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

A major goal of modern medicine is to identify key genes and their products that are altered in the diseased state and to elucidate the molecular mechanisms underlying disease development, progression, and resistance to therapy. This is a daunting task given the exceptionally high complexity of the human genome. The paradigm for research has historically been hypothesis-driven despite the fact that the hypotheses under scrutiny often rest on tenuous subjective grounds or are derived from and dependent on chance observation. The imminent deciphering of the complete human genome, coupled with recent advances in high-throughput bioanalytical technology, has made possible a new paradigm in which data-based hypothesis-generation is the initial step in the investigative process, followed by hypothesis-testing. Genomics technologies are the primary source of the new hypothesis-generating capabilities that are now empowering biomedical researchers. The synergistic interaction between contemporary genomics technologies and the hypothesis-generation paradigm is well-illustrated by the discovery and subsequent ongoing study of the role of insulin-like growth factor binding protein 2 (IGFBP2) in human glioma biology. Using gene expression microarray technology, the IGFBP2 gene was recently found to be highly and differentially overexpressed in the most advanced grade of human glioma, glioblastoma. Based on this discovery, subsequent functional studies were initiated that suggest that IGFBP2 overexpression may contribute to the invasive nature of glioblastoma, and that IGFBP2 may exert its function via a newly identified novel binding protein. The IGFBP2 story is but one example of the power and potential of the new molecular methodologies that are transforming modern diagnostic and investigative neuropathology.
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PMID:Insulin-like growth factor binding protein 2: gene expression microarrays and the hypothesis-generation paradigm. 1177 Sep 4

Tissue microarrays (TMAs) are composite paraffin blocks constructed by extracting cylindrical tissue core "biopsies" from different paraffin donor blocks and re-embedding these into a single recipient (microarray) block at defined array coordinates. Using this technique, up to 1000 or more tissue samples can be composited into a single paraffin block. Tissue microarrays permit high-volume simultaneous analysis of molecular targets at the DNA, mRNA, and protein levels under identical, standardized conditions on a single glass slide, and also provide maximal preservation and utilization of limited and irreplaceable archival tissue samples. This versatile technique facilitates retrospective and prospective human tissue studies, animal tissue studies, and cell line cytospin cell block studies. In this review, we present the technical aspects of TMA construction and sectioning, validation aspects of the technique, TMA advantages and limitations, and a sampling of the broad range of TMA uses in modern neuropathologic clinical diagnosis, research, and education. A specific illustration of the most widely employed and increasingly important TMA application is also presented: confirmation via TMA-based immunohistochemistry of the differential expression of a marker (IGFBP2) initially identified by gene expression profiling to be overexpressed in glioblastoma.
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PMID:Tissue microarrays: applications in neuropathology research, diagnosis, and education. 1177 Sep 5

Glioblastomas rarely metastasize outside the CNS. We biologically characterized a case of secondary glioblastoma associated with extracranial progression and distant metastasis. A 42-year-old male patient was subjected to craniotomy for a left temporal tumor (astrocytoma grade II) and subsequently underwent another 3 craniotomies due to tumor recurrences. At the third craniotomy, extracranial progression was noted, and the tumor was classified as a glioblastoma. In order to pinpoint the genes expressed differentially in the intracranial primary tumor and the metastatic tumors, we used cDNA microarray. The patterns of gene expression in these 2 samples were highly similar, suggesting that the mechanism of metastasis was direct infiltration of tumor cells into extracranial blood vessels. Insulin-like growth factor binding protein-2 was overexpressed in both primary and metastatic tumors. Immunohistochemical studies of DNA-dependent protein kinase, which participates in the repair of DNA, was strongly positive in the samples obtained at the first and second operations, but the positive rates were markedly reduced in the specimens obtained at the third and fourth operations. These results suggest that insulin-like growth factor binding protein-2 and deficiency of DNA-dependent protein kinase proteins promoted tumor progression in the present case.
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PMID:Biologic characterization of a secondary glioblastoma with extracranial progression and systemic metastasis. 1262 29

Comparison of gene expressing profiles between gliomas with different grades revealed frequent overexpression of insulin-like growth factor binding protein 2 (IGFBP2) in glioblastoma (GBM), the most advanced stage of glioma. To determine whether IGFBP2 is involved in the proliferative and invasive nature of GBM, we established stable SNB19 GBM cell lines that overexpress IGFBP2. Although there was no marked difference in the cell growth between IGFBP2 overexpressing SNB19(BP2) lines when compared with the control cells, these clones showed significantly increased invasive rates when compared with the parental or vector transfected SNB19 cells. Total RNAs from controls and SNB19(BP2) clones were used for microarray analysis to detect IGFBP2-mediated alterations in gene expression. When compared with parental or vector-transfected control cells, SNB19(BP2) cells consistently showed 3-5-fold increase in the expression of matrix metalloproteinase-2 (MMP-2) as well as other invasion related genes. Increased MMP-2 expression in SNB19(BP2) cells was subsequently confirmed by real time reverse-transcription PCR, Western blotting, and gelatin zymography. Furthermore, consistent with increased MMP-2 expression in SNB19(BP2) cells, transient transfection of a MMP-2 promoter/luciferase reporter also resulted in 3-6-fold higher luciferase activity in SNB19(BP2) cells than in parental or vector-transfected control cells. Finally, tissue microarray analysis of 68 GBM tissue specimens showed a significant correlation between the overexpression of IGFBP2 and elevated MMP-2 expression. Taken together, our data provide evidence that IGFBP2 contributes to glioma progression in part by enhancing MMP-2 gene transcription and in turn tumor cell invasion.
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PMID:Insulin-like growth factor binding protein 2 enhances glioblastoma invasion by activating invasion-enhancing genes. 1290 97

The development of targeted treatment strategies adapted to individual patients requires identification of the different tumor classes according to their biology and prognosis. We focus here on the molecular aspects underlying these differences, in terms of sets of genes that control pathogenesis of the different subtypes of astrocytic glioma. By performing cDNA-array analysis of 53 patient biopsies, comprising low-grade astrocytoma, secondary glioblastoma (respective recurrent high-grade tumors), and newly diagnosed primary glioblastoma, we demonstrate that human gliomas can be differentiated according to their gene expression. We found that low-grade astrocytoma have the most specific and similar expression profiles, whereas primary glioblastoma exhibit much larger variation between tumors. Secondary glioblastoma display features of both other groups. We identified several sets of genes with relatively highly correlated expression within groups that: (a). can be associated with specific biological functions; and (b). effectively differentiate tumor class. One prominent gene cluster discriminating primary versus nonprimary glioblastoma comprises mostly genes involved in angiogenesis, including VEGF fms-related tyrosine kinase 1 but also IGFBP2, that has not yet been directly linked to angiogenesis. In situ hybridization demonstrating coexpression of IGFBP2 and VEGF in pseudopalisading cells surrounding tumor necrosis provided further evidence for a possible involvement of IGFBP2 in angiogenesis. The separating groups of genes were found by the unsupervised coupled two-way clustering method, and their classification power was validated by a supervised construction of a nearly perfect glioma classifier.
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PMID:Classification of human astrocytic gliomas on the basis of gene expression: a correlated group of genes with angiogenic activity emerges as a strong predictor of subtypes. 1458 54

The progression of gliomas has been extensively studied at the genomic level using cDNA microarrays. However, systematic examinations at the protein translational and post-translational levels are far more limited. We constructed a glioma protein lysate array from 82 different primary glioma tissues, and surveyed the expression and phosphorylation of 46 different proteins involved in signaling pathways of cell proliferation, cell survival, apoptosis, angiogenesis, and cell invasion. An analysis algorithm was employed to robustly estimate the protein expressions in these samples. When ranked by their discriminating power to separate 37 glioblastomas (high-grade gliomas) from 45 lower-grade gliomas, the following 12 proteins were identified as the most powerful discriminators: IBalpha, EGFRpTyr845, AKTpThr308, phosphatidylinositol 3-kinase (PI3K), BadpSer136, insulin-like growth factor binding protein (IGFBP) 2, IGFBP5, matrix metalloproteinase 9 (MMP9), vascular endothelial growth factor (VEGF), phosphorylated retinoblastoma protein (pRB), Bcl-2, and c-Abl. Clustering analysis showed a close link between PI3K and AKTpThr308, IGFBP5 and IGFBP2, and IBalpha and EGFRpTyr845. Another cluster includes MMP9, Bcl-2, VEGF, and pRB. These clustering patterns may suggest functional relationships, which warrant further investigation. The marked association of phosphorylation of AKT at Thr308, but not Ser473, with glioblastoma suggests a specific event of PI3K pathway activation in glioma progression.
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PMID:Pathway alterations during glioma progression revealed by reverse phase protein lysate arrays. 1661 7

Insulin-like growth factor binding proteins (IGFBPs) comprise a family of proteins that bind and regulate the functions of IGFs. One of the IGFBPs, IGFBP2, has recently been shown to be overexpressed in glioblastoma. Overexpression of IGFBP2 contributes to the invasiveness of glioblastoma and correlates with histologic grade and survival in patients with diffuse gliomas, suggesting that IGFBP2 expression may contribute to the glioma formation and/or progression. The expression of other IGFBP family members in gliomas has, however, not been examined in detail. This study was designed to evaluate the expression of IGFBP3 and IGFBP5 in diffuse gliomas using immunohistochemistry applied to a tissue array constructed from 259 gliomas, including ten gliosarcomas. Expression of IGFBP5 correlated significantly with glioma histologic grade. 83% (58/70) of glioblastomas (WHO Grade IV) were positive for IGFBP5, which was significantly higher than WHO Grade III gliomas (41%, 41/101) or WHO Grade II gliomas (18%, 13/72) (p<0.001). In contrast, IGFBP3 was expressed in 17%, 23%, and 17% of WHO Grade IV, Grade III, and Grade II gliomas, respectively (p>0.05). There was no significant difference in IGFBP3 expression among different grades of glioma. Our study thus demonstrates that the expression of IGFBP5, but not IGFBP3, increases with glioma anaplastic progression. The strong correlation between overexpression of IGFBP5 and histologic grade suggests that, in addition to IGFBP2, IGFBP5 may also play a role in glioma progression.
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PMID:Overexpression of IGFBP5, but not IGFBP3, correlates with the histologic grade of human diffuse glioma: a tissue microarray and immunohistochemical study. 1670 Jun 16

PTEN is an important tumor-suppressor gene associated with many cancers. Through expression profiling of glioblastoma tissue samples and prostate cancer xenografts, we identified a molecular signature for loss of the PTEN tumor suppressor in glioblastoma and prostate tumors. The PTEN signature consists of a minimum of nine genes, several of which are involved in various pathways already implicated in tumor formation. Among these signature genes, the most significant was an increase in insulin growth factor-binding protein 2 (IGFBP-2) mRNA. Up-regulation of IGFBP-2 was confirmed at the protein level by Western blot analysis and validated in samples not included in the microarray analysis. The link between IGFBP-2 and PTEN was of particular interest because elevated serum IGFBP-2 levels have been reported in patients with prostate and brain tumors. To further investigate this link, we determined that IGFBP-2 expression is negatively regulated by PTEN and positively regulated by phosphatidylinositol 3-kinase (PI3K) and Akt activation. In addition, Akt-driven transformation is impaired in IGFBP2(-/-) mouse embryo fibroblasts, implicating a functional role for IGFBP-2 in PTEN signaling. Collectively, these studies establish that PTEN and IGFBP-2 expression are inversely correlated in human brain and prostate cancers and implicate serum IGFBP-2 levels as a potential serum biomarker of PTEN status and PI3K Akt pathway activation in cancer patients.
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PMID:Insulin growth factor-binding protein 2 is a candidate biomarker for PTEN status and PI3K/Akt pathway activation in glioblastoma and prostate cancer. 1737 10

IGFBP2 is overexpressed in the most common brain tumor, glioblastoma (GBM), and its expression is inversely correlated to GBM patient survival. Previous reports have demonstrated a role for IGFBP2 in glioma cell invasion and astrocytoma development. However, the function of IGFBP2 in the restricted, self-renewing, and tumorigenic GBM cell population comprised of tumor-initiating stem cells has yet to be determined. Herein we demonstrate that IGFBP2 is overexpressed within the stem cell compartment of GBMs and is integral for the clonal expansion and proliferative properties of glioma stem cells (GSCs). In addition, IGFBP2 inhibition reduced Akt-dependent GSC genotoxic and drug resistance. These results suggest that IGFBP2 is a selective malignant factor that may contribute significantly to GBM pathogenesis by enriching for GSCs and mediating their survival. Given the current dearth of selective molecular targets against GSCs, we anticipate our results to be of high therapeutic relevance in combating the rapid and lethal course of GBM.
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PMID:IGFBP2 promotes glioma tumor stem cell expansion and survival. 2051 48

Exosomes are nanometer-sized lipid vesicles released ubiquitously by cells, which have been shown to have a normal physiological role, as well as influence the tumor microenvironment and aid metastasis. Recent studies highlight the ability of exosomes to convey tumor-suppressive and oncogenic mRNAs, microRNAs, and proteins to a receiving cell, subsequently activating downstream signaling pathways and influencing cellular phenotype. Here, we show that radiation increases the abundance of exosomes released by glioblastoma cells and normal astrocytes. Exosomes derived from irradiated cells enhanced the migration of recipient cells, and their molecular profiling revealed an abundance of molecules related to signaling pathways important for cell migration. In particular, connective tissue growth factor (CTGF) mRNA and insulin-like growth factor binding protein 2 (IGFBP2) protein levels were elevated, and coculture of nonirradiated cells with exosomes isolated from irradiated cells increased CTGF protein expression in the recipient cells. Additionally, these exosomes enhanced the activation of neurotrophic tyrosine kinase receptor type 1 (TrkA), focal adhesion kinase, Paxillin, and proto-oncogene tyrosine-protein kinase Src (Src) in recipient cells, molecules involved in cell migration. Collectively, our data suggest that radiation influences exosome abundance, specifically alters their molecular composition, and on uptake, promotes a migratory phenotype.
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PMID:Ionizing radiation and glioblastoma exosomes: implications in tumor biology and cell migration. 2446 66


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