Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Between 1965 and 1988, at the Children's Hospital of Buenos Aires, 22 children developed two successive malignant tumors of different histology. The first tumor was diagnosed between 3 months and 12 years of age: 13 retinoblastoma, 2 rhabdomyosarcoma, 2 non-Hodgkin lymphoma, 2 Hodgkin disease, 1 brain stem glioma, 1 endodermal sinus tumor and 1 Ewing sarcoma. Familial cancer was registered in 6 patients. Children were treated with surgery, intensive chemo and radiotherapy. The second malignancy developed after 2 to 13 years: 10 osteosarcoma, 2 Ewing sarcoma, 2 rhabdomyosarcoma, 2 glioblastoma, 1 medulloblastoma, 1 synoviosarcoma, 1 fibrosarcoma, 1 thyroid carcinoma, 1 acute lymphoblastic leukemia and 1 acute myeloblastic leukemia. In 17 patients, the tumor developed in irradiated field. There was no evidence of the first tumor and only 1 patient was still under chemotherapy. Oncologic treatment was frustrating for these second tumors and 18 children died. Three are alive with no evidence of disease at 2 years, 2 years and 4 months and 3 years after diagnosis. One patient was lost to follow-up. It if postulated that second malignant tumors are consecutive to genetic predisposition and/or to the oncogenic effect of chemo and radiotherapy. The intensity of each treatment modality must be reduced as much as possible to obtain survival while limiting the secondary effects.
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PMID:[Second malignant tumor in children. Report of 22 cases]. 210 57

High molecular weight DNAs prepared from a variety of human tumors maintained in nude mice were assayed for their ability to transform NIH 3T3 cells. DNAs from 4 of 21 tumors tested induced transformed foci in cultures of NIH 3T3 cells. They were from a Ewing sarcoma line, a glioblastoma line, a leiomyosarcoma line, and a lung carcinoma line. Hybridization analyses of the NIH 3T3 transformant DNAs with a human repetitive sequence as probe revealed that four distinct transforming DNA sequences were transferred to NIH 3T3 cells from the four tumor lines. The transforming DNA in a lung carcinoma line was a human homologue of the oncogene of Kirsten murine sarcoma virus (Ki-ras). On the other hand, the three other transforming DNAs showed no similarity to any known human transforming gene detected by the NIH 3T3 transformation assay. Further analyses with a series of cloned oncogenes as probes revealed that the transforming DNA in a glioblastoma line was a human homologue of the oncogene of 3611-murine sarcoma virus (raf). However, the two transforming DNAs in a Ewing sarcoma line and a leiomyosarcoma line had no sequence homology to any of the cloned oncogenes.
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PMID:Detection of a raf-related and two other transforming DNA sequences in human tumors maintained in nude mice. 299 56

We identified betulinic acid (BetA) as a new cytotoxic agent active against neuroectodermal tumor cells including neuroblastoma, medulloblastoma, glioblastoma and Ewing's sarcoma cells representing the most common solid tumors of childhood. BetA induced apoptosis independent of wild-type p53 protein and accumulation of death-inducing ligand/receptor systems such as CD95. BetA had a direct effect on mitochondria resulting in the release of soluble apoptogenic factors such as cytochrome c or AIF from mitochondria into the cytosol where they induced activation of caspases. Overexpression of the anti-apoptotic proteins Bcl-2 or Bcl-XL that blocked loss of the mitochondrial membrane potential and cytochrome c release from mitochondria conferred resistance to BetA at the level of mitochondrial dysfunction, protease activation and nuclear fragmentation. Neuroblastoma cells resistant to CD95- or doxorubicin-triggered apoptosis remained sensitive to treatment with BetA suggesting that BetA may bypass some forms of resistance. Moreover, BetA exhibited potent antitumor activity on primary tumor cell cultures from all neuroblastoma (4/4), all medulloblastoma (4/4) and most glioblastoma patients (20/24) ex vivo. These findings suggest that BetA may be a promising new agent in the treatment of neuroectodermal tumors in vivo.
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PMID:Betulinic acid: a new chemotherapeutic agent in the treatment of neuroectodermal tumors. 1047 70

Primitive neuroectodermal tumors (PNET) occur either in the central nervous system (CNS; central PNET, cPNET) or in the peripheral sites (peripheral PNET, pPNET). Recent molecular approaches have been defining a new concept of PNET, that is, the pPNET including Ewing's sarcoma (ES) which expresses MIC2 glycoprotein and shows the specific chimeric gene of EWS-FLI1. The expression of MIC2 and the genetic rearrangement of EWS-FLI1 are considered to be highly specific to the pPNET/ES. This study examined the expression of MIC2 and EWS-FLI1 gene by means of immunohistochemistry and reverse transcriptase-polymerase chain reaction (RT-PCR) on various small round cell tumors originating in the CNS or non-CNS organs. All peripheral PNET tested expressed MIC2 and were positive for EWS-FLI1 (11/11). In contrast, all cPNET and other blastic CNS tumors were negative for MIC2: medulloblastoma (0/3), cerebral PNET (0/2), spinal PNET (0/2), glioblastoma (0/2), retinoblastoma (0/3), and pineoblastoma (0/2). These MIC2-negative tumors were also negative for the chimeric gene product of EWS-FLI1. Interestingly, one PNET originating in the intracranial dura mater was positive for both MIC2 and EWS-FLI1 fusion gene. The results indicate that cPNET lacks any genetic or protein markers, except for a meningeal PNET which falls into the same phenotypic spectrum of pPNET.
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PMID:Alternative EWS-FLI1 fusion gene and MIC2 expression in peripheral and central primitive neuroectodermal tumors. 1130 41

The initial identification of the ALK gene, expressed as C-terminal part of the transforming fusion protein NPM-ALK in the t(2;5)(p23;q35) lymphoma-associated chromosomal translocation, revealed a novel receptor tyrosine kinase (RTK). In order to expand the knowledge on ALK expression in the human system, we examined a panel of human cell lines for ALK expression and found that transcription is completely repressed in cell lines of entodermal origin (0/21). Furthermore, full length receptor expression is absent in cell lines of the hematopoietic system with the exception of t(2;5)-associated anaplastic large cell lymphomas lines (ALCL), which are known to express chimeric NPM-ALK mRNA. Cell lines established from solid tumors of ectodermal origin, including melanoma and breast carcinoma, exhibited widespread mRNA expression of the ALK receptor at a broad range (53/64), an association which was found to be strongest in cell lines derived from neuroblastoma (6/6), glioblastoma (8/8) as well as in cell lines established from Ewing sarcoma (4/4) and retinoblastomas (2/2). Because of the reported involvement of neutrophin tyrosine kinase receptors in autocrine differentiation in neuroblastomas, we analyzed cell lines positive for full length or chimeric ALK protein for the presence of phoshotyrosine residues within the intracellular region of ALK. While the constitutive activation of chimeric NPM-ALK molecules could be shown, no evidence was found for induced or constitutively activated ALK receptors in neuroblastoma, melanoma or breast carcinoma cell lines. Although the receptor could be shown to be consistently expressed with exclusive specificity in tissues developed from the ectoderm, our results do not support any involvement of ALK in the stimulation of tumorigenic cell growth or differentiation so far, indicating that ALK expression is a physiologic rather than a pathologic phenomenon.
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PMID:Expression and functional analysis of the anaplastic lymphoma kinase (ALK) gene in tumor cell lines. 1211 86

Altered expression of CCN3 has been observed in a variety of musculoskeletal tumours, including Ewing's sarcoma (ES). Despite its widespread distribution, very little is known about its biological functions and molecular mechanisms of action. We transfected CCN3 gene into a CCN3-negative ES cell line and analysed the in vitro and in vivo behaviours of stably transfected clones. Forced expression of CCN3 significantly reduced cell proliferation in vitro, growth in anchorage-independent conditions, and tumorigenicity in nude mice. Despite the antiproliferative effect, CCN3-transfected ES cells displayed increased migration and invasion of Matrigel. The decreased expression of alpha2beta1 integrin receptor and the increased amount of cell surface-associated matrix metalloproteinase (MMP)-9 following the expression of CCN3 may be the basis for the increased migratory abilities of transfected cells. Cells lacking alpha2beta1 are less facilitated to have stable anchorage since the predominant collagen extracted from ES tissue is indeed type I collagen, and proMMP-9 was recently found to provide a cellular switch between stationary and migratory ES cell phase. Our findings are in line with those recently obtained in glioblastoma. However, the underlying molecular mechanisms appear to be different, further highlighting the importance of the cellular context in the regulation of function of CCN proteins.
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PMID:In Ewing's sarcoma CCN3(NOV) inhibits proliferation while promoting migration and invasion of the same cell type. 1582 36

An early event of cell migration is characterized as the rapid reorganization of the actin cytoskeleton. Recently, we have demonstrated that rapamycin inhibits tumor cell motility. To understand the underlying mechanism, this study was set to determine whether rapamycin inhibition of cell motility is related to its prevention of F-actin reorganization. We found that rapamycin prevented type I insulin-like growth factor (IGF-I)-stimulated F-actin reorganization in human rhabdomyosarcoma (Rh30), Ewing sarcoma (Rh1), glioblastoma (U-373) and prostate carcinoma (PC-3) cells, and concurrently inhibited phosphorylation of focal adhesion proteins, including focal adhesion kinase (FAK), paxillin and p130(Cas) in the cells. The effect of rapamycin was blocked by expression of a rapamycin-resistant mutant of mTOR (mTORrr), but not a kinase-dead mTORrr. Downregulation of raptor mimicked the effect of rapamycin. Cells infected with a recombinant adenovirus expressing constitutively active and rapamycin-resistant mutant of p70 S6 kinase 1 (S6K1) conferred to resistance to rapamycin. Further, IGF-I failed to stimulate F-actin reorganization and phosphorylation of the focal adhesion proteins in the S6K1-downregulated cells. Expression of constitutively hypophosphorylated eukaryotic initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1-5A) inhibited IGF-I-stimulated F-actin reorganization, but did not alter the cellular protein or phosphorylation levels of the focal adhesion proteins. The results suggest that rapamycin inhibits IGF-I-induced F-actin reorganization and phosphorylation of the focal adhesion proteins by disruption of mTOR-raptor complex. Both S6K1 and 4E-BP1 pathways, mediated by the mTOR-raptor complex, are involved in the regulation of IGF-I-stimulated F-actin reorganization, but only the former controls IGF-I-stimulated phosphorylation of the focal adhesion proteins.
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PMID:Rapamycin inhibits F-actin reorganization and phosphorylation of focal adhesion proteins. 1850 40

Rhabdomyosarcoma, consisting of alveolar (aRMS) and embryonal (eRMS) subtypes, is the most common type of sarcoma in children. Currently, there are no targeted drug therapies available for rhabdomyosarcoma. In searching for new molecular therapeutic targets, we carried out genome-wide small interfering RNA (siRNA) library screens targeting human phosphatases (n = 206) and kinases (n = 691) initially against an aRMS cell line, RH30. Sixteen phosphatases and 50 kinases were identified based on growth inhibition after 72 hours. Inhibiting polo-like kinase 1 (PLK1) had the most remarkable impact on growth inhibition (approximately 80%) and apoptosis on all three rhabdomyosarcoma cell lines tested, namely, RH30, CW9019 (aRMS), and RD (eRMS), whereas there was no effect on normal muscle cells. The loss of PLK1 expression and subsequent growth inhibition correlated with decreased p-CDC25C and Cyclin B1. Increased expression of WEE 1 was also noted. The induction of apoptosis after PLK1 silencing was confirmed by increased p-H2AX, propidium iodide uptake, and chromatin condensation, as well as caspase-3 and poly(ADP-ribose) polymerase cleavage. Pediatric Ewing's sarcoma (TC-32), neuroblastoma (IMR32 and KCNR), and glioblastoma (SF188) models were also highly sensitive to PLK1 inhibition. Finally, based on cDNA microarray analyses, PLK1 mRNA was overexpressed (>1.5 fold) in 10 of 10 rhabdomyosarcoma cell lines and in 47% and 51% of primary aRMS (17 of 36 samples) and eRMS (21 of 41 samples) tumors, respectively, compared with normal muscles. Similarly, pediatric Ewing's sarcoma, neuroblastoma, and osteosarcoma tumors expressed high PLK1. We conclude that PLK1 could be a promising therapeutic target for the treatment of a wide range of pediatric solid tumors including rhabdomyosarcoma.
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PMID:Small interfering RNA library screen of human kinases and phosphatases identifies polo-like kinase 1 as a promising new target for the treatment of pediatric rhabdomyosarcomas. 1988 53

Cancer cells are characterized by genetic mutations that deregulate cell proliferation and suppress cell death. To arrest the uncontrolled replication of malignant cells, conventional chemotherapies systemically disrupt cell division, causing diverse and often severe side effects as a result of collateral damage to normal cells. Seeking to address this shortcoming, we pursue therapeutic regulation that is conditional, activating selectively in cancer cells. This functionality is achieved using small conditional RNAs that interact and change conformation to mechanically transduce between detection of a cancer mutation and activation of a therapeutic pathway. Here, we describe small conditional RNAs that undergo hybridization chain reactions (HCR) to induce cell death via an innate immune response if and only if a cognate mRNA cancer marker is detected within a cell. The sequences of the small conditional RNAs can be designed to accept different mRNA markers as inputs to HCR transduction, providing a programmable framework for selective killing of diverse cancer cells. In cultured human cancer cells (glioblastoma, prostate carcinoma, Ewing's sarcoma), HCR transduction mediates cell death with striking efficacy and selectivity, yielding a 20- to 100-fold reduction in population for cells containing a cognate marker, and no measurable reduction otherwise. Our results indicate that programmable mechanical transduction with small conditional RNAs represents a fundamental principle for exploring therapeutic conditional regulation in living cells.
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PMID:Selective cell death mediated by small conditional RNAs. 2324 21

Aneuploidy is frequently observed in cancers and is considered a crucial mechanism in cancer development. STAG2 is a gene that encodes a component of cohesion complex required for normal chromosomal segregation. Recently, somatic mutation of STAG2 gene and loss of STAG2 protein have been reported in glioblastoma, Ewing's sarcoma and melanoma. The aim of this study was to see whether such alterations of STAG2 are also common in other cancers. In this study, we analyzed STAG2 somatic mutation in 45 colorectal carcinomas (CRC), 45 gastric carcinomas (GC), 45 breast carcinomas, 45 non-small cell lung cancers and 45 prostate carcinomas (PCA) by single-strand conformation polymorphism. We analyzed also STAG2 protein expression in 100 GC, 103 CRC and 107 PCA by immunohistochemistry. STAG2 protein was well expressed in normal stomach, colon and prostate epithelial cells, while it was lost in 27% of GC, 23% of CRC and 30% of PCA. The loss of STAG2 was observed irrespective of subtypes, stages and grades of the cancers. However, we could not find any STAG2 mutations in these cancers. The loss of expression of STAG2 in GC, CRC and PCA tissues compared to their corresponding normal cells indicates that STAG2 loss is common in carcinomas as well. The data suggest also that loss of expression of STAG2, but not somatic mutation, might be responsible to STAG2 inactivation and is common in studied types of carcinomas.
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PMID:Mutational and expressional analyses of STAG2 gene in solid cancers. 2266 12


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