ 0.01. When vaccinated with cell complex, the best group was that transfected with high producer plasmid, reaching a tumor growth inhibition of 56% (p ≤ 0.05. Significant survival (40% was only observed in the groups vaccinated with free transfected B16 cells.

  19. A Proposal to Localize Fermi GBM GRBs Through Coordinated Scanning of the GBM Error Circle via Optical Telescopes

    Science.gov (United States)

    Ukwatta, T. N.; Linnemann, J. T.; Tollefson, K.; Abeysekara, A. U.; Bhat, P. N.; Sonbas, E.; Gehrels, N.

    2011-01-01

    We investigate the feasibility of implementing a system that will coordinate ground-based optical telescopes to cover the Fermi GBM Error Circle (EC). The aim of the system is to localize GBM detected GRBs and facilitate multi-wavelength follow-up from space and ground. This system will optimize the observing locations in the GBM EC based on individual telescope location, Field of View (FoV) and sensitivity. The proposed system will coordinate GBM EC scanning by professional as well as amateur astronomers around the world. The results of a Monte Carlo simulation to investigate the feasibility of the project are presented.

  20. Metabolic changes in tumor cells and tumor-associated macrophages: A mutual relationship.

    Science.gov (United States)

    Netea-Maier, Romana T; Smit, Johannes W A; Netea, Mihai G

    2018-01-28

    In order to adapt to the reduced availability of nutrients and oxygen in the tumor microenvironment and the increased requirements of energy and building blocks necessary for maintaining their high proliferation rate, malignant cells undergo metabolic changes that result in an increased production of lactate, nitric oxide, reactive oxygen species, prostaglandins and other byproducts of arachidonic acid metabolism that influence both the composition of the inflammatory microenvironment and the function of the tumor-associated macrophages (TAMs). In response to cues present in the TME, among which products of altered tumor cell metabolism, TAMs are also required to reprogram their metabolism, with activation of glycolysis, fatty acid synthesis and altered nitrogen cycle metabolism. These changes result in functional reprogramming of TAMs which includes changes in the production of cytokines and angiogenetic factors, and contribute to the tumor progression and metastasis. Understanding the metabolic changes governing the intricate relationship between the tumor cells and the TAMs represents an essential step towards developing novel therapeutic approaches targeting the metabolic reprogramming of the immune cells to potentiate their tumoricidal potential and to circumvent therapy resistance. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  1. Diagnosis and classification of Goodpasture's disease (anti-GBM).

    Science.gov (United States)

    Hellmark, Thomas; Segelmark, Mårten

    2014-01-01

    Goodpasture's disease or anti-glomerular basement membrane disease (anti-GBM-disease) is included among immune complex small vessel vasculitides. The definition of anti-GBM disease is a vasculitis affecting glomerular capillaries, pulmonary capillaries, or both, with GBM deposition of anti-GBM autoantibodies. The disease is a prototype of autoimmune disease, where the patients develop autoantibodies that bind to the basement membranes and activate the classical pathway of the complement system, which start a neutrophil dependent inflammation. The diagnosis of anti-GBM disease relies on the detection of anti-GBM antibodies in conjunction with glomerulonephritis and/or alveolitis. Overt clinical symptoms are most prominent in the glomeruli where the inflammation usually results in a severe rapidly progressive glomerulonephritis. Despite modern treatment less than one third of the patients survive with a preserved kidney function after 6 months follow-up. Frequencies vary from 0.5 to 1 cases per million inhabitants per year and there is a strong genetic linkage to HLA-DRB1(∗)1501 and DRB1(∗)1502. Essentially, anti-GBM disease is now a preferred term for what was earlier called Goodpasture's syndrome or Goodpasture's disease; anti-GBM disease is now classified as small vessel vasculitis caused by in situ immune complex formation; the diagnosis relies on the detection of anti-GBM in tissues or circulation in conjunction with alveolar or glomerular disease; therapy is effective only when detected at an early stage, making a high degree of awareness necessary to find these rare cases; 20-35% have anti-GBM and MPO-ANCA simultaneously, which necessitates testing for anti-GBM whenever acute test for ANCA is ordered in patients with renal disease. Copyright © 2014 Elsevier Ltd. All rights reserved.

  2. Multicellular tumor spheroid interactions with bone cells and bone

    International Nuclear Information System (INIS)

    Wezeman, F.H.; Guzzino, K.M.; Waxler, B.

    1985-01-01

    In vitro coculture techniques were used to study HSDM1C1 murine fibrosarcoma multicellular tumor spheroid (HSDM1C1-MTS) interactions with mouse calvarial bone cells having osteoblastic characteristics and mouse bone explants. HSDM1C1-MTS attached to confluent bone cell monolayers and their attachment rate was quantified. HSDM1C1-MTS interaction with bone cells was further demonstrated by the release of 3 H-deoxyuridine from prelabeled bone cells during coculture with multicellular tumor spheroids. HSDM1C1-MTS-induced cytotoxicity was mimicked by the addition of 10(-5) M prostaglandin E2 (PGE2) to 3 H-deoxyuridine-labeled bone cells. The effects of low (10(-9) M) and high (10(-5) M) concentrations of PGE2 on bone cell proliferation were also studied. Higher concentrations of PGE2 inhibited bone cell proliferation. HSDM1C1-MTS resorbed living explants in the presence of indomethacin, suggesting that other tumor cell products may also participate in bone resorption. HSDM1C1-MTS caused direct bone resorption as measured by the significantly elevated release of 45 Ca from prelabeled, devitalized calvaria. However, the growth of a confluent bone cell layer on devitalized, 45 Ca-prelabeled calvaria resulted in a significant reduction in the amount of 45 Ca released subsequent to the seeding of HSDM1C1-MTS onto the explants. Bone cells at the bone surface may act as a barrier against invasion and tumor cell-mediated bone resorption. Violation of this cellular barrier is achieved, in part, by tumor cell products

  3. HAMLET binding to α-actinin facilitates tumor cell detachment.

    Science.gov (United States)

    Trulsson, Maria; Yu, Hao; Gisselsson, Lennart; Chao, Yinxia; Urbano, Alexander; Aits, Sonja; Mossberg, Ann-Kristin; Svanborg, Catharina

    2011-03-08

    Cell adhesion is tightly regulated by specific molecular interactions and detachment from the extracellular matrix modifies proliferation and survival. HAMLET (Human Alpha-lactalbumin Made LEthal to Tumor cells) is a protein-lipid complex with tumoricidal activity that also triggers tumor cell detachment in vitro and in vivo, suggesting that molecular interactions defining detachment are perturbed in cancer cells. To identify such interactions, cell membrane extracts were used in Far-western blots and HAMLET was shown to bind α-actinins; major F-actin cross-linking proteins and focal adhesion constituents. Synthetic peptide mapping revealed that HAMLET binds to the N-terminal actin-binding domain as well as the integrin-binding domain of α-actinin-4. By co-immunoprecipitation of extracts from HAMLET-treated cancer cells, an interaction with α-actinin-1 and -4 was observed. Inhibition of α-actinin-1 and α-actinin-4 expression by siRNA transfection increased detachment, while α-actinin-4-GFP over-expression significantly delayed rounding up and detachment of tumor cells in response to HAMLET. In response to HAMLET, adherent tumor cells rounded up and detached, suggesting a loss of the actin cytoskeletal organization. These changes were accompanied by a reduction in β1 integrin staining and a decrease in FAK and ERK1/2 phosphorylation, consistent with a disruption of integrin-dependent cell adhesion signaling. Detachment per se did not increase cell death during the 22 hour experimental period, regardless of α-actinin-4 and α-actinin-1 expression levels but adherent cells with low α-actinin levels showed increased death in response to HAMLET. The results suggest that the interaction between HAMLET and α-actinins promotes tumor cell detachment. As α-actinins also associate with signaling molecules, cytoplasmic domains of transmembrane receptors and ion channels, additional α-actinin-dependent mechanisms are discussed.

  4. Antiangiogenic Agent Might Upgrade tumor Cell Sensitivity to Ionizing Radiation

    International Nuclear Information System (INIS)

    Badr, N.M.S.A.

    2013-01-01

    The understanding of the fundamental role of angiogenesis and metastasis in cancer growth has led to tremendous interest in research regarding its regulatory mechanisms and clinical implications in the management of cancer. The present study was conducted to evaluate the influence of the angiogenic regulators modification on the tumor growth and the cell sensitivity to ionizing radiation targeting the improvement of cancer therapeutic protocols. Accordingly, the antiangiogenic activity of apigenin and selenium was tested in vitro via MTT assay. The action of Apigenin and or Selenium was examined in vivo by using a model of solid tumor carcinoma (EAC). The growth rate of solid tumor in all experimental groups was measured by Caliper. The irradiated mice were exposed to 6.5 Gy of gamma rays. Apigenin 50 mg/kg body weight and selenium 5 μg per mice were daily administrated for 14 consecutive days after tumor volume reached 1mm 3 . The angiogenic activators TNF-α (key cytokine) in spleen, serum MMP 2 and MMP 9, liver and tumor NO, the lipid peroxidation (LPx) and angiogenic inhibitor TIMP-1 in spleen as well as, antioxidant markers (CAT, SOD, GPX) in tumor and liver tissue and DNA fragmentation in splenocytes were estimated to monitor efficacy of Apigenin and selenium in cancer treatment strategy. All parameters were determined as a time course on days 16 and 22 after tumor volume reached 1mm 3 . The using of MTT assay on EAC cells shows inhibition in EAC cell proliferation after the incubation with apigenin and /or selenium. The administration of apigenin and /or selenium to mice bearing tumor and to irradiated mice bearing tumor reduce significantly the TNF-α expression, MMP 2,9 , NO , LPx level and increased the antioxidant enzymes (GPx , SOD and CAT) activities. The DNA fragmentation and the antiangiogenic factors TIMP-1 were significantly increased when compared with their values in mice bearing tumor or in irradiated mice bearing tumor. From the results

  5. Mitochondrial DNA mutations in human tumor cells

    OpenAIRE

    LI, HUI; HONG, ZE-HUI

    2012-01-01

    Mitochondria play significant roles in cellular energy metabolism, free radical generation and apoptosis. The dysfunction of mitochondria is correlated with the origin and progression of tumors; thus, mutations in the mitochondrial genome that affect mitochondrial function may be one of the causal factors of tumorigenesis. Although the role of mitochondrial DNA (mtDNA) mutations in carcinogenesis has been investigated extensively by various approaches, the conclusions remain controversial to ...

  6. The anti-tumor effect of the quinoline-3-carboxamide tasquinimod: blockade of recruitment of CD11b+ Ly6Chi cells to tumor tissue reduces tumor growth

    International Nuclear Information System (INIS)

    Deronic, Adnan; Leanderson, Tomas; Ivars, Fredrik

    2016-01-01

    Previous work has demonstrated immunomodulatory, anti-tumor, anti-metastatic and anti-angiogenic effects of the small molecule quinoline-3-carboxamide tasquinimod in pre-clinical cancer models. To better understand the anti-tumor effects of tasquinimod in transplantable tumor models, we have evaluated the impact of the compound both on recruitment of myeloid cells to tumor tissue and on tumor-induced myeloid cell expansion as these cells are known to promote tumor development. Mice bearing subcutaneous 4 T1 mammary carcinoma tumors were treated with tasquinimod in the drinking water. A BrdU-based flow cytometry assay was utilized to assess the impact of short-term tasquinimod treatment on myeloid cell recruitment to tumors. Additionally, long-term treatment was performed to study the anti-tumor effect of tasquinimod as well as its effects on splenic myeloid cells and their progenitors. Myeloid cell populations were also immune-depleted by in vivo antibody treatment. Short-term tasquinimod treatment did not influence the proliferation of splenic Ly6C hi and Ly6G hi cells, but instead reduced the influx of Ly6C hi cells to the tumor. Treatment with tasquinimod for various periods of time after tumor inoculation revealed that the anti-tumor effect of this compound mainly operated during the first few days of tumor growth. Similar to tasquinimod treatment, antibody-mediated depletion of Ly6C hi cells within that same time frame, caused reduced tumor growth, thereby confirming a significant role for these cells in tumor development. Additionally, long-term tasquinimod treatment reduced the splenomegaly and expansion of splenic myeloid cells during a later phase of tumor development. In this phase, tasquinimod normalized the tumor-induced alterations in myeloerythroid progenitor cells in the spleen but had only limited impact on the same populations in the bone marrow. Our results indicate that tasquinimod treatment reduces tumor growth by operating early after tumor

  7. Oriented collagen fibers direct tumor cell intravasation

    KAUST Repository

    Han, Weijing; Chen, Shaohua; Yuan, Wei; Fan, Qihui; Tian, Jianxiang; Wang, Xiaochen; Chen, Longqing; Zhang, Xixiang; Wei, Weili; Liu, Ruchuan; Qu, Junle; Jiao, Yang; Austin, Robert H.; Liu, Liyu

    2016-01-01

    that the local fiber alignment enhanced cell-ECM interactions. Specifically, metastatic MDA-MB-231 breast cancer cells followed the local fiber alignment direction during the intravasation into rigid Matrigel (∼10 mg/mL protein concentration).

  8. The pattern of distribution of laminin in neurogenic tumors, granular cell tumors, and nevi of the oral mucosa

    DEFF Research Database (Denmark)

    Reibel, J; Wewer, U; Albrechtsen, R

    1985-01-01

    . Accentuated staining was seen in Verocay bodies. In granular cell myoblastomas (GCM), small groups of tumor cells were encircled by laminin-positive material, whereas individual tumor cells were unstained. In nevi, diffusely spread nevus cells were surrounded by a rim of laminin, whereas when arranged...

  9. MRI of islet cell tumors of the pancreas

    International Nuclear Information System (INIS)

    Ohtomo, Kuni; Itai, Yuji; Yoshikawa, Koki; Kokubo, Taka; Yashiro, Naofumi; Iio, Masahiro; Atomi, Yu

    1986-01-01

    Magnetic resonance imaging (MRI) was performed in five patients with islet cell tumors of the pancreas, using 0.35 T and 1.5 T superconductive magnets. MRI identified tumors in 3 patients. The tumors seen in the 3 patients appeared as areas of higher signal intensity than the liver on spin-echo (SE) images with repetition time of 1,600 msec/echo time of 35 or 70 msec, and as areas of similar or lower intensity on SE 400/35 or 70 images. The tumor imaged by SE techniques with 1,600/35 msec, 400/35 msec, and 1,600/35 or 70 msec in one patient was manifested by prolongation of T1 and T2, as compared with the liver. Tumors in the remaining two patients, which were not detected on MRI, were 15 mm or smaller. MRI remains to be improved in the visualization of small lesions. (Namekawa, K.)

  10. Curcumin targets fibroblast–tumor cell interactions in oral squamous cell carcinoma

    International Nuclear Information System (INIS)

    Dudás, József; Fullár, Alexandra; Romani, Angela; Pritz, Christian; Kovalszky, Ilona; Hans Schartinger, Volker; Mathias Sprinzl, Georg; Riechelmann, Herbert

    2013-01-01

    Co-culture of periodontal ligament fibroblasts (PDLs) and SCC-25 oral squamous carcinoma cells (OSCC) results in conversion of PDLs into carcinoma-associated fibroblasts (CAFs) and induces epithelial-to mesenchymal transition (EMT) of OSCC tumor cells. We hypothesized that Curcumin targets this dynamic mutual interaction between CAFs and tumor cells. Normal and 2 μM Curcumin-treated co-culture were performed for 4 days, followed by analysis of tumor cell invasivity, mRNA/protein expression of EMT-markers and mediators, activity measure of matrix metalloproteinase 9 (MMP-9), and western blot analysis of signal transduction in tumor cells and fibroblasts. In Curcumin-treated co-culture, in tumor cells, the levels of nuclear factor κB (NFκBα) and early response kinase (ERK)—decreased, in fibroblasts, integrin αv protein synthesis decreased compared to corresponding cells in normal co-culture. The signal modulatory changes induced by Curcumin caused decreased release of EMT-mediators in CAFs and reversal of EMT in tumor cells, which was associated with decreased invasion. These data confirm the palliative potential of Curcumin in clinical application. - Graphical abstract: Co-culture of periodontal ligament fibroblasts (PDLs) and SCC-25 oral squamous carcinoma cells (OSCC) results in conversion of PDLs into carcinoma-associated fibroblasts (CAFs) and induces epithelial-to mesenchymal transition (EMT) of tumor cells. Curcumin targets this dynamic mutual interaction between CAFs and tumor cells by inhibiting the production of EMT mediators in CAFs and by modification of intracellular signaling in tumor cells. This causes less invasivity and reversal of EMT in tumor cells. Highlights: ► Curcumin targets tumor–fibroblast interaction in head and neck cancer. ► Curcumin suppresses mediators of epithelial–mesenchymal transition. ► Curcumin decreases the invasivity of tumor cells

  11. Curcumin targets fibroblast–tumor cell interactions in oral squamous cell carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Dudás, József, E-mail: jozsef.dudas@i-med.ac.at [Department of Otorhinolaryngology and Head and Neck Surgery, Medical University Innsbruck, Anichstrasse 35, A-6020 Innsbruck (Austria); Fullár, Alexandra, E-mail: fullarsz@gmail.com [Department of Otorhinolaryngology and Head and Neck Surgery, Medical University Innsbruck, Anichstrasse 35, A-6020 Innsbruck (Austria); 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllői út 26, 1085 Budapest (Hungary); Romani, Angela, E-mail: angela.romani@i-med.ac.at [Department of Otorhinolaryngology and Head and Neck Surgery, Medical University Innsbruck, Anichstrasse 35, A-6020 Innsbruck (Austria); Pritz, Christian, E-mail: christian.pritz@i-med.ac.at [Department of Otorhinolaryngology and Head and Neck Surgery, Medical University Innsbruck, Anichstrasse 35, A-6020 Innsbruck (Austria); Kovalszky, Ilona, E-mail: koval@korb1.sote.hu [1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllői út 26, 1085 Budapest (Hungary); Hans Schartinger, Volker, E-mail: volker.schartinger@i-med.ac.at [Department of Otorhinolaryngology and Head and Neck Surgery, Medical University Innsbruck, Anichstrasse 35, A-6020 Innsbruck (Austria); Mathias Sprinzl, Georg, E-mail: georg.sprinzl@i-med.ac.at [Department of Otorhinolaryngology and Head and Neck Surgery, Medical University Innsbruck, Anichstrasse 35, A-6020 Innsbruck (Austria); Riechelmann, Herbert, E-mail: herbert.riechelmann@i-med.ac.at [Department of Otorhinolaryngology and Head and Neck Surgery, Medical University Innsbruck, Anichstrasse 35, A-6020 Innsbruck (Austria)

    2013-04-01

    Co-culture of periodontal ligament fibroblasts (PDLs) and SCC-25 oral squamous carcinoma cells (OSCC) results in conversion of PDLs into carcinoma-associated fibroblasts (CAFs) and induces epithelial-to mesenchymal transition (EMT) of OSCC tumor cells. We hypothesized that Curcumin targets this dynamic mutual interaction between CAFs and tumor cells. Normal and 2 μM Curcumin-treated co-culture were performed for 4 days, followed by analysis of tumor cell invasivity, mRNA/protein expression of EMT-markers and mediators, activity measure of matrix metalloproteinase 9 (MMP-9), and western blot analysis of signal transduction in tumor cells and fibroblasts. In Curcumin-treated co-culture, in tumor cells, the levels of nuclear factor κB (NFκBα) and early response kinase (ERK)—decreased, in fibroblasts, integrin αv protein synthesis decreased compared to corresponding cells in normal co-culture. The signal modulatory changes induced by Curcumin caused decreased release of EMT-mediators in CAFs and reversal of EMT in tumor cells, which was associated with decreased invasion. These data confirm the palliative potential of Curcumin in clinical application. - Graphical abstract: Co-culture of periodontal ligament fibroblasts (PDLs) and SCC-25 oral squamous carcinoma cells (OSCC) results in conversion of PDLs into carcinoma-associated fibroblasts (CAFs) and induces epithelial-to mesenchymal transition (EMT) of tumor cells. Curcumin targets this dynamic mutual interaction between CAFs and tumor cells by inhibiting the production of EMT mediators in CAFs and by modification of intracellular signaling in tumor cells. This causes less invasivity and reversal of EMT in tumor cells. Highlights: ► Curcumin targets tumor–fibroblast interaction in head and neck cancer. ► Curcumin suppresses mediators of epithelial–mesenchymal transition. ► Curcumin decreases the invasivity of tumor cells.

  12. Molecular aspects of tumor cell migration and invasion

    Directory of Open Access Journals (Sweden)

    Giuseppina Bozzuto

    2010-03-01

    Full Text Available Cell migration and invasion are crucial steps in many physiological events. However, they are also implicated in the physiopathology of many diseases, such as cancer. To spread through the tissues, tumor cells use mechanisms that involve several molecular actors: adhesion receptor families, receptor tyrosine kinases, cytoskeleton proteins, adapter and signalling proteins interplay in a complex scenario. The balance of cellular signals for proliferation and survival responses also regulates migratory behaviours of tumor cells. To complicate the scene of crime drug resistance players can interfere thus worsening this delicate situation. The complete understanding of this molecular jungle is an impossible mission: some molecular aspects are reviewed in this paper.

  13. TU-AB-BRA-11: Evaluation of Fully Automatic Volumetric GBM Segmentation in the TCGA-GBM Dataset: Prognosis and Correlation with VASARI Features

    International Nuclear Information System (INIS)

    Rios Velazquez, E; Meier, R; Dunn, W; Gutman, D; Alexander, B; Wiest, R; Reyes, M; Bauer, S; Aerts, H

    2015-01-01

    Purpose: Reproducible definition and quantification of imaging biomarkers is essential. We evaluated a fully automatic MR-based segmentation method by comparing it to manually defined sub-volumes by experienced radiologists in the TCGA-GBM dataset, in terms of sub-volume prognosis and association with VASARI features. Methods: MRI sets of 67 GBM patients were downloaded from the Cancer Imaging archive. GBM sub-compartments were defined manually and automatically using the Brain Tumor Image Analysis (BraTumIA), including necrosis, edema, contrast enhancing and non-enhancing tumor. Spearman’s correlation was used to evaluate the agreement with VASARI features. Prognostic significance was assessed using the C-index. Results: Auto-segmented sub-volumes showed high agreement with manually delineated volumes (range (r): 0.65 – 0.91). Also showed higher correlation with VASARI features (auto r = 0.35, 0.60 and 0.59; manual r = 0.29, 0.50, 0.43, for contrast-enhancing, necrosis and edema, respectively). The contrast-enhancing volume and post-contrast abnormal volume showed the highest C-index (0.73 and 0.72), comparable to manually defined volumes (p = 0.22 and p = 0.07, respectively). The non-enhancing region defined by BraTumIA showed a significantly higher prognostic value (CI = 0.71) than the edema (CI = 0.60), both of which could not be distinguished by manual delineation. Conclusion: BraTumIA tumor sub-compartments showed higher correlation with VASARI data, and equivalent performance in terms of prognosis compared to manual sub-volumes. This method can enable more reproducible definition and quantification of imaging based biomarkers and has a large potential in high-throughput medical imaging research

  14. TU-AB-BRA-11: Evaluation of Fully Automatic Volumetric GBM Segmentation in the TCGA-GBM Dataset: Prognosis and Correlation with VASARI Features

    Energy Technology Data Exchange (ETDEWEB)

    Rios Velazquez, E [Dana-Farber Cancer Institute | Harvard Medical School, Boston, MA (United States); Meier, R [Institute for Surgical Technology and Biomechanics, Bern, NA (Switzerland); Dunn, W; Gutman, D [Emory University School of Medicine, Atlanta, GA (United States); Alexander, B [Dana- Farber Cancer Institute, Brigham and Womens Hospital, Harvard Medic, Boston, MA (United States); Wiest, R; Reyes, M [Institute for Surgical Technology and Biomechanics, University of Bern, Bern, NA (Switzerland); Bauer, S [Institute for Surgical Technology and Biomechanics, Support Center for Adva, Bern, NA (Switzerland); Aerts, H [Dana-Farber/Brigham Womens Cancer Center, Boston, MA (United States)

    2015-06-15

    Purpose: Reproducible definition and quantification of imaging biomarkers is essential. We evaluated a fully automatic MR-based segmentation method by comparing it to manually defined sub-volumes by experienced radiologists in the TCGA-GBM dataset, in terms of sub-volume prognosis and association with VASARI features. Methods: MRI sets of 67 GBM patients were downloaded from the Cancer Imaging archive. GBM sub-compartments were defined manually and automatically using the Brain Tumor Image Analysis (BraTumIA), including necrosis, edema, contrast enhancing and non-enhancing tumor. Spearman’s correlation was used to evaluate the agreement with VASARI features. Prognostic significance was assessed using the C-index. Results: Auto-segmented sub-volumes showed high agreement with manually delineated volumes (range (r): 0.65 – 0.91). Also showed higher correlation with VASARI features (auto r = 0.35, 0.60 and 0.59; manual r = 0.29, 0.50, 0.43, for contrast-enhancing, necrosis and edema, respectively). The contrast-enhancing volume and post-contrast abnormal volume showed the highest C-index (0.73 and 0.72), comparable to manually defined volumes (p = 0.22 and p = 0.07, respectively). The non-enhancing region defined by BraTumIA showed a significantly higher prognostic value (CI = 0.71) than the edema (CI = 0.60), both of which could not be distinguished by manual delineation. Conclusion: BraTumIA tumor sub-compartments showed higher correlation with VASARI data, and equivalent performance in terms of prognosis compared to manual sub-volumes. This method can enable more reproducible definition and quantification of imaging based biomarkers and has a large potential in high-throughput medical imaging research.

  15. MHC-I modulation due to changes in tumor cell metabolism regulates tumor sensitivity to CTL and NK cells

    Science.gov (United States)

    Catalán, Elena; Charni, Seyma; Jaime, Paula; Aguiló, Juan Ignacio; Enríquez, José Antonio; Naval, Javier; Pardo, Julián; Villalba, Martín; Anel, Alberto

    2015-01-01

    Tumor cells have a tendency to use glucose fermentation to obtain energy instead of mitochondrial oxidative phosphorylation (OXPHOS). We demonstrated that this phenotype correlated with loss of ERK5 expression and with reduced MHC class I expression. Consequently, tumor cells could evade cytotoxic T lymphocyte (CTL)-mediated immune surveillance, but also increase their sensitivity to natural killer (NK) cells. These outcomes were evaluated using two cellular models: leukemic EL4 cells and L929 transformed fibroblasts and their derived ρ° cell lines, which lack mitochondrial DNA. We have also used a L929 cell sub-line that spontaneously lost matrix attachment (L929dt), reminiscent of metastasis generation, that also downregulated MHC-I and ERK5 expression. MHC-I expression is lower in ρ° cells than in the parental cell lines, but they were equally sensitive to CTL. On the contrary, ρ° cells were more sensitive to activated NK cells than parental cells. On the other hand, L929dt cells were resistant to CTL and NK cells, showed reduced viability when forced to perform OXPHOS, and surviving cells increased MHC-I expression and became sensitive to CTL. The present results suggest that when the reduction in MHC-I levels in tumor cells due to glycolytic metabolism is partial, the increase in sensitivity to NK cells seems to predominate. However, when tumor cells completely lose MHC-I expression, the combination of treatments that increase OXPHOS with CTL-mediated immunotherapy could be a promising therapeutic approach. PMID:25949869

  16. MHC-I modulation due to changes in tumor cell metabolism regulates tumor sensitivity to CTL and NK cells.

    Science.gov (United States)

    Catalán, Elena; Charni, Seyma; Jaime, Paula; Aguiló, Juan Ignacio; Enríquez, José Antonio; Naval, Javier; Pardo, Julián; Villalba, Martín; Anel, Alberto

    2015-01-01

    Tumor cells have a tendency to use glucose fermentation to obtain energy instead of mitochondrial oxidative phosphorylation (OXPHOS). We demonstrated that this phenotype correlated with loss of ERK5 expression and with reduced MHC class I expression. Consequently, tumor cells could evade cytotoxic T lymphocyte (CTL)-mediated immune surveillance, but also increase their sensitivity to natural killer (NK) cells. These outcomes were evaluated using two cellular models: leukemic EL4 cells and L929 transformed fibroblasts and their derived ρ° cell lines, which lack mitochondrial DNA. We have also used a L929 cell sub-line that spontaneously lost matrix attachment (L929dt), reminiscent of metastasis generation, that also downregulated MHC-I and ERK5 expression. MHC-I expression is lower in ρ° cells than in the parental cell lines, but they were equally sensitive to CTL. On the contrary, ρ° cells were more sensitive to activated NK cells than parental cells. On the other hand, L929dt cells were resistant to CTL and NK cells, showed reduced viability when forced to perform OXPHOS, and surviving cells increased MHC-I expression and became sensitive to CTL. The present results suggest that when the reduction in MHC-I levels in tumor cells due to glycolytic metabolism is partial, the increase in sensitivity to NK cells seems to predominate. However, when tumor cells completely lose MHC-I expression, the combination of treatments that increase OXPHOS with CTL-mediated immunotherapy could be a promising therapeutic approach.

  17. Testicular germ cell tumors: Molecular genetic and clinicomorphological aspects

    Directory of Open Access Journals (Sweden)

    M. V. Nemtsova

    2015-03-01

    Full Text Available Testicular tumors are the most common form of solid cancer in young men. According to the 2004 WHO classification, testicular germ cell tumors (TGCT may present with different histological types. Embryonic cells of varying grade may be a source of TGCT and the occurrence of this type of tumors is directly related to the formation of a pool of male sex cells and gametogenesis. The paper gives information on mo- lecular stages for the process of formation of male sex cells in health, as well as ways of their impairments leading to TGCT. An investigation of the profiles of gene expression and the spectrum of molecular damages revealed genes responsible for a predisposition to the sporadic and hereditary forms of TGCT. The paper presents the current molecular genetic and clinicomorphological characteristics of TGCT. 

  18. Wilms’ Tumor Blastemal Stem Cells Dedifferentiate to Propagate the Tumor Bulk

    Science.gov (United States)

    Shukrun, Rachel; Pode-Shakked, Naomi; Pleniceanu, Oren; Omer, Dorit; Vax, Einav; Peer, Eyal; Pri-Chen, Sara; Jacob, Jasmine; Hu, Qianghua; Harari-Steinberg, Orit; Huff, Vicki; Dekel, Benjamin

    2014-01-01

    Summary An open question remains in cancer stem cell (CSC) biology whether CSCs are by definition at the top of the differentiation hierarchy of the tumor. Wilms’ tumor (WT), composed of blastema and differentiated renal elements resembling the nephrogenic zone of the developing kidney, is a valuable model for studying this question because early kidney differentiation is well characterized. WT neural cell adhesion molecule 1-positive (NCAM1+) aldehyde dehydrogenase 1-positive (ALDH1+) CSCs have been recently isolated and shown to harbor early renal progenitor traits. Herein, by generating pure blastema WT xenografts, composed solely of cells expressing the renal developmental markers SIX2 and NCAM1, we surprisingly show that sorted ALDH1+ WT CSCs do not correspond to earliest renal stem cells. Rather, gene expression and proteomic comparative analyses disclose a cell type skewed more toward epithelial differentiation than the bulk of the blastema. Thus, WT CSCs are likely to dedifferentiate to propagate WT blastema. PMID:25068119

  19. Anti-EGFRvIII Chimeric Antigen Receptor-Modified T Cells for Adoptive Cell Therapy of Glioblastoma

    Science.gov (United States)

    Ren, Pei-pei; Li, Ming; Li, Tian-fang; Han, Shuang-yin

    2017-01-01

    Glioblastoma (GBM) is one of the most devastating brain tumors with poor prognosis and high mortality. Although radical surgical treatment with subsequent radiation and chemotherapy can improve the survival, the efficacy of such regimens is insufficient because the GBM cells can spread and destroy normal brain structures. Moreover, these non-specific treatments may damage adjacent healthy brain tissue. It is thus imperative to develop novel therapies to precisely target invasive tumor cells without damaging normal tissues. Immunotherapy is a promising approach due to its capability to suppress the growth of various tumors in preclinical model and clinical trials. Adoptive cell therapy (ACT) using T cells engineered with chimeric antigen receptor (CAR) targeting an ideal molecular marker in GBM, e.g. epidermal growth factor receptor type III (EGFRvIII) has demonstrated a satisfactory efficacy in treating malignant brain tumors. Here we summarize the recent progresses in immunotherapeutic strategy using CAR-modified T cells oriented to EGFRvIII against GBM. PMID:28302023

  20. Correlation of proliferative and clonogenic tumor cells in multiple myeloma

    International Nuclear Information System (INIS)

    Karp, J.E.; Burke, P.J.; Saylor, P.L.; Humphrey, R.L.

    1984-01-01

    To expand on the findings from previous clinical trials that the growth of residual tumor is increased at a predictable time following initial drug administration, malignant plasma cells from bone marrows of patients with multiple myeloma (MM) were examined for changes in proliferation and clonogenicity induced in vivo by cyclophosphamide and in vitro by drug-induced humoral stimulatory activity. Peak plasma cell [ 3 H]thymidine labeling index (LI) occurred predictably following drug and paralleled changes in agar colony formation by marrow cells obtained during therapy. Colony-forming capacity of pretreatment MM marrow populations was enhanced when those cells were cultured with humoral stimulatory activity, similar to the increased colony formation detected in Day 9 postcyclophosphamide marrows at the time of peak plasma cell LI. To further define a relationship between proliferative plasma cells and colony-forming tumor cells, MM marrows were fractionated by sedimentation on an isokinetic gradient. Enrichment of a proliferative tumor cell cohort was achieved, evidenced by [ 3 H]thymidine LI. Colony-forming cells were also enriched by isokinetic gradient sedimentation, and agar colony formation by MM marrow cell fractions correlated with the kinetic characteristics of the isolated subpopulations. These studies of whole and fractionated human MM marrow cell populations suggest that the kinetically active cells which are induced to proliferate in vivo and in vitro are closely related to the clonogenic tumor cells which produce colonies in agar and which, like those cells measured by [ 3 H]thymidine LI, respond to growth stimulation by drug-induced humoral stimulatory activity

  1. Clinical applications of circulating tumor DNA and circulating tumor cells in pancreatic cancer.

    Science.gov (United States)

    Riva, Francesca; Dronov, Oleksii I; Khomenko, Dmytro I; Huguet, Florence; Louvet, Christophe; Mariani, Pascale; Stern, Marc-Henri; Lantz, Olivier; Proudhon, Charlotte; Pierga, Jean-Yves; Bidard, Francois-Clement

    2016-03-01

    Pancreatic ductal adenocarcinoma (PDAC) is the most frequent pancreatic cancer type and is characterized by a dismal prognosis due to late diagnosis, local tumor invasion, frequent distant metastases and poor sensitivity to current therapy. In this context, circulating tumor cells and circulating tumor DNA constitute easily accessible blood-borne tumor biomarkers that may prove their clinical interest for screening, early diagnosis and metastatic risk assessment of PDAC. Moreover these markers represent a tool to assess PDAC mutational landscape. In this review, together with key biological findings, we summarize the clinical results obtained using "liquid biopsies" at the different stages of the disease, for early and metastatic diagnosis as well as monitoring during therapy. Copyright © 2016 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  2. Utility of MRI versus tumor markers for post-treatment surveillance of marker-positive CNS germ cell tumors.

    Science.gov (United States)

    Cheung, Victoria; Segal, Devorah; Gardner, Sharon L; Zagzag, David; Wisoff, Jeffrey H; Allen, Jeffrey C; Karajannis, Matthias A

    2016-09-01

    Patients with marker-positive central nervous system (CNS) germ cell tumors are typically monitored for tumor recurrence with both tumor markers (AFP and b-hCG) and MRI. We hypothesize that the recurrence of these tumors will always be accompanied by an elevation in tumor markers, and that surveillance MRI may not be necessary. We retrospectively identified 28 patients with CNS germ cell tumors treated at our institution that presented with an elevated serum or cerebrospinal fluid (CSF) tumor marker at the time of diagnosis. We then identified those who had a tumor recurrence after having been in remission and whether each recurrence was detected via MRI changes, elevated tumor markers, or both. Four patients suffered a tumor recurrence. Only one patient had simultaneously elevated tumor markers and MRI evidence of recurrence. Two patients had evidence of recurrence on MRI without corresponding elevations in serum or CSF tumor markers. One patient had abnormal tumor markers with no evidence of recurrence on MRI until 6 months later. We conclude that in patients with marker-positive CNS germ cell tumors who achieve complete remission, continued surveillance imaging in addition to measurement of tumor markers is indicated to detect recurrences.

  3. All-Sky Monitoring of Variable Sources with Fermi GBM

    Science.gov (United States)

    Wilson-Hodge, Colleen A.; Cherry, Michael L.; Case, Gary L.; Camero-Arranz, Ascension; Chaplin, Vandiver; Connaughton, Valerie; Finger, Mark H.; Jenke, Pater; Rodi, James C.; Baumgartner, Wayne H.; hide

    2011-01-01

    This slide presentation reviews the monitoring of variable sources with the Fermi Gamma Ray Burst Monitor (GBM). It reviews the use of the Earth Occultation technique, the observations of the Crab Nebula with the GBM, and the comparison with other satellite's observations. The instruments on board the four satellites indicate a decline in the Crab from 2008-2010.

  4. In search of druggable targets for GBM amino acid metabolism

    NARCIS (Netherlands)

    Panosyan, Eduard H.; Lin, Henry J.; Koster, Jan; Lasky, Joseph L.

    2017-01-01

    Background: Amino acid (AA) pathways may contain druggable targets for glioblastoma (GBM). Literature reviews and GBM database (http://r2.amc.nl) analyses were carried out to screen for such targets among 95 AA related enzymes. Methods: First, we identified the genes that were differentially

  5. Diffuse-type giant cell tumor of the subcutaneous thigh

    International Nuclear Information System (INIS)

    Sanghvi, D.A.; Purandare, N.C.; Jambhekar, N.A.; Agarwal, A.; Agarwal, M.G.

    2007-01-01

    Diffuse-type giant cell tumor is an extra-articular form of pigmented villonodular synovitis. The localized form of this lesion (tenosynovial giant cell tumor) is frequent, representing the most common subset arising from the synovium of a joint, bursa or tendon sheath, with 85% of cases occurring in the fingers. The less frequent diffuse-type giant cell tumors are commonly located in the periarticular soft tissues, but on rare occasions these lesions can be purely intramuscular or subcutaneous We report the case of a 26-year-old female with diffuse-type giant cell tumor of the subcutaneous thigh, remote from a joint, bursa or tendon sheath. A review of the literature did not reveal any similar description of a diffuse-type giant cell tumor completely within the subcutaneous thigh, remote from a joint, bursa or tendon sheath. These lesions were initially regarded as inflammatory or reactive processes, but since the identification of clonal abnormalities in these patients, and in view of their capacity for autonomous growth, they are now widely considered to represent benign neoplasms. (orig.)

  6. Treatment of giant cell tumor of bone: Current concepts

    OpenAIRE

    Puri Ajay; Agarwal Manish

    2007-01-01

    Giant cell tumor (GCT) of bone though one of the commonest bone tumors encountered by an orthopedic surgeon continues to intrigue treating surgeons. Usually benign, they are locally aggressive and may occasionally undergo malignant transformation. The surgeon needs to strike a balance during treatment between reducing the incidence of local recurrence while preserving maximal function. Differing opinions pertaining to the use of adjuvants for extension of curettage, the relative role of bone ...

  7. Giant cell tumor of the frontal sinus: case report

    Energy Technology Data Exchange (ETDEWEB)

    Matushita, Joao Paulo, E-mail: jpauloejulieta@gmail.com [Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG (Brazil). Hospital das Clinicas; Matushita, Julieta S.; Matushita Junior, Joao Paulo Kawaoka [Centro de Diagnostico por Imagem Dr. Matsushita, Belo Horizonte, MG (Brazil); Matushita, Cristina S. [Universidade Federal do Rio de Janeiro (UFRJ), RJ (Brazil). Hospital Universitario Clementino Fraga Filho; Simoes, Luiz Antonio Monteiro; Carvalho Neto, Lizando Franco de

    2013-06-15

    The authors report the case of a giant cell tumor of the frontal sinus in a 54-year-old male patient. This tumor location is rare, and this is the third case reported in the literature with radiographic documentation and histopathological confirmation. The patient underwent surgery, with curettage of frontal sinus and placement of a prosthesis. He died because a voluntary abrupt discontinuation of corticosteroids. (author)

  8. Gonadal vein tumor thrombosis due to renal cell carcinoma

    Directory of Open Access Journals (Sweden)

    Hamidreza Haghighatkhah

    2015-01-01

    Full Text Available Renal cell carcinoma (RCC had a tendency to extend into the renal vein and inferior vena cava, while extension into the gonadal vein has been rarely reported. Gonadal vein tumor thrombosis appears as an enhancing filling defect within the dilated gonadal vein anterior to the psoas muscle and shows an enhancement pattern identical to that of the original tumor. The possibility of gonadal vein thrombosis should be kept in mind when looking at an imaging study of patients with RCC

  9. Stereotactic radiotherapy for pediatric intracranial germ cell tumors

    International Nuclear Information System (INIS)

    Zissiadis, Yvonne; Dutton, Sharon; Kieran, Mark; Goumnerova, Liliana; Scott, R. Michael; Kooy, Hanne M.; Tarbell, Nancy J.

    2001-01-01

    Purpose: Intracranial germ cell tumors are rare, radiosensitive tumors seen most commonly in the second and third decades of life. Radiotherapy alone has been the primary treatment modality for germinomas, and is used with chemotherapy for nongerminomatous tumors. Stereotactic radiotherapy techniques minimize the volume of surrounding normal tissue irradiated and, hence, the late radiation morbidity. This study reports our experience with stereotactic radiotherapy in this group of tumors. Methods and Materials: Between December 1992 and December 1998, 18 patients with intracranial germ cell tumors were treated with stereotactic radiotherapy. A total of 23 histologically proven tumors were treated. Thirteen patients had a histologic diagnosis of germinoma, and 5 patients had germinoma with nongerminomatous elements. Of those patients with a histologic diagnosis of germinoma, 5 had multiple midline tumors. The median age of the patients was 12.9 years (range, 5.6-17.5 years). Results: A boost using stereotactic radiotherapy was delivered to 19 tumors following whole-brain radiation in 8 cases and craniospinal radiation in 11 cases. Three tumors were treated with stereotactic radiotherapy to the tumor volume alone following chemotherapy, and 1 tumor received a boost using stereotactic radiosurgery following craniospinal radiation. A median dose of 2520 cGy (range, 1500-3600) cGy was given to the whole brain, and a median dose of 2160 (range, 2100-2600) cGy was given to the spinal field. The median boost dose to the tumor was 2600 (range, 2160-3600) cGy, given by stereotactic radiotherapy delivered to the 95% isodose line. At a median follow-up time of 40 (range, 12-73) months, no local or marginal recurrences were reported in patients with germinoma. Two patients with nongerminomatous tumors have relapsed. One had elevation of tumor markers only at 37 months following treatment, and the other had persistent disease following chemotherapy and radiation therapy. Eight

  10. Functional differences between PD-1+ and PD-1- CD4+ effector T cells in healthy donors and patients with glioblastoma multiforme.

    Directory of Open Access Journals (Sweden)

    Brittany A Goods

    Full Text Available Immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1 have been highly successful in the treatment of cancer. While PD-1 expression has been widely investigated, its role in CD4+ effector T cells in the setting of health and cancer remains unclear, particularly in the setting of glioblastoma multiforme (GBM, the most aggressive and common form of brain cancer. We examined the functional and molecular features of PD-1+CD4+CD25-CD127+Foxp3-effector cells in healthy subjects and in patients with GBM. In healthy subjects, we found that PD-1+CD4+ effector cells are dysfunctional: they do not proliferate but can secrete large quantities of IFNγ. Strikingly, blocking antibodies against PD-1 did not rescue proliferation. RNA-sequencing revealed features of exhaustion in PD-1+ CD4 effectors. In the context of GBM, tumors were enriched in PD-1+ CD4+ effectors that were similarly dysfunctional and unable to proliferate. Furthermore, we found enrichment of PD-1+TIM-3+ CD4+ effectors in tumors, suggesting that co-blockade of PD-1 and TIM-3 in GBM may be therapeutically beneficial. RNA-sequencing of blood and tumors from GBM patients revealed distinct differences between CD4+ effectors from both compartments with enrichment in multiple gene sets from tumor infiltrating PD-1-CD4+ effectors cells. Enrichment of these gene sets in tumor suggests a more metabolically active cell state with signaling through other co-receptors. PD-1 expression on CD4 cells identifies a dysfunctional subset refractory to rescue with PD-1 blocking antibodies, suggesting that the influence of immune checkpoint inhibitors may involve recovery of function in the PD-1-CD4+ T cell compartment. Additionally, co-blockade of PD-1 and TIM-3 in GBM may be therapeutically beneficial.

  11. Blood vessel endothelium-directed tumor cell streaming in breast tumors requires the HGF/C-Met signaling pathway.

    Science.gov (United States)

    Leung, E; Xue, A; Wang, Y; Rougerie, P; Sharma, V P; Eddy, R; Cox, D; Condeelis, J

    2017-05-11

    During metastasis to distant sites, tumor cells migrate to blood vessels. In vivo, breast tumor cells utilize a specialized mode of migration known as streaming, where a linear assembly of tumor cells migrate directionally towards blood vessels on fibronectin-collagen I-containing extracellular matrix (ECM) fibers in response to chemotactic signals. We have successfully reconstructed tumor cell streaming in vitro by co-plating tumors cells, macrophages and endothelial cells on 2.5 μm thick ECM-coated micro-patterned substrates. We found that tumor cells and macrophages, when plated together on the micro-patterned substrates, do not demonstrate sustained directional migration in only one direction (sustained directionality) but show random bi-directional walking. Sustained directionality of tumor cells as seen in vivo was established in vitro when beads coated with human umbilical vein endothelial cells were placed at one end of the micro-patterned 'ECM fibers' within the assay. We demonstrated that these endothelial cells supply the hepatocyte growth factor (HGF) required for the chemotactic gradient responsible for sustained directionality. Using this in vitro reconstituted streaming system, we found that directional streaming is dependent on, and most effectively blocked, by inhibiting the HGF/C-Met signaling pathway between endothelial cells and tumor cells. Key observations made with the in vitro reconstituted system implicating C-Met signaling were confirmed in vivo in mammary tumors using the in vivo invasion assay and intravital multiphoton imaging of tumor cell streaming. These results establish HGF/C-Met as a central organizing signal in blood vessel-directed tumor cell migration in vivo and highlight a promising role for C-Met inhibitors in blocking tumor cell streaming and metastasis in vivo, and for use in human trials.

  12. Anti tumor vaccination with hybrid dendritic-tumour cells

    International Nuclear Information System (INIS)

    Barbuto, Jose Alexandre M.; Neves, Andreia R.; Ensina, Luis Felipe C.; Anselmo, Luciene B.

    2005-01-01

    Dendritic cells are the most potent antigen-presenting cells, and the possibility of their use for cancer vaccination has renewed the interest in this therapeutic modality. Nevertheless, the ideal immunization protocol with these cells has not been described yet. In this paper we describe the preliminary results of a protocol using autologous tumor and allogeneic dendritic hybrid cell vaccination every 6 weeks, for metastatic melanoma and renal cell carcinoma (RCC) patients. Thirty-five patients were enrolled between March 2001 and March 2003. Though all patients included presented with large tumor burdens and progressive diseases, 71% of them experienced stability after vaccination, with durations up to 19 months. Among RCC patients 3/22 (14%) presented objective responses. The median time to progression was 4 months for melanoma and 5.7 months for RCC patients; no significant untoward effects were noted. Furthermore, immune function, as evaluated by cutaneous delayed-type hypersensitivity reactions to recall antigens and by peripheral blood proliferative responses to tumor-specific and nonspecific stimuli, presented a clear tendency to recover in vaccinated patients. These data indicate that dendritic cell-tumor cell hybrid vaccination affects the natural history of advanced cancer and provide support for its study in less advanced patients, who should, more likely, benefit even more from this approach. (author)

  13. Origins and molecular biology of testicular germ cell tumors.

    Science.gov (United States)

    Reuter, Victor E

    2005-02-01

    Testicular germ cell tumors can be divided into three groups (infantile/prepubertal, adolescent/young adult and spermatocytic seminoma), each with its own constellation of clinical histology, molecular and clinical features. They originate from germ cells at different stages of development. The most common testicular cancers arise in postpubertal men and are characterized genetically by having one or more copies of an isochromosome of the short arm of chromosome 12 [i(12p)] or other forms of 12p amplification and by aneuploidy. The consistent gain of genetic material from chromosome 12 seen in these tumors suggests that it has a crucial role in their development. Intratubular germ cell neoplasia, unclassified type (IGCNU) is the precursor to these invasive tumors. Several factors have been associated with their pathogenesis, including cryptorchidism, elevated estrogens in utero and gonadal dysgenesis. Tumors arising in prepubertal gonads are either teratomas or yolk sac tumors, tend to be diploid and are not associated with i(12p) or with IGCNU. Spermatocytic seminoma (SS) arises in older patients. These benign tumors may be either diploid or aneuploid and have losses of chromosome 9 rather than i(12p). Intratubular SS is commonly encountered but IGCNU is not. The pathogenesis of prepubertal GCT and SS is poorly understood.

  14. Clinical results of BNCT for malignant brain tumors in children

    International Nuclear Information System (INIS)

    Nakagawa, Yoshinobu; Kageji, Teruyoshi; Mizobuchi, Yoshifumi; Kumada, Hiroaki; Nakagawa, Yoshiaki

    2009-01-01

    It is very difficult to treat the patients with malignant brain tumor in children, especially under 3 years, because the conventional irradiation cannot be applied due to the damage of normal brain tissue. However, boron neutron capture therapy (BNCT) has tumor selectivity such that it can make damage only in tumor cells. We evaluated the clinical results and courses in patients with malignant glioma under 15 years. Among 183 patients with brain tumors treated by our group using BSH-based intra-operative BNCT, 23 patients were under 15 years. They included 4 patients under 3 years. There were 3 glioblastomas (GBM), 6 anaplastic astrocytomas(AAS), 7 primitive neuroectodermal tumors (PNET), 6 pontine gliomas and 1 anaplastic ependymoma. All GBM and PNET patients died due to CSF and/or CNS dissemination without local tumor regrowth. All pontine glioma patients died due to regrowth of the tumor. Four of 6 anaplastic astrocytoma and 1 anaplastic ependymoma patients alive without tumor recurrence. BNCT can be applied to malignant brain tumors in children, especially under 3 years instead of conventional radiation. Although it can achieve the local control in the primary site, it cannot prevent CSF dissemination in patients with glioblastoma.

  15. Natural killer cells and interleukin-1: a possible role in natural killer-tumor cell interaction

    Energy Technology Data Exchange (ETDEWEB)

    Traub, L M

    1986-01-01

    Effector cells with broad cytolytic reactivity against various tumor cell lines have been detected in the peripheral blood of normal individuals. This phenomenon, known as natural killing, appeared to be significantly depressed in a small group of patients with extensive primary hepatocellular carcinoma. These data, together with that of others showing depressed interleukin-1 (IL-1) production in these patients, were taken to indicate that IL-1 played a functional role in natural killer (NK) cell biology. The hypothesis was confirmed by the demonstration that preincubation of tumor target cells with IL-1 enhanced their susceptibility to NK cell killing. In this study tumor target cells were labelled with /sup 51/Cr.

  16. NKT Cell Networks in the Regulation of Tumor Immunity

    Science.gov (United States)

    Robertson, Faith C.; Berzofsky, Jay A.; Terabe, Masaki

    2014-01-01

    CD1d-restricted natural killer T (NKT) cells lie at the interface between the innate and adaptive immune systems and are important mediators of immune responses and tumor immunosurveillance. These NKT cells uniquely recognize lipid antigens, and their rapid yet specific reactions influence both innate and adaptive immunity. In tumor immunity, two NKT subsets (type I and type II) have contrasting roles in which they not only cross-regulate one another, but also impact innate immune cell populations, including natural killer, dendritic, and myeloid lineage cells, as well as adaptive populations, especially CD8+ and CD4+ T cells. The extent to which NKT cells promote or suppress surrounding cells affects the host’s ability to prevent neoplasia and is consequently of great interest for therapeutic development. Data have shown the potential for therapeutic use of NKT cell agonists and synergy with immune response modifiers in both pre-clinical studies and preliminary clinical studies. However, there is room to improve treatment efficacy by further elucidating the biological mechanisms underlying NKT cell networks. Here, we discuss the progress made in understanding NKT cell networks, their consequent role in the regulation of tumor immunity, and the potential to exploit that knowledge in a clinical setting. PMID:25389427

  17. NKT cell networks in the regulation of tumor immunity.

    Science.gov (United States)

    Robertson, Faith C; Berzofsky, Jay A; Terabe, Masaki

    2014-01-01

    CD1d-restricted natural killer T (NKT) cells lie at the interface between the innate and adaptive immune systems and are important mediators of immune responses and tumor immunosurveillance. These NKT cells uniquely recognize lipid antigens, and their rapid yet specific reactions influence both innate and adaptive immunity. In tumor immunity, two NKT subsets (type I and type II) have contrasting roles in which they not only cross-regulate one another, but also impact innate immune cell populations, including natural killer, dendritic, and myeloid lineage cells, as well as adaptive populations, especially CD8(+) and CD4(+) T cells. The extent to which NKT cells promote or suppress surrounding cells affects the host's ability to prevent neoplasia and is consequently of great interest for therapeutic development. Data have shown the potential for therapeutic use of NKT cell agonists and synergy with immune response modifiers in both pre-clinical studies and preliminary clinical studies. However, there is room to improve treatment efficacy by further elucidating the biological mechanisms underlying NKT cell networks. Here, we discuss the progress made in understanding NKT cell networks, their consequent role in the regulation of tumor immunity, and the potential to exploit that knowledge in a clinical setting.

  18. NKT cell networks in the regulation of tumor immunity

    Directory of Open Access Journals (Sweden)

    Faith C Robertson

    2014-10-01

    Full Text Available CD1d-restricted natural killer T (NKT cells lie at the interface between the innate and adaptive immune systems and are important mediators of immune responses and tumor immunosurveillance. These NKT cells uniquely recognize lipid antigens, and their rapid yet specific reactions influence both innate and adaptive immunity. In tumor immunity, two NKT subsets (type I and type II have contrasting roles in which they not only cross-regulate one another, but also impact innate immune cell populations, including natural killer, dendritic and myeloid lineage cells, as well as adaptive populations, especially CD8+ and CD4+ T cells. The extent to which NKT cells promote or suppress surrounding cells affects the host’s ability to prevent neoplasia and is consequently of great interest for therapeutic development. Data have shown the potential for therapeutic use of NKT cell agonists and synergy with immune response modifiers in both pre-clinical studies and preliminary clinical studies. However, there is room to improve treatment efficacy by further elucidating the biological mechanisms underlying NKT cell networks. Here, we discuss the progress made in understanding NKT cell networks, their consequent role in the regulation of tumor immunity, and the potential to exploit that knowledge in a clinical setting.

  19. p53-Mediated Molecular Control of Autophagy in Tumor Cells

    Directory of Open Access Journals (Sweden)

    Maria Mrakovcic

    2018-03-01

    Full Text Available Autophagy is an indispensable mechanism of the eukaryotic cell, facilitating the removal and renewal of cellular components and thereby balancing the cell’s energy consumption and homeostasis. Deregulation of autophagy is now regarded as one of the characteristic key features contributing to the development of tumors. In recent years, the suppression of autophagy in combination with chemotherapeutic treatment has been approached as a novel therapy in cancer treatment. However, depending on the type of cancer and context, interference with the autophagic machinery can either promote or disrupt tumorigenesis. Therefore, disclosure of the major signaling pathways that regulate autophagy and control tumorigenesis is crucial. To date, several tumor suppressor proteins and oncogenes have emerged as eminent regulators of autophagy whose depletion or mutation favor tumor formation. The mammalian cell “janitor” p53 belongs to one of these tumor suppressors that are most commonly mutated in human tumors. Experimental evidence over the last decade convincingly reports that p53 can act as either an activator or an inhibitor of autophagy depending on its subcellular localization and its mode of action. This finding gains particular significance as p53 deficiency or mutant variants of p53 that accumulate in the cytoplasm of tumor cells enable activation of autophagy. Accordingly, we recently identified p53 as a molecular hub that regulates autophagy and apoptosis in histone deacetylase inhibitor-treated uterine sarcoma cells. In light of this novel experimental evidence, in this review, we focus on p53 signaling as a mediator of the autophagic pathway in tumor cells.

  20. Lysosomal cysteine peptidases - Molecules signaling tumor cell death and survival.

    Science.gov (United States)

    Pišlar, Anja; Perišić Nanut, Milica; Kos, Janko

    2015-12-01

    Lysosomal cysteine peptidases - cysteine cathepsins - are general intracellular protein-degrading enzymes that control also a variety of specific physiological processes. They can trigger irreversible events leading to signal transduction and activation of signaling pathways, resulting in cell survival and proliferation or cell death. In cancer cells, lysosomal cysteine peptidases are involved in multiple processes during malignant progression. Their translocation from the endosomal/lysosomal pathway to nucleus, cytoplasm, plasma membrane and extracellular space enables the activation and remodeling of a variety of tumor promoting proteins. Thus, lysosomal cysteine peptidases interfere with cytokine/chemokine signaling, regulate cell adhesion and migration and endocytosis, are involved in the antitumor immune response and apoptosis, and promote cell invasion, angiogenesis and metastasis. Further, lysosomal cysteine peptidases modify growth factors and receptors involved in tyrosine kinase dependent pathways such as MAPK, Akt and JNK, thus representing key signaling tools for the activation of tumor cell growth and proliferation. Copyright © 2015 Elsevier Ltd. All rights reserved.

  1. Neil Hayes, M.D., M.P.H., Explains TCGA Findings on GBM Subtypes - TCGA

    Science.gov (United States)

    New findings by researchers at UNC Lineberger Comprehensive Cancer Center suggest that the most common form of malignant brain cancer in adults, glioblastoma multiforme (GBM), is probably not a single disease but a set of diseases, each with a distinct underlying molecular disease process. The study was published by Cell Press in the January issue of the journal Cancer Cell and the researchers are part of the The Cancer Genome Atlas.

  2. Intercellular Communication of Tumor Cells and Immune Cells after Exposure to Different Ionizing Radiation Qualities

    OpenAIRE

    Diegeler, Sebastian; Hellweg, Christine E.

    2017-01-01

    Ionizing radiation can affect the immune system in many ways. Depending on the situation, the whole body or parts of the body can be acutely or chronically exposed to different radiation qualities. In tumor radiotherapy, a fractionated exposure of the tumor (and surrounding tissues) is applied to kill the tumor cells. Currently, mostly photons, and also electrons, neutrons, protons, and heavier particles such as carbon ions, are used in radiotherapy. Tumor elimination can be supported by an e...