Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Migration and invasion are prerequisites for the neoplastic phenotype of malignant glioma. Ectopic expression of BCL-2 enhances migration and invasion of glioma cells and promotes their synthesis of transforming growth factor-beta2 (TGF-beta2). We here report that BCL-2-expressing cells show enhanced expression and activity of the proprotein convertase, furin, which processes metalloproteinases (MMP) and TGF-beta. Consistent with a biological role for a BCL-2-dependent increase in furin-like protease (FLP) activity, BCL-2-expressing cells exhibit enhanced MMP activity. Both a pseudosubstrate furin inhibitor, decanoyl-Arg-Val-Lys-Arg-chloromethylketone (dec-RVKR-cmk), or alpha 1-anti-trypsin Portland (PDX), a recombinant furin-inhibitory protein, suppress constitutive and BCL-2-mediated MMP activity and invasion. This inhibition is not overcome by TGF-beta or hepatocyte growth factor (HGF). A neutralizing TGF-beta antibody attenuates, but not abrogates, the invasive properties conferred by exogenous expression of BCL-2, whereas the MMP inhibitor o-phenantroline (o-PA) abolishes the pro-invasive action of BCL-2. Exogenous HGF results in enhanced, and expression of dominant-negative ezrin in reduced, FLP activity, and dec-RVKR-cmk blunts the HGF-induced expression of mature TGF-beta2. Consequently, HGF and BCL-2 family proteins use a furin-dependent pathway to promote invasion via TGF-beta and MMP in human malignant glioma cells and the pro-invasive properties of TGF-beta require furin- dependent MMP activity.
 ...
PMID:BCL-2-induced glioma cell invasiveness depends on furin-like proteases. 1558 4

The role that transforming growth factor beta1 (TGF-beta1) plays in influencing growth of glioma cells is somewhat controversial. To further understand the potential growth-regulatory effects of TGF-beta1,we constructed an animal astroglial tumor model by injecting either wild-type or virally transduced human U-87 glioblastoma cells into nude rat brains. Wild type U-87 cells produced very low amounts of TGF-beta1 and were highly tumorigenic. In contrast, U-87 cells transduced to express high levels of TGF-beta1 showed reduced tumor size in vivo, in a dose-dependent manner. This reduction in tumor size was not due to either decreased vascularity or increased apoptosis. To test whether TGF-beta1 overproduction inhibited tumor growth through an autocrine mechanism, the highest TGF-beta1 producing cells were then double transduced with a vector expressing the kinase-truncated type II TGF-beta receptor. Cells expressing high levels of truncated TGF-beta receptor were less sensitive to TGF-beta1 mediated growth inhibition in vitro and produced more aggressive tumors in vivo. The data suggest that the degree of tumorigenicity of the U-87 high-grade glioblastoma cell line may be associated with correspondingly low level of production of TGF-beta1. These results also would tend to support the possibility that TGF-beta1 may be useful in treating some high-grade gliomas.
 ...
PMID:Increased expression of TGF-beta1 reduces tumor growth of human U-87 Glioblastoma Cells in vivo. 1618 82

CD70 (CD27 ligand) promotes the expansion of primed lymphocytes by enhancing cell survival. Surprisingly, we previously observed that CD70 aberrantly expressed on human glioma cells promoted immune cell apoptosis and inhibited alloreactive lysis. Here we report that ectopic expression of CD70 in mouse glioma cells enhances apoptosis of T, B and NK cells in coculture, but nevertheless promotes glioma cell lysis by NK cells in vitro. In nude mice, CD70 expression in SMA-560 gliomas delays the glioma growth upon subcutaneous (s.c.) or intracerebral (i.c.) inoculation, suggesting a role for CD70/CD27-dependent NK cell activity in tumor surveillance. In syngeneic immunocompetent VM/Dk mice, CD70 allows the rejection of s.c. and i.c. implanted SMA-560 tumors. The tumorigenicity of CD70-expressing glioma cells is abrogated when TGF-beta signaling is blocked. Moreover, mice surviving the s.c. CD70 glioma challenge subsequently also reject wild-type glioma cells administered i.c. Similarly, CD70-expressing GL-261 gliomas are rejected in syngeneic C57BL/6 mice, while glioma growth is restored in C57BL/6 CD27(-/-) mice, suggesting that the CD70/CD27 interaction recruits a tumor-specific T-cell repertoire and induces tumor-specific memory. Altogether, these observations indicate that the net effect of aberrant CD70 expression in gliomas is immune stimulatory rather than immune paralytic and encourage its application in tumor immunotherapy.
 ...
PMID:Immune stimulatory effects of CD70 override CD70-mediated immune cell apoptosis in rodent glioma models and confer long-lasting antiglioma immunity in vivo. 1621 61

TGF-beta overexpression is a hallmark of various malignant tumors. This is due to the pivotal role of TGF-beta as it regulates key mechanisms of tumor development, namely immunosuppression, metastasis, angiogenesis, and proliferation. We have developed a new immunotherapeutic approach for the treatment of malignant tumors based on the specific inhibition of TGF-beta2 by the antisense oligodeoxynucleotide AP 12009. After providing preclinical proof of concept, we assessed safety and efficacy of AP 12009 in clinical phase I/II open-label dose escalation studies in high-grade glioma patients. Median survival time after recurrence exceeded the up to date literature data for chemotherapy. A phase I/II study in pancreatic carcinoma and malignant melanoma is currently ongoing. Our results implicate targeted TGF-beta2 suppression as a promising therapeutic approach for malignant tumor therapy.
 ...
PMID:Targeted tumor therapy with the TGF-beta 2 antisense compound AP 12009. 1637 33

The median survival of patients with glioblastoma treated by surgery, radiotherapy and chemotherapy is in the range of 12 months. These limits in the efficacy of current treatment modalities call for the development of novel therapeutic approaches targeting the specific biological features of this type of cancer. Glioblastomas are a rich source of immunosuppressive molecules which may interfere with immune recognition and rejection as well as clinical strategies of active immunotherapy. The most prominent glioblastoma-associated immunosuppressant is the cytokine, transforming growth factor (TGF)-beta, a multifunctional cytokine which not only interferes with multiple steps of afferent and efferent immune responses, but also stimulates migration, invasion and angiogenesis. The complex regulation of TGF-beta bioavailability includes its synthesis as a proprotein, proteolytic processing by furin-like proteases, assembly in a latent complex, and finally liberation from latency by multiple effector mechanisms, a process collectively referred to as activation. Several in vitro paradigms and rodent glioma models have been used to demonstrate that the antagonism of TGF-beta holds promise for the treatment of glioblastoma, employing antisense strategies, inhibition of pro-TGF-beta processing, scavenging TGF-beta by decorin, or blocking TGF-beta activity by specific TGF-beta receptor (TGF-betaR) I kinase antagonists. Moreover, the local application of TGF-beta(2) antisense oligonucleotides is currently evaluated in a randomized clinical trial for recurrent malignant glioma. In summary, we propose that TGF-beta-antagonistic treatment strategies are among the most promising of the current innovative approaches for glioblastoma, particularly in conjunction with novel approaches of cellular immunotherapy and vaccination.
 ...
PMID:Transforming growth factor-beta: a molecular target for the future therapy of glioblastoma. 1645 48

We performed a phase I clinical trial in grade IV astrocytoma to assess the safety of a whole-cell vaccine comprising autologous tumor cells genetically modified by a transforming growth factor-beta2 (TGF-beta2) antisense vector. Blocking secretion of the immunosuppressive molecule TGF-beta in this manner should inhibit one of the major mechanisms by which tumor cells evade immune surveillance and should lead to clinically effective antitumor immunity. Six patients with progressive WHO grade IV astrocytoma were enrolled in the trial. Patients received 2-7 subcutaneous injections of 5 x 10(6)-2 x 10(7) autologous tumor cells per injection. TGF-beta2 secretion by the tumor cells used to vaccinate patients was inhibited by 53-98%. Treatment was well tolerated with only low-grade, transient treatment-related toxicities reported. Two patients had partial regressions and two had stable disease following therapy. The overall median survival was 68 weeks. Median survival of the responding patients was 78 weeks, compared to a historic value of 47 weeks for glioma patients treated conventionally. There were indications of humoral and cellular immunity induced by the vaccine. These findings support further clinical evaluation of vaccines comprised of TGF-beta antisense-modified tumor cells.
 ...
PMID:Phase I clinical trial of a TGF-beta antisense-modified tumor cell vaccine in patients with advanced glioma. 1682 91

Radiotherapy is an important treatment for patients suffering from high-grade malignant gliomas. Non-targeted (bystander) effects may influence these cells' response to radiation and the investigation of these effects may therefore provide new insights into mechanisms of radiosensitivity and responses to radiotherapy as well as define new targets for therapeutic approaches. Normal primary human astrocytes (NHA) and T98G glioma cells were irradiated with helium ions using the Gray Cancer Institute microbeam facility targeting individual cells. Irradiated NHA and T98G glioma cells generated signals that induced gammaH2AX foci in neighbouring non-targeted bystander cells up to 48 h after irradiation. gammaH2AX bystander foci were also observed in co-cultures targeting either NHA or T98G cells and in medium transfer experiments. Dimethyl sulphoxide, Filipin and anti-transforming growth factor (TGF)-beta 1 could suppress gammaH2AX foci in bystander cells, confirming that reactive oxygen species (ROS) and membrane-mediated signals are involved in the bystander signalling pathways. Also, TGF-beta 1 induced gammaH2AX in an ROS-dependent manner similar to bystander foci. ROS and membrane signalling-dependent differences in bystander foci induction between T98G glioma cells and normal human astrocytes have been observed. Inhibition of ataxia telangiectasia mutated (ATM) protein and DNA-PK could not suppress the induction of bystander gammaH2AX foci whereas the mutation of ATM- and rad3-related (ATR) abrogated bystander foci induction. Furthermore, ATR-dependent bystander foci induction was restricted to S-phase cells. These observations may provide additional therapeutic targets for the exploitation of the bystander effect.
 ...
PMID:ATR-dependent radiation-induced gamma H2AX foci in bystander primary human astrocytes and glioma cells. 1690 3

Due to the dismal prognosis of malignant glioma with currently available therapies there is an urgent need for new treatments based on a better molecular understanding of gliomagenesis. Several concepts of molecular therapies for malignant glioma are currently being studied in preclinical and clinical settings, including small molecules targeting specific receptor-mediated signaling pathways and gene therapy. Many growth factors, growth factor receptors--usually receptor tyrosine kinases--and receptor-associated signaling pathways are critically involved in gliomagenesis. Numerous selective inhibitors, which specifically block such molecules, are currently evaluated for clinical applicability. Several gene therapy approaches have shown antitumor efficacy in experimental studies, and the first clinical trials for the treatment of malignant glioma were conducted in the 1990s. In clinical trials, retroviral herpes-simplex-thymidinkinase- (HSV-Tk-) gene therapy has been the pioneering and most commonly used approach. However, efficient gene delivery into the tumor cells still remains the crucial obstacle for successful clinical gene therapy. During the past few years a number of new gene transfer vectors based on adeno-, adeno-associated-, herpes- and lentiviruses as well as new carrier cell systems, including neural and endothelial progenitor cells, have been developed. In addition, antisense technologies have advanced in recent years and entered clinical testing utilizing intratumoral administration by convection-enhanced delivery, exemplified by ongoing clinical trials of intratumoral administration of antisense TGF-beta. This paper summarizes some of these recent developments in molecular therapies for malignant glioma, focusing on targeted therapies using selective small molecules and gene therapy concepts.
 ...
PMID:Molecular therapies for malignant glioma. 1694 67

Malignant gliomas are typically angiogenic and secrete high levels of VEGF. Hypoxia has been identified as an important regulator of VEGF. However, malignant gliomas express high levels of VEGF in both hypoxic perinecrotic and vital tumor areas. In this study, we examined intracellular signaling pathways involved in the secretion of VEGF in glioma cells under normoxic conditions. Human malignant glioma cell lines, T98G, U373MG, U87MG, and A172, and human fetal lung fibroblasts (HFL) were cultured both with and without IL-1beta under normoxic conditions. VEGF, IL-1, IL-6, and TNF-alpha were measured with ELISA. VEGF mRNA levels were estimated by RT-PCR. Inhibitors of COX-2, MAPK, and phosphatidyl inositol 3-kinase (PI3-K), and blocking antibodies to TGF-beta II and TNF-alpha, or IL-1 receptor antagonist, were used to examine their effects on VEGF secretion. Phosphorylation of MAPK was examined by immunoblotting. The basal levels of VEGF secretion were significantly higher in U87MG, U373MG, and T98G, than HFL. IL-1beta significantly stimulated VEGF secretion in these glioma cells. Inhibitors of p38 MAPK and/or JNK significantly suppressed VEGF secretion both in the presence and absence of IL-1beta, while inhibitors of COX-2, ERK1/2, and PI3-K did not. Constitutive phosphorylation of p38 MAPK and JNK was observed in these glioma cells. The levels of IL-1beta in U87MG were significantly higher than in other glioma cell lines, and IL-1 receptor antagonist suppressed basal secretion of VEGF from U87MG. In conclusion, p38 MAPK and JNK pathways play an important role in VEGF secretion from malignant glioma cells under normoxic conditions, possibly contributing to VEGF-induced angiogenesis in malignant gliomas at vital tumor areas where there is no hypoxia.
 ...
PMID:Activation of p38 MAPK and/or JNK contributes to increased levels of VEGF secretion in human malignant glioma cells. 1696 94

Due to its immunosuppressive properties, the cytokine transforming growth factor (TGF)-beta has become a promising target in the experimental treatment of human malignant gliomas. Here, we report that the antifibrotic drug 5-methyl-1-phenyl-2-(1H)-pyridone (pirfenidone, PFD) elicits growth-inhibitory effects and reduces TGF-beta2 protein levels in human glioma cell lines. This reduction in TGF-beta2 is biologically relevant since PFD treatment reduces the growth inhibition of TGF-beta-sensitive CCL-64 cells mediated by conditioned media of glioma cells. The downregulation of TGF-beta is mediated at multiple levels. PFD leads to a reduction of TGF-beta2 mRNA levels and of the mature TGF-beta2 protein due to decreased expression and direct inhibition of the TGF-beta pro-protein convertase furin. In addition, PFD reduces the protein levels of the matrix metalloproteinase (MMP)-11, a TGF-beta target gene and furin substrate involved in carcinogenesis. These data define PFD or PFD-related agents as promising agents for human cancers associated with enhanced TGF-beta activity.
 ...
PMID:Pirfenidone inhibits TGF-beta expression in malignant glioma cells. 1723 58


<< Previous 1 2 3 4 5 6 7 8 Next >>