UMLS:C0017636 - FACTA Search

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Query: UMLS:C0017636 (glioblastoma)
18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glioblastoma multiforme is the most common highly aggressive human brain cancer, and receptor tyrosine kinases have been implicated in the progression of this malignancy. We have recently identified anaplastic lymphoma kinase (ALK) as a tyrosine kinase receptor for pleiotrophin, a secreted growth factor that is highly expressed during embryonic brain development and in tumors of the central nervous system. Here we report on the contribution of pleiotrophin-ALK signaling to glioblastoma growth. We found ALK overexpressed in human glioblastoma relative to normal brain and detected ALK mRNA in glioblastoma cell lines. We reduced the endogenous ALK in glioblastoma cells by ribozyme targeting and demonstrated that this prevents pleiotrophin-stimulated phosphorylation of the anti-apoptotic protein Akt. Furthermore, this depletion of ALK reduced tumor growth of xenografts in athymic nude mice and prolonged survival of the animals because of increased apoptosis in the tumors. These findings directly implicate ALK signaling as a rate-limiting factor in the growth of glioblastoma multiforme and suggest potential utility of therapeutic targeting of ALK.
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PMID:Pleiotrophin signaling through anaplastic lymphoma kinase is rate-limiting for glioblastoma growth. 1180 60

It is well recognized that malignant gliomas escape an immune response by hiding behind the blood-brain barrier and by producing proteins that suppress systemic immunity. However, if gliomas can be made to be more immunogenic or if a tumor vaccine can be produced, then access to all tumor cells including those that infiltrate into the brain can be achieved through the patient's immune response. Several strategies have been investigated for immunotherapy. Laboratory studies and animal models have shown that these immune cells will attack the tumor cell, reduce the size of implanted tumors, and that the immune memory is sufficient to suppress tumor growth when the animal is rechallenges with a tumor implant. Since the development of hybridoma technology, monoclonal antibodies against human cancer cells have been produced and antigens have been identified. Hagiwara reported the production of a human monoclonal antibody, CLN-IgG, made by fusing UC 729-6, human lymphoblastoid B-cell line, with lymphocytes obtained from a patient with the cervical carcinoma. It has been reported that CLN-IgG recognized the antigen expressed in various histological types of human cancers including malignant gliomas. The effect of human monoclonal antibody(CLN-IgG) on malignant brain tumors was evaluated in patients with malignant glioma. Early phase II study was concluded that this specific immunotherapy with CLN-IgG is safe and effective therapy in patients with malignant glioma. We treated 10 cases of malignant gliomas with CLN-IgG. All patients had received radiotherapy and chemotherapy before this immunotherapy using the human monoclonal antibody. The human monoclonal antibody(CLN-IgG) was administered intravenously once or twice/week during 24 weeks. Six cases of glioblastoma, 1 medulloblastoma and 3 cases of potine glioma histologically unverified, were treated. Five cases of 6 glioblastomas died 4 to 12 months after this treatment, 3 cases of pontine glioma showed good responses, 2 cases showed marked decrease of tumor size and 1 case showed no regrowth of tumor on MRI imaging. For the above reasons, Human monoclonal antibody(CLN-IgG) might be useful as an immunotherapy of malignant gliomas.
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PMID:[Monoclonal immunotherapy with human monoclonal antibody(CLN-IgG) in glioma patients]. 1190 65

Unregulated expression of vascular endothelial growth factor-A (VEGF-A) plays an important role in tumor growth. We have identified a cell type-specific enhancer, HS-1100, that contributes to VEGF-A transcriptional activation in tumorigenic glioblastoma cell lines. This enhancer exhibits increased accessibility to DNase I in glioblastoma cell lines that express high levels of VEGF-A but not in several other cell lines that express much lower levels of VEGF-A. HS-1100 contains a number of sequence elements that are highly conserved among human, mouse, and rat, including the hypoxia-response element (HRE). We show that the HRE contributes significantly to the cell type-specific enhancer activity of HS-1100 in U87MG glioblastoma cells. We use chromatin immunoprecipitation assays to show that endothelial PAS domain protein 1 (EPAS1) can efficiently bind to the endogenous HRE in U87MG cells but not in HEK293 cells in which the chromosomal HS-1100 is not accessible to DNase I. A dominant negative EPAS1 significantly reduces HS-1100 enhancer activity and VEGF-A levels in U87MG cells. Our results provide insight into the molecular mechanisms of VEGF-A up-regulation during cancer development.
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PMID:Activation of vascular endothelial growth factor A transcription in tumorigenic glioblastoma cell lines by an enhancer with cell type-specific DNase I accessibility. 1191 13

To investigate the mechanisms of proteolysis within the glioma, and tissue reactions against glioblastoma, immunohistochemical detection both outside and inside of the tumor was performed using seven brains with glioblastoma that were obtained from autopsies. Immunohistochemistry was performed to detect vascular endothelial growth factor (VEGF), matrix metalloproteinases (MMP)-1,-2,-9, membrane-type matrix metalloproteinase (MT-MMP), interleukin (IL)1-beta, and IL-6. The data were translated into color graphics and the localization of these proteins was analyzed. In glial cells around the tumor, GFAP, VEGF, MMP-2, and MT-MMP were strongly expressed. Moreover, IL1-beta was also expressed strongly in the glial cells at the periphery of the tumor. IL-6 was recognized outside of the tumor, but was expressed only in the swollen astrocytes and normal pyramidal cells. These data suggest that in the periphery of the tumor, tissue reconstruction processes take place with concomitant degradation of the matrix by MMP-2 and MT-MMP, as well as vascular remodeling promoted by VEGF. The fact that IL1-beta, but not IL-6, was expressed strongly in the glial cells around the tumor, may indicate that these proteins expressed outside of the tumor are not utilized for tumor growth, but may be used to guard the tumor against invasions, such as immune response.
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PMID:Immunohistochemical analysis of reactive astrocytes around glioblastoma: an immunohistochemical study of postmortem glioblastoma cases. 1193 42

Presently, there is no effective treatment for glioblastoma, the most malignant and common brain tumor. Growth factors are potential targets for therapeutic strategies because they are essential for tumor growth and progression. Peptidylglycine alpha-amidating monooxygenase is the enzyme producing alpha-amidated bioactive peptides from their inactive glycine-extended precursors. The high expression of peptidylglycine alpha-amidating monooxygenase mRNA in glioblastoma and glioma cell lines points to the involvement of alpha-amidated peptides in tumorigenic growth processes in the brain. After screening of amidated peptides, it was found that human glioblastoma cell lines express high levels of adrenomedullin (AM) mRNA, and that immunoreactive AM is released into the culture medium. AM is a multifunctional regulatory peptide with mitogenic and angiogenic capabilities among others. Real-time quantitative reverse transcriptase-polymerase chain reaction analysis showed that AM mRNA was correlated to the tumor type and grade, with high expression in all glioblastomas analyzed, whereas a low expression was found in anaplastic astrocytomas and barely detectable levels in low-grade astrocytomas and oligodendrogliomas. In the present study we also demonstrate the presence of mRNA encoding the putative AM receptors, calcitonin receptor-like receptor/receptor activity-modifying protein-2 and -3 (CRLR/RAMP2; CRLR/RAMP3) in both glioma tissues and glioblastoma cell lines and further show that exogenously added AM can stimulate the growth of these glioblastoma cells in vitro. These findings suggest that AM may function as an autocrine growth factor for glioblastoma cells. One way to test the autocrine hypothesis is to interrupt the function of the endogenously produced AM. Herein, we demonstrate that a polyclonal antibody specific to AM, blocks the binding of the hormone to its cellular receptors and decreases by 33% (P < 0.001) the growth of U87 glioblastoma cells in vitro. Intratumoral administration of the anti-AM antibody resulted in a 70% (P < 0.001) reduction in subcutaneous U87 xenograft weight 21 days after treatment. Furthermore, the density of vessels was decreased in the antibody-treated tumors. These findings support that AM may function as a potent autocrine/paracrine growth factor for human glioblastomas and demonstrate that inhibition of the action of AM (produced by tumor cells) may suppress tumor growth in vivo.
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PMID:Neutralization of adrenomedullin inhibits the growth of human glioblastoma cell lines in vitro and suppresses tumor xenograft growth in vivo. 1194 13

Cancer chemotherapy targeted to angiogenic vessels is expected to cause indirect tumor regression through the damage of the neovasculature without the induction of drug resistance. To develop a tool for neovasculature-specific drug delivery, we isolated novel peptides homing to angiogenic vessels formed by a dorsal air sac method from a phage-displayed peptide library. Three distinct phage clones that markedly accumulated in murine tumor xenografts presented PRPGAPLAGSWPGTS-, DRWRPALPVVLFPLH- or ASSSYPLIHWRPWAR-peptide respectively. After the determination of the epitope sequences of these peptides, we modified liposomes with epitope penta-peptides. Liposome modified with APRPG-peptide showed high accumulation in murine tumor xenografts, and APRPG-modified liposome encapsulating adriamycin effectively suppressed experimental tumor growth. Finally, specific binding of APRPG-modified liposome to human umbilical endothelial cells, and that of PRP-containing peptide to angiogenic vessels in human tumors, i.e., islet cell tumor and glioblastoma, were demonstrated. The present study indicates the usefulness of APRPG-peptide as a tool for anti-neovascular therapy, a novel modality of cancer treatment.
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PMID:Anti-neovascular therapy using novel peptides homing to angiogenic vessels. 1196 39

Nude mice were challenged with human U-87 MG glioblastoma tumors to assess the efficacy of different cytostatics and different application protocols. While the intraperitoneal application of BCNU solutions (3 times 20 mg BCNU/kg) had no effect on tumor growth, the application of polymer matrices made of a physical mixture of poly(1,3-bis[carboxyphenoxpropane]-co-sebacic acid) 20:80 with poly(D,L-lactic-co-glycolic acid) loaded with 0.25 mg BCNU, slowed down the growth of tumors significantly. When the animals were treated with implants carrying 0.25 mg BCNU they responded to the treatment whether the tumor had been inoculated recently (9 days ago) or whether it was fully established (after 20 days). After its sensitivity was proven, the xenograft model was used to further investigate the efficacy of anticancer drugs and some treatment regimens using polymer implants. Thus the tumor model allowed to discriminate between the efficacy of different doses of BCNU. Only implants loaded with 0.75 or 1 mg of BCNU led to a substantial suppression of tumor growth over approximately 2 months. While BCNU was only able to suppress the growth of the tumor, the combination of BCNU with paclitaxel led to a complete remission in some animals. These preliminary results suggest that combinations of cytostatics might improve local chemotherapy of malignant glioma substantially. Based on our data it will be worthwhile to investigate implants that release drugs such as BCNU and paclitaxel closer. Amongst other factors we will try to elucidate the effect of repetitive doses of drugs using programmable implants.
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PMID:Efficacy of BCNU and paclitaxel loaded subcutaneous implants in the interstitial chemotherapy of U-87 MG human glioblastoma xenografts. 1199 15

Rats bearing a 5-day intracranial (i.c.) syngeneic glioma were treated with a subcutaneous (s.c.) vaccination consisting of irradiated glioma cells or a multimodality approach composed of radiotherapy plus s.c. vaccination. Vaccination of rats harboring a T9 glioma with 5 x 10(6) irradiated T9.F glioma cells (a clone derived from the T9 glioblastoma cell line) resulted in a marked enhancement of i.c. glioma growth and a significant decrease in survival. Histopathology of the tumors from vaccinated rats revealed a massive glioma composed of healthy tumor tissue lacking any marked inflammation, edema or hemorrhage. Analysis of the tumor-infiltrating mononuclear cells indicated that gliomas from vaccinated rats contained a 10-fold greater lymphoid infiltrate per milligram of tumor as compared to tumors from non-vaccinated rats, suggesting that the vaccination had induced immune cells to localize to the i.c. glioma. Combined treatment consisting of 15 Gy of whole head irradiation of the 5-day glioma followed by vaccination with T9.F cells resulted in a significant increase in survival compared to that of non-treated rats, 45% of which remained tumor-free. Microscopic evaluation in survivors of the tumor implantation site revealed the presence of hemosiderin-laden macrophages and other mononuclear cells, with the absence of tumor cells within the residual lesion. When survivors were challenged s.c. with viable T9.F glioma cells, a delayed-type hypersensitivity (DTH) reaction appeared at the challenge site. T cells purified from these rats proliferated and secreted Th(1)-associated cytokines when stimulated with irradiated T9.F glioma cells, and lysed T9.F target cells. In contrast, when these rats were challenged s.c. with the unrelated MadB106 adenocarcinoma, tumor formation was observed. These findings indicate that the treatment of an established i.c. glioma with a cellular vaccination alone may induce enhanced tumor growth; however, when the vaccination is combined with radiation therapy, the results are beneficial in terms of increased survival time or complete remission that is accompanied by the development of tumor-specific cellular immunity.
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PMID:Irradiated tumor cell vaccine for treatment of an established glioma. I. Successful treatment with combined radiotherapy and cellular vaccination. 1201 5

Overexpression of the MDM2 oncogene is one of the molecular characteristics of gliomas. In this study we determined the therapeutic effects of an antisense anti-MDM2 oligonucleotide administered alone or in combination with the clinically used chemotherapeutic agents Paclitaxel and Irinotecan. In cultured cells with various p53 status, U87-MG (p53wt/wt), A172 (p53wt/mt) and T98G (p53mt/mt), the antisense oligonucleotide, produced a dose- and sequence-dependent reduction in MDM2 expression and elevation in p53 (in U87-MG and A172 cells) and p21 levels (in all three cell lines), resulting in an increase in apoptosis and cytotoxicity. Synergistic effects on p53 and p21 levels between the oligonucleotide and chemotherapeutic agents were also observed in vitro. In in vivo studies with U87-MG xenografts, the oligonucleotide inhibited tumor growth and improved the therapeutic efficacy of paclitaxel and irinotecan 39- and 63-fold, respectively. In conclusion, inhibiting MDM2 expression could be a novel pharmacological approach to glioblastoma therapy.
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PMID:Antisense anti-MDM2 oligonucleotides as a novel approach to the treatment of glioblastoma multiforme. 1201 71

Glioblastoma multiforme, the most common form of malignant brain tumor,is resistant to all forms of therapy and causes death within 9-12 months of diagnosis. Glioblastomas are known to contain numerous genetic and physiological alterations affecting cell survival and proliferation; one of the most common alterations being platelet-derived growth factor (PDGF) autocrine signaling characterized by coexpression of PDGF and its receptor. The PDGF family consists of four members, PDGF-A, -B, -C, and -D, that signal through the alpha and beta PDGF receptor (PDGFR) tyrosine kinases. Numerous studies have demonstrated expression of PDGF-A, PDGF-B, and the PDGFRs in gliomablastomas, but such studies have not been conducted for the newly identified PDGF-C and -D. Therefore, we examined the expression of all PDGF ligands and receptors in 11 glioma cell lines and 5 primary glioblastoma tumor tissues by quantitative reverse transcription-PCR. Expression of PDGF/PDGFR pairs that are known to functionally interact were identified in all of the samples. Interestingly, PDGF-C expression was ubiquitous in brain tumor cells and tissues but was very low or absent in normal adult and fetal brain. PDGF-D was expressed in 10 of 11 brain tumor cell lines and 3 of 5 primary brain tumor samples. As a strategy for blocking PDGFR signaling, CT52923, a potent selective small molecule piperazinyl quinazoline kinase inhibitor of the PDGFR, was identified. In model systems using NIH/3T3 cells, CT52923 blocked PDGF autocrine-mediated phosphorylation of PDGFR, Akt, and mitogen-activated protein kinase (MAPK), while having no effect on v-fms or V12-ras-mediated Akt or extracellular signal-regulated protein kinase (Erk) phosphorylation. More importantly, p.o. administration of CT52923 to nude mice caused a significant 61% reduction (P < 0.006) in tumor growth of NIH/3T3 cells transformed by PDGF, whereas tumor formation by cells expressing v-fms was unaffected. We next characterized PDGF autocrine signaling in five glioblastoma cell lines. In all of the cases, PDGF autocrine signaling was evident because treatment with 1-10 microM CT52923 inhibited PDGFR autophosphorylation when present at a detectable level and blocked downstream Akt and/or Erk phosphorylation. The functional significance of PDGF autocrine signaling in these cells was demonstrated by the fact that the CT52923 inhibited soft agar colony formation, and, when given p.o. to nude mice, it effectively reduced tumor formation by 44% (P < 0.0019) after s.c. injection of C6 glioblastoma cells. This study of glioblastoma cells and primary tissues is the first to implicate PDGF-C and -D in brain tumor formation and confirms the existence of autocrine signaling by PDGF-A and -B. More importantly, treatment with the PDGFR antagonist CT52923 inhibited survival and/or mitogenic pathways in all of the glioblastoma cell lines tested and prevented glioma formation in a nude mouse xenograft model. Together these findings demonstrate the potential therapeutic utility of this class of compounds for the treatment of glioblastoma.
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PMID:Platelet-derived growth factor (PDGF) autocrine signaling regulates survival and mitogenic pathways in glioblastoma cells: evidence that the novel PDGF-C and PDGF-D ligands may play a role in the development of brain tumors. 1209 82

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