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)

Insulin-like growth factor-binding protein 7 (IGFBP7) is a selective biomarker of glioblastoma (GBM) vessels, strongly expressed in tumor endothelial cells and vascular basement membrane. IGFBP7 gene regulation and its potential role in tumor angiogenesis remain unclear. Mechanisms of IGFBP7 induction and its angiogenic capacity were examined in human brain endothelial cells (HBECs) exposed to tumor-like conditions. HBEC treated with GBM cell (U87MG)-conditioned media (-CM) exhibited fourfold upregulation of IGFBP7 mRNA and protein compared to control cells. IGFBP7 gene regulation in HBEC was methylation independent. U87MG-CM analysed by enzyme-linked immunosorbent assay contained approximately 5 pM transforming growth factor (TGF)-beta1, a concentration sufficient to stimulate IGFBP7 in HBEC to similar levels as U87MG-CM. Both pan-TGF-beta-neutralizing antibody (1D11) and the TGF-beta1 receptor (activin receptor-like kinase 5, ALK5) antagonist, SB431542, blocked U87MG-CM-induced IGFBP7 expression in HBEC, indicating that TGF-beta1 is an important tumor-secreted effector capable of IGFBP7 induction in endothelial cells. HBEC exposed to either U87MG-CM or IGFBP7 protein exhibited increased capillary-like tube (CLT) formation in Matrigel. Both TGF-beta1- and U87MG-CM-induced Smad-2 phosphorylation and U87MG-CM-induced CLT formation in HBEC were inhibited by the ALK5 antagonist, SB431542. These data suggest that proangiogenic IGFBP7 may be induced in brain endothelial cells by TGF-betas secreted by GBM, most likely through TGF-beta1/ALK5/Smad-2 pathway.
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PMID:Glioblastoma-secreted factors induce IGFBP7 and angiogenesis by modulating Smad-2-dependent TGF-beta signaling. 1871 1

Glioma-initiating cells (GICs) are responsible for the initiation and recurrence of gliomas. Here, we identify a molecular mechanism that regulates the self-renewal capacity of patient-derived GICs. We show that TGF-beta and LIF induce the self-renewal capacity and prevent the differentiation of GICs. TGF-beta induces the self-renewal capacity of GICs, but not of normal human neuroprogenitors, through the Smad-dependent induction of LIF and the subsequent activation of the JAK-STAT pathway. The effect of TGF-beta and LIF on GICs promotes oncogenesis in vivo. Some human gliomas express high levels of LIF that correlate with high expression of TGF-beta2 and neuroprogenitor cell markers. Our results show that TGF-beta and LIF have an essential role in the regulation of GICs in human glioblastoma.
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PMID:TGF-beta increases glioma-initiating cell self-renewal through the induction of LIF in human glioblastoma. 1934 22

For patients with brain tumors identification of diagnostic and prognostic markers in easy accessible biological material, such as plasma or cerebrospinal fluid (CSF), would greatly facilitate patient management. MIC-1/GDF15 (growth differentiation factor 15) is a secreted protein of the TGF-beta superfamily and emerged as a candidate marker exhibiting increasing mRNA expression during malignant progression of glioma. Determination of MIC-1/GDF15 protein levels by ELISA in the CSF of a cohort of 94 patients with intracranial tumors including gliomas, meningioma and metastasis revealed significantly increased concentrations in glioblastoma patients (median, 229 pg/ml) when compared with control cohort of patients treated for non-neoplastic diseases (median below limit of detection of 156 pg/ml, p < 0.0001, Mann-Whitney test). However, plasma MIC-1/GDF15 levels were not elevated in the matching plasma samples from these patients. Most interestingly, patients with glioblastoma and increased CSF MIC-1/GDF15 had a shorter survival (p = 0.007, log-rank test). In conclusion, MIC-1/GDF15 protein measured in the CSF may have diagnostic and prognostic value in patients with intracranial tumors.
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PMID:Elevated levels of MIC-1/GDF15 in the cerebrospinal fluid of patients are associated with glioblastoma and worse outcome. 1952 60

Recent large-scale tumor resequencing studies have identified a number of mutations that might be involved in tumorigenesis. Analysis of the frequency of specific mutations across different tumors has been able to identify some, but not all of the mutated genes that contribute to tumor initiation and progression. One reason for this is that other functionally important genes are likely to be mutated more rarely and only in specific contexts. Thus, for example, mutation in one member of a collection of functionally related genes may result in the same net effect, and/or mutations in certain genes may be observed less frequently if they play functional roles in later stages of tumor development, such as metastasis. We modified and applied a network reconstruction and coexpression module identification-based approach to identify functionally related gene modules targeted by somatic mutations in cancer. This method was applied to available breast cancer, colorectal cancer, and glioblastoma sequence data, and identified Wnt/TGF-beta cross-talk, Wnt/VEGF signaling, and MAPK/focal adhesion kinase pathways as targets of rare driver mutations in breast, colorectal cancer, and glioblastoma, respectively. These mutations do not appear to alter genes that play a central role in these pathways, but rather contribute to a more refined shaping or "tuning" of the functioning of these pathways in such a way as to result in the inhibition of their tumor-suppressive signaling arms, and thereby conserve or enhance tumor-promoting processes.
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PMID:Identification of rare cancer driver mutations by network reconstruction. 1957 99

A series of novel 3,4-disubstituted pyrazoles were synthesized. The cytotoxicity against U87MG glioma cell line have been investigated in vitro and three of these compounds showed promising inhibitory activity on cell growth with an IC50 lower than 90 microM. AutoDock molecular docking into type I TGF-beta receptor (TGF-beta-RI; PDB: 1py5) has been done for lead optimization of the mentioned compounds as potential TGF-beta-RI1 inhibitors. In particular, 3-aryl-4-amido pyrazole containing long omega-amino-aliphatic chain emerged as a good candidate for further optimization. Entrapment into targetable PEG-based micelles improved growth inhibition IC50 values up to 100 nM and this could lead to a novel drug delivery strategy for treating glioblastoma.
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PMID:Design and synthesis of novel 3,4-disubstituted pyrazoles for nanomedicine applications against malignant gliomas. 2012 19

Gliomas constitute more than 50% of primary brain tumours in man. Perhaps the most important hallmark of these tumours is their diffuse invasion of the normal brain structures. The biological factors involved in the control of both their proliferation and invasion are, however, not well known. We studied the expression of receptors for epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), platelet derived growth factor (PDGF), and transforming growth factor beta-1 (TGF-beta 1) in low grade astrocytoma (IPNT-H)-, grade III astrocytoma (IPSB-18)-, and glioblastoma (IPRM-5)- derived cell lines. The effects of EGF, bFGF, PDGF, and TGF-beta 1 on proliferation, migration, and invasion in vitro were also investigated. When tested individually, EGF, bFGF and PDGF, were found to differentially stimulate proliferation, motility and invasion of the cell lines examined. When combined, these three growth factors acted synergistically to stimulate these biological properties. In addition, TGF-beta 1 exhibited positive and negative effects on the mitogenic action of the other growth factors in IPNT-H cells but inhibited their activity in IPSB-18 and IPRM-5 cells. Moreover, TGF-beta 1 was found to modulate negatively and positively the migration and invasion promoting action of the other growth factors in IPNT-H and IPSB-18 cells, while it strongly potentiated this action in IPRM-5 cells. These results suggest that all the growth factors examined may play key roles in the control of the biological properties of human glioma cells in vitro. Together with our findings that TGF-beta 1 is overexpressed in human glioblastoma in vivo, these results also suggest that co-operation between growth factors and TGF-beta 1 may be of central importance in tumour progression of gliomas.
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PMID:Synergism between growth-factors in the control of glioma cell-proliferation, migration and invasion in-vitro. 2155 43

The molecular pathways involved in neovascularization of regenerating tissues and tumor angiogenesis resemble each other. However, the regulatory mechanisms of neovascularization under neoplastic circumstances are unbalanced leading to abnormal protein expression patterns resulting in the formation of defective and often abortive tumor vessels. Because gliomas are among the most vascularized tumors, we compared the protein expression profiles of proliferating vessels in glioblastoma with those in tissues in which physiological angiogenesis takes place. By using a combination of laser microdissection and LTQ Orbitrap mass spectrometry comparisons of protein profiles were made. The approach yielded 29 and 12 differentially expressed proteins for glioblastoma and endometrium blood vessels, respectively. The aberrant expression of five proteins, i.e. periostin, tenascin-C, TGF-beta induced protein, integrin alpha-V, and laminin subunit beta-2 were validated by immunohistochemistry. In addition, pathway analysis of the differentially expressed proteins was performed and significant differences in the usage of angiogenic pathways were found. We conclude that there are essential differences in protein expression profiles between tumor and normal physiological angiogenesis.
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PMID:A proteome comparison between physiological angiogenesis and angiogenesis in glioblastoma. 2227 69

Immune cell infiltration varies widely between different glioblastomas (GBMs). The underlying mechanism, however, remains unknown. Here we show that TGF-beta regulates proliferation, migration, and tumorigenicity of mesenchymal GBM cancer stem cells (CSCs) in vivo and in vitro. In contrast, proneural GBM CSCs resisted TGF-beta due to TGFR2 deficiency. In vivo, a substantially increased infiltration of immune cells was observed in mesenchymal GBMs, while immune infiltrates were rare in proneural GBMs. On a functional level, proneural CSC lines caused a significantly stronger TGF-beta-dependent suppression of NKG2D expression on CD8(+) T and NK cells in vitro providing a mechanistic explanation for the reduced immune infiltration of proneural GBMs. Thus, the molecular subtype of CSCs TGF-beta-dependently contributes to the degree of immune infiltration.
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PMID:The cancer stem cell subtype determines immune infiltration of glioblastoma. 2267 16

MicroRNAs(miR) play an important role in cell growth, differentiation, proliferation and apoptosis, which can function either as oncogenes or as tumor suppressors in their effect on tumor growth. Smad3 is often underexpressed in very diverse types of malignant tumors and has an important tumor suppressive function; however, the underlying mechanism in solid cancer including glioblastomas(GBM) is not fully explored. The aim of this study is to explore the role of miR-92b in regulation of smad3 in GBM. In our study, we found that miR-92b expression was significantly increased in GBM tissues compared with normal brain tissues by Q-RT-PCR and in situ hybridization (P<0.01). However, expression of smad3 in GBM samples was significantly reduced compared with normal brain tissues by western blot and immunohistochemistry (P<0.05). Using 3'UTR luciferase reporter gene assay, we found that miR-92b directly affected smad3 expression in GBM cells by targeting the 3'-untranslated region. Silencing of miR-92b was able to significantly inhibit the viability of GBM cells in three GBM cell lines through up-regulating the TGF-beta/smad3/p21 signaling pathway in vitro. Furthermore, the tumor growth and the weight of U87 cells in the miR-92b inhibitor group were significantly inhibited when compared with that of the control group in vivo. Our data demonstrated that miR-92b may be considered as a tumor oncogene to promote GBM cell proliferation, and thus may serve as a potentially useful target for development of miRNA-based therapies in the future.
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PMID:The miR-92b functions as a potential oncogene by targeting on Smad3 in glioblastomas. 2389 8

Glioblastoma (GBM) is the most common malignant brain tumor. Radiotherapy post surgical resection remained the mainstay of the management of GBM for decades until the addition of temozolomide was shown to prolong the median overall survival (OS) by 2.5 months to 14.6 months in 2005. Infiltrative growth to surrounding normal brain tissue and cooption of vascular niches, peripheral microvasuclar hyperplasia, and central hypoxic regions with pseudopalisading necrosis are characteristics of GBM and are causally linked to their exceptional radio- and chemo-resistant phenotype. An intratumoral hierarchy is postulated consisting of tumor stem cells in the apex with high DNA-repair proficiency resisting radiotherapy. It is conceivable that the stem cell property is more dynamic than originally anticipated. Niche effects such as exposure to hypoxia and intercellular communication in proximities to endothelial or bone marrow-derived cells (BMDC), for example, may activate such "stem cell" programs. GBM are exceptionally stroma-rich tumors and may consist of more than 70% stroma components, such as microglia and BMDC. It becomes increasingly apparent that treatment of GBM needs to integrate therapies targeting all above-mentioned distinct pathophysiological features. Accordingly, recent approaches in GBM therapy include inhibition of invasion (e.g., integrin, EGFR, CD95, and mTOR inhibition), antiangiogenesis and stroma modulators (TGFbeta, VEGF, angiopoetin, cMET inhibitors) and activation of immune response (vaccination and blockage of negative co-stimulatory signals). In addition, high LET-radiotherapy, for example with carbon ions, is postulated to ablate tumor stem cell and hypoxic cells more efficiently as compared with conventional low-LET photon irradiation. We discuss current key concepts, their limitations, and potentials to improve the outcome in this rapidly progressive and devastating disease.
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PMID:For the next trick: new discoveries in radiobiology applied to glioblastoma. 2485 53


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