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

Treatment of malignant gliomas has changed substantially over the last few years. An oral alkylating agent, temozolomide, has become the standard agent for glioma management. Although it is generally well tolerated, it can cause lymphopenia and may lead to opportunistic infections. We report on a patient with malignant glioma who developed opportunistic cytomegalovirus (CMV) pneumonia following the termination of temozolomide therapy. The patient was admitted with acute dyspnea, fever and hypoxia, and she was diagnosed with CMV pneumonitis using a PCR-based CMV-DNA analysis. After treatment with ganciclovir, she recovered dramatically. To our knowledge, although there have been reported cases of Pneumocystis carinii infection associated with temozolomide therapy, there has only been one other case of CMV infection. We also review this report.
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PMID:Opportunistic cytomegalovirus infection in a patient receiving temozolomide for treatment of malignant glioma. 2007 51

Proteasome inhibitor, which inhibits NF-kappaB activation, has been reported to activate c-Jun N-terminal kinase (JNK)-c-Jun pathway. In this study, we investigated the effects of proteasome inhibitor on the human cytomegalovirus (HCMV) major immediate early (MIE) gene expression in human central nervous system (CNS)-derived cell lines. Treatment of HCMV-infected 118MGC glioma and U373-MG astrocytoma cells with three proteasome inhibitors, MG132, clasto-lactacystin beta-lactone, and epoxomicin, suppressed MIE protein expression. In contrast, in HCMV-infected IMR-32 neuroblastoma cells, the proteasome inhibitors increased MIE protein expression, even in the presence of NF-kappaB inhibitor SN-50. A luciferase reporter assay demonstrated that MG132 markedly elevated the MIE promoter/enhancer (MIEP) activity in IMR-32 cells, but down-regulated it in 118MGC and U373-MG cells. Mutation in five cAMP response elements (CREs) within the MIEP resulted in a loss of the ability to respond to MG132 in IMR-32 cells. Moreover, Western blotting analysis revealed that MG132 induced c-Jun phosphorylation in all three CNS-derived cell lines, whereas a high level of activating transcription factor-2 (ATF-2) phosphorylation was observed only in IMR-32 cells. Finally, MG132-induced MIE protein expression was suppressed by JNK inhibitor that reduced the phosphorylation levels of both c-Jun and ATF-2. Taken together, these results suggest that the proteasome inhibitors activate CRE binding proteins consisting of c-Jun and ATF-2 through activating the JNK-c-Jun pathway, thereby inducing MIE protein synthesis in IMR-32 cells under the condition where NF-kappaB activity is inhibited.
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PMID:Proteasome inhibitor differentially regulates expression of the major immediate early genes of human cytomegalovirus in human central nervous system-derived cell lines. 1920 84

Human cytomegalovirus (HCMV) has tropism for glial cells, among many other cell types. It was reported previously that the stable expression of HCMV immediate-early protein 1 (IE1) could dramatically reduce the RNA level of glial fibrillary acidic protein (GFAP), an astroglial cell-specific intermediate filament protein, which is progressively lost with an increase in glioma malignancy. To understand this phenomenon in the context of virus infection, a human glioblastoma cell line, U373MG, was infected with HCMV (strain AD169 or Towne). The RNA level of GFAP was reduced by more than 10-fold at an m.o.i. of 3 at 48 h post-infection, whilst virus treated with neutralizing antibody C23 or with UV light had a much-reduced effect. Treatment of infected cells with ganciclovir did not prevent HCMV-mediated downregulation of GFAP. Although the expression of GFAP RNA is downregulated in IE1-expressing cells, a mutant HCMV strain lacking IE1 still suppressed GFAP, indicating that other IE proteins may be involved. IE2 is also proposed to be involved in GFAP downregulation, as an adenoviral vector expressing IE2 could also reduce the RNA level of GFAP. Data from the mutational analysis indicated that HCMV infection might affect the expression of this structural protein significantly, primarily through the C-terminal acidic region of the IE1 protein.
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PMID:Human cytomegalovirus infection downregulates the expression of glial fibrillary acidic protein in human glioblastoma U373MG cells: identification of viral genes and protein domains involved. 1926 42

Some investigators have postulated a viral cause of malignant glioma, possibly SV40 [Miller G. Brain cancer. A viral link to glioblastoma? Science 2009;323(5910):30-1] or cytomegalovirus (CMV). A source of other brain tumor viruses might be the anopheles mosquito, the vector of malaria. Evidence of an association of anopheles with brain tumors can be found in the relationship between malaria outbreaks in United States and reports of brain tumor incidence by state. There is a significant association between US malaria outbreaks in 2004 and the reports of brain tumor incidence 2000-2004 from 19 US states (p<0.001). Because increased numbers of both malaria cases and brain tumors could be due solely to the fact that some states, such as New York, have much larger populations than other states, such as North Dakota, multiple linear regression was performed with number of brain tumors as the dependent variable, malaria and population as independent variables. The effect of malaria was significant (p<0.001), and independent of the effect of population (p<0.001). Perhaps anopheles transmits an obscure virus that initially causes only a mild transitory illness but much later a brain tumor. If a mosquito-transmitted brain tumor virus could be identified, development of a brain tumor vaccine might be possible.
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PMID:Anopheles mosquito transmission of brain tumor. 1965 35

Adult stem cells may serve as powerful cellular vehicles to deliver therapeutic genes for cancer therapy. In such applications, effective and safe transduction to load stem cells with genes of interest is essential. To examine whether baculovirus can be used to fulfill this task, we tested a range of baculoviral vectors in human bone marrow mesenchymal stem cells (MSCs). A vector using the human cytomegalovirus immediate-early gene promoter to drive transgene expression and the woodchuck hepatitis virus posttranscriptional regulatory element to enhance translation was able to transduce MSCs with efficiency close to 80%. Following the observation that baculoviral transduction did not significantly affect surface marker expression of the stem cells, we tested the feasibility of using baculovirus-transduced MSCs for targeted cancer therapy. We transduced cells with a baculoviral vector harboring the herpes simplex virus thymidine kinase gene, and performed tail vein injection of the transduced cells into mice preinoculated subcutaneously with human U87 glioma cells. After ganciclovir prodrug injection, we observed inhibition of tumor growth and significantly prolonged survival of tumor-inoculated animals. Our findings suggest that baculoviral transduction of MSCs is an attractive option to generate targeting vehicles for systemic cancer therapy.
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PMID:Baculovirus-transduced bone marrow mesenchymal stem cells for systemic cancer therapy. 2053 21

Human cytomegalovirus (HCMV) is a beta-herpesvirus that causes persistent infection in humans and can cause severe disease in fetuses and immunocompromised individuals. Although HCMV is not currently causally implicated in human cancer, emerging evidence suggests that HCMV infection and expression may be specifically associated with human malignancies including malignant glioma, colon, and prostate cancer. In addition, multiple investigators have demonstrated that HCMV can dysregulate signaling pathways involved in initiation and promotion of malignancy, including tumor suppressor, mitogenic signaling, inflammatory, immune regulation, angiogenesis and invasion, and epigenetic mechanisms. This review highlights some of the recent evidence that HCMV might play a role in modulating the tumor microenvironment as well as in the initiation and promotion of tumor cells themselves.
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PMID:Is HCMV a tumor promoter? 2103 94

Few consistent etiological factors have been identified for primary brain tumors. Inverse associations to asthma and low levels of varicella-zoster virus, immunoglobulin (Ig) levels in prevalent cases have indicted a role for the immune system in the development of glioma. Because samples from prevalent cases of glioma could be influenced by treatments such as steroids and chemotherapy, we investigated pre-diagnostic samples from three large Scandinavian cohorts. To test the hypothesis that immune response levels to these viruses are associated etiologically with glioma risk, we investigated pre-diagnostic immunoglobulin levels for cytomegalovirus (CMV), varicella-zoster virus (VZV), adenovirus (Ad), and Epstein-Barr virus (EBV) including the nuclear antigen (EBNA1) using plasma samples from 197 cases of adult glioma and 394 controls collected from population-based cohorts in Sweden and Denmark. Low VZV IgG levels were marginally significantly more common in glioma cases than the controls (odds ratio (OR) = 0.68, 95% CI 0.41-1.13) for the fourth compared with the first quartile (p = 0.06 for trend). These results were more prominent when analyzing cases with blood sampling at least 2 years before diagnosis (OR = 0.63, 95% CI 0.37-1.08) (p = 0.03). No association with glioma risk was observed for CMV, EBV, and adenovirus.
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PMID:Human immunoglobulin G levels of viruses and associated glioma risk. 2171 96

Human cytomegalovirus (HCMV) infections are seen often in glioblastoma multiforme (GBM) tumors, but whether the virus contributes to GBM pathogenesis is unclear. In this study, we explored an oncogenic role for the G-protein-coupled receptor-like protein US28 encoded by HCMV that we found to be expressed widely in human GBMs. Immunohistochemical and reverse transcriptase PCR approaches established that US28 was expressed in approximately 60% of human GBM tissues and primary cultures examined. In either uninfected GBM cells or neural progenitor cells, thought to be the GBM precursor cells, HCMV infection or US28 overexpression was sufficient to promote secretion of biologically active VEGF and to activate multiple cellular kinases that promote glioma growth and invasion, including phosphorylated STAT3 (p-STAT3) and endothelial nitric oxide synthase (e-NOS). Consistent with these findings, US28 overexpression increased primary GBM cell invasion in Matrigel. Notably, this invasive phenotype was further enhanced by exposure to CCL5/RANTES, a US28 ligand, associated with poor patient outcome in GBM. Conversely, RNA interference-mediated knockdown of US28 in human glioma cells persistently infected with HCMV led to an inhibition in VEGF expression and glioma cell invasion in response to CCL5 stimulation. Analysis of clinical GBM specimens further revealed that US28 colocalized in situ with several markers of angiogenesis and inflammation, including VEGF, p-STAT3, COX2, and e-NOS. Taken together, our results indicate that US28 expression from HCMV contributes to GBM pathogenesis by inducing an invasive, angiogenic phenotype. In addition, these findings argue that US28-CCL5 paracrine signaling may contribute to glioma progression and suggest that targeting US28 may provide therapeutic benefits in GBM treatment.
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PMID:Human cytomegalovirus US28 found in glioblastoma promotes an invasive and angiogenic phenotype. 2190 Mar 96

Human cytomegalovirus (HCMV) was first reported to be strongly associated with human malignant gliomas in 2002. HCMV is a herpesvirus that causes congenital brain infection and multi-organ disease in immumocompromised individuals. Malignant gliomas are the most common and aggressive adult brain tumors and glioblastoma multiforme (GBM), the highest grade glioma, is associated with a life expectancy of less than two years. HCMV gene products encode for multiple proteins that can promote the various signaling pathways critical to tumor growth, including those involved in mitogenesis, mutagenesis, apoptosis, inflammation, angiogenesis, invasion and immuno-evasion. Several groups have now demonstrated that human malignant gliomas are universally infected with HCMV and express gene products that can promote key signaling pathways in glioma pathogenesis. In this review I discuss specific HCMV gene products that we and others have recently found to be expressed in GBM in vivo, including the HCMV IE1, US28, gB and IL-10 proteins. The roles these HCMV gene products play in dysregulating key pathways in glioma biology, including the PDGFR, AKT, STAT3, and monocyte/microglia function are discussed. Finally, I review emerging human clinical trials for GBM based on anti-HCMV strategies.
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PMID:Evolving evidence implicates cytomegalovirus as a promoter of malignant glioma pathogenesis. 2203 12

The human cytomegalovirus (HCMV) and glioma symposium was convened on April 17, 2011 in Washington, DC, and was attended by oncologists and virologists involved in studying the relationship between HCMV and gliomas. The purpose of the meeting was to reach a consensus on the role of HCMV in the pathology of gliomas and to clarify directions for future research. First, the group summarized data that describe how HCMV biology overlaps with the key pathways of cancer. Then, on the basis of published data and ongoing research, a consensus was reached that there is sufficient evidence to conclude that HCMV sequences and viral gene expression exist in most, if not all, malignant gliomas, that HCMV could modulate the malignant phenotype in glioblastomas by interacting with key signaling pathways; and that HCMV could serve as a novel target for a variety of therapeutic strategies. In summary, existing evidence supports an oncomodulatory role for HCMV in malignant gliomas, but future studies need to focus on determining the role of HCMV as a glioma-initiating event.
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PMID:Consensus on the role of human cytomegalovirus in glioblastoma. 2231 19


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