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)

Small numbers of proangiogenic bone marrow-derived cells (BMDCs) can play pivotal roles in tumor progression. In this issue of Cancer Cell, two papers, utilizing different tumor angiogenesis models, both find that activated MMP-9 delivered by BMDCs modulates neovessel remodeling, thereby promoting tumor growth. The changes in microvascular anatomy induced by MMP-9-expressing BMDCs are strikingly different between the preirradiated tumor vascular bed model employed by Ahn and Brown and the invasive glioblastoma model utilized by Du et al., likely mirroring the complexity of the real tumor microenvironment and the intricacy of roles of different BMDC populations in mediating tumor neoangiogenesis.
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PMID:A catalytic role for proangiogenic marrow-derived cells in tumor neovascularization. 1832 25

Inhibition of tumor angiogenesis through modulation of vascular endothelial growth factor (VEGF) and its signaling pathway has been clinically validated as a viable therapeutic modality in the treatment of cancer. The use of artificial transcription factors based on Cys2-His2 zinc-finger proteins (ZFPs) targeting the VEGF promoter offers a novel strategy for modulating VEGF levels in tumors. In order to demonstrate the utility of VEGF-targeted ZFPs as therapeutic agents, we generated adenoviruses (Ads) expressing VEGF promoter-targeted transcriptional repressor ZFP, F435-KOX. A replication-incompetent Ad expressing F435-KO X, namely, Ad-DeltaE1-KOX, significantly reduced VEGF expression and functionally led to inhibition of angiogenesis. In vivo, an oncolytic Ad expressing F435-KOX, namely, Ad-DeltaB7-KOX, elicited a pronounced antitumor effect against a human glioblastoma xenograft model, U87MG. Further, consistent with its expected mechanism of action, Ad-DeltaB7-KOX was shown to greatly reduce the level of VEGF and vessel density in tumor tissue and increase terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL)-positive apoptotic cells in tumors. Survival rates were also significantly increased in Ad-DeltaB7-KOX-treated mice. Taken together, the findings from this study identify F435-KOX as a novel and potent ZFP transcription factor that can inhibit VEGF-A-mediated angiogenesis and offer a novel therapeutic modality in the treatment of cancer.
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PMID:Novel cancer antiangiotherapy using the VEGF promoter-targeted artificial zinc-finger protein and oncolytic adenovirus. 1839 29

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

We previously found that FoxM1B is overexpressed in human glioblastomas and that forced FoxM1B expression in anaplastic astrocytoma cells leads to the formation of highly angiogenic glioblastoma in nude mice. However, the molecular mechanisms by which FoxM1B enhances glioma angiogenesis are currently unknown. In this study, we found that vascular endothelial growth factor (VEGF) is a direct transcriptional target of FoxM1B. FoxM1B overexpression increased VEGF expression, whereas blockade of FoxM1 expression suppressed VEGF expression in glioma cells. Transfection of FoxM1 into glioma cells directly activated the VEGF promoter, and inhibition of FoxM1 expression by FoxM1 siRNA suppressed VEGF promoter activation. We identified two FoxM1-binding sites in the VEGF promoter that specifically bound to the FoxM1 protein. Mutation of these FoxM1-binding sites significantly attenuated VEGF promoter activity. Furthermore, FoxM1 overexpression increased and inhibition of FoxM1 expression suppressed the angiogenic ability of glioma cells. Finally, an immunohistochemical analysis of 59 human glioblastoma specimens also showed a significant correlation between FoxM1 overexpression and elevated VEGF expression. Our findings provide both clinical and mechanistic evidence that FoxM1 contributes to glioma progression by enhancing VEGF gene transcription and thus tumor angiogenesis.
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PMID:FoxM1B transcriptionally regulates vascular endothelial growth factor expression and promotes the angiogenesis and growth of glioma cells. 1897 15

Several cancer chemopreventive agents have been demonstrated to exert antiangiogenic effects. Blocking tumor angiogenesis, a process critical for tumor mass expansion and metastasis, represents an intriguing approach not only to cancer therapy, but also to cancer chemoprevention. We found that angiogenesis is a common and key target of many chemopreventive molecules, where they most likely suppress the angiogenic switch in premalignant tumors, a concept we termed "angioprevention." In this manuscript we use as an example the synthetic retinoid N-(4-hydroxyphenyl)retinamide (4HPR), a molecule with confirmed clinical applications in breast cancer adjuvant therapy to prevent cancer recurrence and under evaluation in neuroblastoma and glioblastoma treatment.
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PMID:Anti-angiogenic properties of chemopreventive drugs: fenretinide as a prototype. 1921 59

In recent clinical observation, the growth of endothelial tumors, such as hemangiomas of infancy, was repressed by the non-selective beta-adrenergic antagonist propranolol possibly through targeting of the vascular endothelial compartment. As human brain microvascular endothelial cells (HBMEC) play an essential role as structural and functional components in tumor angiogenesis, we assessed whether propranolol could target HBMEC's in vitro angiogenic properties. We found that biopsies from human glioblastoma as well as from experimental brain tumor-associated vasculature expressed high levels of the beta2-adrenergic receptor, suggesting adrenergic adaptative processes could take place during tumor vascularization. We observed that in vitro tubulogenesis was significantly reduced by propranolol when HBMEC were seeded on Matrigel. Propranolol, as much as 100microM, did not reduce cell viability and did not alter HBMEC migration as assessed with Boyden chambers. Secretion of the key angiogenic and extracellular matrix degrading enzymes MMP-2 and MMP-9 was assessed by zymography. Propranolol significantly reduced MMP-9 secretion upon treatment with the tumor-promoting agent phorbol 12-myristate 13-acetate, while secretion of MMP-2 remained unaffected. This was correlated with a decrease in MMP-9 gene expression which is, in part, explained by a decrease in the nucleocytoplasmic export of the mRNA stabilizing factor HuR. Our data are therefore indicative of a selective role for propranolol in inhibiting MMP-9 secretion and HBMEC tubulogenesis which could potentially add to propranolol's anti-angiogenic properties.
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PMID:Propranolol adrenergic blockade inhibits human brain endothelial cells tubulogenesis and matrix metalloproteinase-9 secretion. 1946 30

Adrenomedullin (AM) is a multifunctional peptide vasodilator that transduces its effects through calcitonin receptor-like receptor/receptor activity modifying protein-2 and -3 (CLR/RAMP2 and CLR/RAMP3). Previously, we reported on the development of an anti-AM antibody that potently inhibits tumor cell proliferation in vitro and tumor growth in vivo. Here, we report the effect of anti-AM receptor antibodies (alphaAMRs) on angiogenesis and tumor growth. We demonstrate that alphaAMRs decrease in a dose-dependent manner the growth of U87 glioblastoma cells and HT-29 colorectal cancer cells, but not A549 lung cancer cells, in vitro. In vivo, AM in Matrigel plugs induces angiogenesis by promoting recruitment of endothelial cells, pericytes, myeloid precursor cells, and macrophages and by promoting channel formation. Remarkably, systemic administration of alphaAMRs every 3 d markedly reduced neovascularization of Matrigel plugs in a dose-dependent fashion, as demonstrated by reduced numbers of the recruited cells and vessel structures. Several human tumor xenografts in athymic mice were used to examine the effect of alphaAMR treatment on tumor angiogenesis and growth. AlphaAMR treatment significantly suppressed the growth of glioblastoma, lung, and colon tumors. Histological examination of alphaAMR-treated tumors showed evidence of disruption of tumor vascularity with decreased microvessel density, depletion of endothelial and pericyte cells, and increased tumor cell apoptosis. These findings support the conclusion that alphaAMR treatment inhibits tumor growth by suppression of angiogenesis and tumor growth and suggest that AMRs may be useful therapeutic targets.
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PMID:Targeting adrenomedullin receptors with systemic delivery of neutralizing antibodies inhibits tumor angiogenesis and suppresses growth of human tumor xenografts in mice. 1954 5

Netrins are secreted molecules and involved in axon guidance, cell migration and tumor development. Recent studies revealed that netrins perform novel functions in such processes as epithelial development and angiogenesis without operating through the classical netrin receptors, DCC (Deleted in Colorectal Cancer) and Unc5h. In the present study, we investigated the roles of netrin-1 and its receptors in cell spreading of human glioblastoma cells, and found that netrin-1 haptotactically enhanced fibronectin-induced cell spreading and focal adhesion formation in U373 glioblastoma cells. Netrin-1 binding to the U373 cell membrane was blocked by an antibody against alphav integrin subunit, but not by an anti-DCC or anti-Unc5h antibody. In addition, enhancement of the fibronectin response by netrin-1 was abrogated by a function blocking antibody against integrin alphavbeta3. Since the alphav subunit of the integrin family plays an important role in the pathophysiological aspects of cell migration, including tumor angiogenesis and metastasis, our data provide important insight into the molecular mechanism of netrin function.
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PMID:Netrin-1 specifically enhances cell spreading on fibronectin in human glioblastoma cells. 1996 60

Tumor angiogenesis is controlled by the integrated action of physicochemical and biological cues; however, the individual contributions of these cues are not well understood. We have designed alginate-based microscale tumor models to define the distinct importance of oxygen concentration, culture dimensionality, and cell-extracellular matrix interactions on the angiogenic capability of oral squamous cell carcinoma, and have verified the relevance of our findings with U87 glioblastoma cells. Our results revealed qualitative differences in the microenvironmental regulation of vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8) secretion in three-dimensional (3D) culture. Specifically, IL-8 secretion was highest under ambient conditions, whereas VEGF secretion was highest in hypoxic cultures. Additionally, 3D integrin engagement by RGD-modified alginate matrices increased IL-8 secretion independently of oxygen, whereas VEGF secretion was only moderately affected by cell-extracellular matrix interactions. Using two-dimensional migration assays and a new 3D tumor angiogenesis model, we demonstrated that the resulting angiogenic signaling promotes tumor angiogenesis by increasing endothelial cell migration and invasion. Collectively, tissue-engineered tumor models improve our understanding of tumor angiogenesis, which may ultimately advance anticancer therapies.
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PMID:Oxygen-controlled three-dimensional cultures to analyze tumor angiogenesis. 2021 69

Under physiological conditions, transferrin receptor 2 (TfR2) is expressed in the liver and its balance is related to the cell cycle rather than to intracellular iron levels. We recently showed that TfR2 is highly expressed in glioblastoma cell lines. Here, we demonstrate that, in these cells, TfR2 appears to localize in lipid rafts, induces extracellular signal-regulated kinase 1/2 phosphorylation after transferrin binding, and contributes to cell proliferation, as shown by RNA silencing experiments. In vitro hypoxic conditions induce a significant TfR2 up-regulation, suggesting a role in tumor angiogenesis. As assessed by immunohistochemistry, the level of TfR2 expression in astrocytic tumors is related to histologic grade, with the highest expression observed in glioblastomas. The level of TfR2 expression represents a favorable prognostic factor, which is associated with the higher sensitivity to temozolomide of TfR2-positive tumor cells in vitro. The endothelial cells of glioblastoma vasculature also stain for TfR2, whereas those of the normal brain vessels do not. Importantly, TfR2 is expressed by the subpopulation of glioblastoma cells with properties of cancer-initiating cells. TfR2-positive glioblastoma cells retain their TfR2 expression on xenografting in immunodeficient mice. In conclusion, our observations demonstrate that TfR2 is a neoantigen for astrocytomas that seems attractive for developing target therapies.
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PMID:Transferrin receptor 2 is frequently and highly expressed in glioblastomas. 2036 Sep 37


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