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)

Increased expression of focal adhesion kinase (FAK) was consistently observed in low- and high-grade astrocytomas and during glioblastoma progression after radiotherapy, but not in the more benign oligodendroglioma. In glioblastoma cell lines deficient for p53, p16(INK4A), and p14(ARF), FAK was inhibited in a dominant-negative manner by the focal adhesion targeting (FAT) domain, reducing invasion. In addition, caspase-3 activity was increased after serum withdrawal, or by cisplatin in the presence of serum, or upon loss of substrate attachment, and was in each case independent of PTEN status. Our results identify FAK as a potential target for anti-invasive strategies against infiltrating glioma cells.
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PMID:PTEN-independent induction of caspase-mediated cell death and reduced invasion by the focal adhesion targeting domain (FAT) in human astrocytic brain tumors which highly express focal adhesion kinase (FAK). 1147 98

Chromosome 10 deletions are among the most common genetic changes in highly malignant glial tumors. It has been noted that loss of heterozygosity (LOH) at 10q23 is a frequent alteration in a variety of human tumors and occurs in approximately 70% of all glioblastomas. By mapping of homozygous deletions on 10q23, a candidate tumor suppressor gene has been isolated, called PTEN for "phosphatase and tensin homolog deleted on chromosome 10" and MMAC1 for "mutated in multiple advanced cancers-1." Mutations of this tumor suppressor gene PTEN/MMAC1 have been reported in anaplastic glial tumors. The objective of this paper was to individuate a prognostic marker in exons 5, 6, 7, and 8 of the PTEN/MMAC1 gene for the high-grade malignant glioma with the most aggressive clinical behavior. In this study, we undertook sequence analysis of these exons in six selected patients with high-grade malignant gliomas who underwent radical aggressive tumor resection followed by radiotherapy within 3 weeks after surgery and subsequent chemotherapy. In them, the exon 5 sequence of the PTEN/MMAC1 gene is suggestive of a genetic survival marker in gliomas with high-grade malignancy.
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PMID:Is exon 5 of the PTEN/MMAC1 gene a prognostic marker in anaplastic glioma? 1148 47

Rare inherited syndromes that to some extent explain familial glioma include Turcot's syndrome, Li-Fraumeni syndrome and neurofibromatosis types I and II. The majority of families with glioma do not meet the clinical criteria for any of these syndromes. In order to study the genetic origin of familial glioma, tumour DNA (n = 35) or blood samples (n = 8) were collected from 25 families. The glioma tumours were tested for microsatellite instability (MSI) with two markers, BAT25 and BAT26, since glioma is associated with hereditary non-polyposis colon cancer (HNPCC) in Turcot's syndrome. Furthermore, p53 was screened from blood DNA (exons 2-11) with temporal temperature gradient electrophoresis (TTGE) since germline mutations in p53 are seen in Li-Fraumeni syndrome. In gliomas, there is a wide variety of somatic mutations, such as, for instance, in p53, the epidermal growth factor receptor (EGFR) and p16. The tumour suppressor gene PTEN is also often somatically mutated in glioma, therefore it is attractive as a candidate gene for germline mutations in familial glioma. Blood DNA was directly sequenced for mutations in PTEN exons 1-9. The analysis showed that no mutations were found in either of the studied tumour suppressor genes, and no MSI-positive tumours were found. A common polymorphism in p53 at codon 72 (arginine/proline) was found in 6/8 of the patients. Apparently, mutation in the tested tumour suppressor genes or DNA mismatch repair genes does not explain the familial glioma observed in these families.
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PMID:Microsatellite instability, PTEN and p53 germline mutations in glioma families. 1166 37

A putative tumor suppressor, the PTEN gene at chromosome 10q23. was identified and found to be mutated in many different human tumors. PTEN was recently found to be also involved in focal cell adhesion and cell migration. To identify the role of PTEN gene in malignant gliomas. we used PCR-SSCP and direct sequencing methods to examine 44 malignant gliomas comprising 29 cases without and 15 cases with meningeal gliomatosis. In malignant gliomas without meningeal gliomatosis, 2/29 (7%) of the cases showed alteration of the PTEN gene. In contrast, 5/15 (33%) of malignant gliomas with meningeal gliomatosis cases showed this alteration. These findings indicate that PTEN gene mutation contributes not only to the neoplastic evolution in gliomas but also to the meningeal dissemination of glioma cells.
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PMID:PTEN mutations in malignant gliomas and their relation with meningeal gliomatosis. 1167 26

Human gliomas are highly invasive, and remain to be a major obstacle for any effective therapeutic remedy. Among many other factors, gliomas express elevated levels of matrix metalloproteinases (MMPs), which have been implicated to play an important role in tumor invasion as well as neovascularization. The tumor suppressor gene mutated in multiple advanced cancers/phosphatase and tensin homologue (MMAC/PTEN) has been shown to inhibit cell migration, spreading, and focal adhesion. In this study, we determined whether MMAC/PTEN inhibits tumor invasion by modulating MMP-2 activity. Our results showed that reintroduction of the MMAC/PTEN gene into human glioma U251 and U87 cells modified their phenotype and growth characteristics. The ability of MMAC/PTEN to induce anoikis in U251 cells was accompanied by a significant inhibition of in vitro invasion (70%). Expression of MMAC/PTEN in U251 and U87 cells inhibited MMP-2 enzymatic activity as determined by zymography. Furthermore, MMAC/PTEN expression strongly decreased MMP-2 mRNA levels, which correlated well with the inhibition of invasion capacity in these cells. Concomitant with MMP-2 expression and activity, MMP-2 promoter activity was also reduced in MMAC/PTEN expressing cells. Our observations suggest that MMAC/PTEN inhibits tumor cell invasion in part by regulating MMP-2 gene transcription and thereby its enzymatic activity. Further characterization of this regulation will facilitate the development of MMAC/PTEN based gene therapy for gliomas.
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PMID:Suppression of matrix metalloproteinase-2 gene expression and invasion in human glioma cells by MMAC/PTEN. 1170 1

The regulation of integrin-mediated cell adhesion and its stabilization involves different phosphorylation and dephosphorylation events. Focal adhesion kinase (FAK) has been recently found to be a substrate of the dual-specific phosphatase PTEN in glioma cells, where it appears to be involved in regulation of cell spreading and migration as part of focal adhesions. We have investigated the role of PTEN in cell adhesion of HT-29 human colon carcinoma cells under static and hydrodynamic conditions of fluid flow. PTEN coprecipitated with FAK and paxillin dependent on the formation of adhesions to collagens. This corresponded with an adhesion-dependent increase in Tyr-phosphatase activity of PTEN. Using preparations of native FAK and PTEN from HT-29 cells in a specific Tyr-phosphatase assay FAK was identified as substrate for this dephosphorylation. If expression of PTEN was reduced using antisense oligonucleotides cell adhesion under dynamic conditions of laminar flow, but not under static conditions was significantly increased. In addition, cell spreading was increased in cells with reduced PTEN expression. We conclude that PTEN appears to be involved in the regulation of integrin-mediated adhesion through dephosphorylation of FAK. This phosphatase might play a role as a negative regulator for the formation of stable HT-29 cell adhesion to extracellular matrix.
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PMID:PTEN regulates tumor cell adhesion of colon carcinoma cells under dynamic conditions of fluid flow. 1185 88

The recognition of molecular subsets among glioblastomas has raised the question whether distinct mutations in glioblastoma-associated genes may serve as prognostic markers. The present study on glioblastomas (GBM) from 97 consecutively sampled adult patients is based on a clinical, histopathological, immunohistochemical, and molecular genetic analysis. Parameters assessed were age at diagnosis, survival, cell type, proliferation, necrosis, microvascular proliferation, sarcomatous growth, lymphocytic infiltration, thromboses, calcifications, GFAP expression, MIB-1 index, loss of heterozygosity (LOH) of the chromosomal arms 1p, 10p, 10q, 17p, 19q and structural alterations in the TP53, EGFR and PTEN genes. As in previous studies, younger age was significantly associated with better survival. Among the molecular parameters, TP53 mutations and LOH10q emerged as favorable and poor prognostic factors, respectively. TP53 mutations were a favorable prognostic factor independent of whether glioblastomas were primary or secondary. LOH1p or 19q, lesions suspected to be over-represented in long term survivors with malignant glioma, were not associated with better survival. However, the combination of LOH1p and LOH19q defined GBM patients with a significantly better survival. Notably, these patients did not exhibit morphological features reminiscent of oligodendroglioma. These findings indicate that genotyping of glioblastoma may provide clinical information of prognostic importance.
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PMID:Impact of genotype and morphology on the prognosis of glioblastoma. 1193 87

The tumor suppressor gene, MMAC/PTEN, has phosphatase, C2, and PDZ-binding domains as well as potential sites of regulation by phosphorylation, including tyrosine phosphorylation, which may contribute to its ability to modulate cell growth and viability. Several obvious and significant motifs were found in MMAC/PTEN, including most notably, a catalytic domain of tyrosine phosphatase (IHCxxGxxRS/T) and several potential tyrosine phosphorylation sites. To examine the functional significance of tyrosine phosphorylation of MMAC/PTEN, retroviral constructs were generated with mutations at two putative tyrosine phosphorylation sites (Y240A/Y240F and Y315A/Y315F). Stable expression of wild-type MMAC/PTEN in U251 human glioma cells (which do not normally produce a functional MMAC/PTEN gene product) resulted in a significant reduction of tumor growth in nude mice, decreased growth rate, saturation density, and colony formation in vitro, as well as dephosphorylation of D3-phosphorylated phosphatidylinositols (PtdIns) in vitro. Mutation of Y240 or Y315 to either alanine or phenylalanine abrogated the ability of MMAC/PTEN to alter growth rate, saturation density, and colony formation in vitro. The ability of MMAC/PTEN to limit tumor growth in nude mice was markedly decreased but not abrogated by mutation of Y240 or Y315 to alanine. Thus, Y240 and Y315 are required for MMAC/PTEN to decrease tumor growth in vitro and in vivo. In contrast to wild-type MMAC/PTEN, mutant MMAC/PTEN containing Y240A or Y315A was unable to dephosphorylate D3-phosphorylated PtdIns in vitro. Thus, Y240A and Y315A are involved in the ability of MMAC/PTEN to dephosphorylate PtdIns and regulate tumor cell growth in vitro and in vivo.
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PMID:Motif analysis of the tumor suppressor gene MMAC/PTEN identifies tyrosines critical for tumor suppression and lipid phosphatase activity. 1194 19

In 1997, the PTEN gene (phosphatase and tensin homolog deleted on chromosome 10) was identified as a tumor suppressor gene on the long arm of chromosome 10. Since then, important progress has been made with respect to the understanding of the role of the Pten protein in the normal development of the brain as well as in the molecular pathogenesis of human gliomas. This review summarizes the current state of the art concerning the involvement of aberrant Pten function in the development of different biologic features of malignant gliomas, such as loss of cell-cycle control and uncontrolled cell proliferation, escape from apoptosis, brain invasion, and aberrant neoangiogenesis. Most of the tumor-suppressive properties of Pten are dependent on its lipid phosphatase activity, which inhibits the phosphatidylinositol-3'-kinase (PI3K)/Akt signaling pathway through dephosphorylation of phosphatidylinositol-(3,4,5)-triphosphate. The additional function of Pten as a dual-specificity protein phosphatase may also play a role in glioma pathogenesis. Besides the wealth of data elucidating the functional roles of Pten, recent studies suggest a diagnostic significance of PTEN gene alterations as a molecular marker for poor prognosis in anaplastic astrocytomas and anaplastic oligodendrogliomas. Furthermore, the possibility of selective targeting of PTEN mutant tumor cells by specific pharmacologic inhibitors of members of the Pten/PI3K/Akt pathway opens up new perspectives for a targeted molecular therapy of malignant gliomas.
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PMID:Pten signaling in gliomas. 1208 51

We have identified a novel germline mutation in the PTEN tumour suppressor gene. The mutation was identified in a patient with a glioma, and turned out to be a heterozygous germline mutation of PTEN (Arg234Gln), without loss of heterozygosity in tumour DNA. The biological consequences of this germline mutation were investigated by means of transfection studies of the mutant PTEN molecule compared to wild-type PTEN. In contrast to the wild-type molecule, the mutant PTEN protein is not capable of inducing apoptosis, induces increased cell proliferation and leads to high constitutive PKB/Akt activation, which cannot be increased anymore by stimulation with insulin. The reported patient, in addition to glioma, had suffered from benign meningioma in the past but did not show any clinical signs of Cowden disease or other hereditary diseases typically associated with PTEN germline mutations. The functional consequences of the mutation in transfection studies are consistent with high proliferative activity. Together, these findings suggest that the Arg234Gln missense mutation in PTEN has oncogenic properties and predisposes to brain tumours of multiple lineages.
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PMID:A novel germline mutation of PTEN associated with brain tumours of multiple lineages. 1208 8


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