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Chicoine, Michael R.; Silbergeld, Daniel L.

doi:10.1023/a:1005808315821

Cited by 61 publications

(8 citation statements)

References 56 publications

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“…4A) (24). Cell migration in this model is a result of cell-substrate versus cell-cell adhesive forces, mimicking the detachment and invasive properties of malignant brain tumor cells (33). Results from these assays indicated that expression of HAPLN4 resulted in a net increase in cell motility (measured as the increase in area occupied by migrating cells) on surfaces coated with HA but not on uncoated surfaces, in agreement with our adhesion tests (Fig.…”

Section: Expression Of Brain-specific Haplns Is Strongly Reduced In Highsupporting

confidence: 83%

“…A, representative images of U251MG cells detaching from a cell aggregate and migrating on a precoated culture well. Images were captured by time-lapse microscopy every 15 min for a total time of 14 h. Pictures in the second row show the result of applying contrast-and edge-enhancing algorithms to measure the total area of dispersion, as previously described (33). B, the average dispersion index (i.e.…”

Section: Discussionmentioning

confidence: 99%

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Reduced Expression of the Hyaluronan and Proteoglycan Link Proteins in Malignant Gliomas

Sim

Viapiano

2009

Journal of Biological Chemistry

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Malignant gliomas have a distinctive ability to infiltrate the brain parenchyma and disrupt the neural extracellular matrix that inhibits motility of axons and normal neural cells. Chondroitin sulfate proteoglycans (CSPGs) are among the major inhibitory components in the neural matrix, but surprisingly, some are up-regulated in gliomas and act as pro-invasive signals. In the normal brain, CSPGs are thought to associate with hyaluronic acid and glycoproteins such as the tenascins and link proteins to form the matrix scaffold. Here, we examined for the first time the expression of link proteins in human brain and malignant gliomas. Our results indicate that HAPLN4 and HAPLN2 are the predominant members of this family in the adult human brain but are strongly reduced in the tumor parenchyma. To test if their absence was related to a pro-invasive gain of function of CSPGs, we expressed HAPLN4 in glioma cells in combination with the CSPG brevican. Surprisingly, HAPLN4 increased glioma cell adhesion and migration and even potentiated the motogenic effect of brevican. Further characterization revealed that HAPLN4 expressed in glioma cells was largely soluble and did not reproduce the strong, hyaluronan-independent association of the native protein to brain subcellular membranes. Taken together, our results suggest that the tumor parenchyma is rich in CSPGs that are not associated to HAPLNs and could instead interact with other extracellular matrix proteins produced by glioma cells. This dissociation may contribute to changes in the matrix scaffold caused by invasive glioma cells. The extracellular matrix (ECM)2 of the adult central nervous system lacks most fibrous proteins (collagens, fibronectin, and laminins) that are present in the matrices of other tissues and is formed instead by a scaffold of hyaluronic acid (HA) with associated glycoproteins (1). The major family of HA binding matrix glycoproteins in the central nervous system is formed by the chondroitin sulfate proteoglycans of the lectican family (aggrecan, versican, neurocan, and brevican), the last two expressed almost exclusively in neural tissue (2). These proteoglycans bind both to HA and to cell-surface receptors (3), regulating the cross-linking and compressibility of the matrix scaffold and, therefore, modulating many neural processes including cell motility during development, axonal navigation, and the stabilization of synapses (4). The lecticans have been identified as a major class of molecules that restrict cellular and axonal motility in neural tissue and are a major component of the glial scar that forms after neural injury and prevents axonal regeneration (5).A second family of HA-binding proteins expressed in the central nervous system is formed by small glycoproteins known as HA-and proteoglycan-link proteins (HAPLNs) or, simply, "link proteins." These glycoproteins bind both to HA and to the lecticans, forming ternary complexes (6, 7). The structure of the link proteins is remarkably similar to the N-terminal region of the lecticans, and t...

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Section: Expression Of Brain-specific Haplns Is Strongly Reduced In Highsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Reduced Expression of the Hyaluronan and Proteoglycan Link Proteins in Malignant Gliomas

Sim

Viapiano

2009

Journal of Biological Chemistry

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“…After 3 d, the populations coalesced into a single spheroid with the human glioblastoma cells invading the structure composed of normal human astrocytes. Glioblastoma is the most common, invasive, and lethal type of astrocytic brain tumor 28 , and these results illustrate the potential of this methodology for analysis of brain tumor invasiveness of normal brain in confrontation culture assays, which have been correlated with clinical outcome 29 .…”

mentioning

confidence: 71%

“…b , Confrontation between human glioblastoma cells and normal astrocytes monitored for 10.5 d. Invasion of the spheroid composed of normal human astrocytes by human glioblastoma cells serves as a standard assay of glioma invasiveness 29 . Scale bar, 200 µm.…”

Section: Figurementioning

confidence: 99%

Three-dimensional tissue culture based on magnetic cell levitation

et al. 2010

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Cell culture is an essential tool for drug discovery, tissue engineering, and stem cell research. Conventional tissue culture produces two-dimensional (2D) cell growth with gene expression, signaling, and morphology that can differ from those in vivo and thus compromise clinical relevancy1–5. Here we report a three-dimensional (3D) culture of cells based on magnetic levitation in the presence of hydrogels containing gold and magnetic iron oxide (MIO) nanoparticles plus filamentous bacteriophage. This methodology allows for control of cell mass geometry and guided, multicellular clustering of different cell types in co-culture through spatial variance of the magnetic field. Moreover, magnetic levitation of human glioblastoma cells demonstrates similar protein expression profiles to those observed in human tumor xenografts. Taken together, these results suggest levitated 3D culture with magnetized phage-based hydrogels more closely recapitulates in vivo protein expression and allows for long-term multi-cellular studies.

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“…The results of recent studies, however, have demonstrated that it may also be due to changes in cellular microenvironments in the brain after treatment [5-8]. In addition, accumulating evidence suggests that molecules that are induced by primary tumors directly regulate motility in various types of malignant cells [9-14]. …”

Section: Introductionmentioning

confidence: 99%

Post-radiation increase in VEGF enhances glioma cell motility in vitro

2012

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BackgroundGlioblastoma multiforme (GBM) is among the most lethal of all human tumors, with frequent local recurrences after radiation therapy (RT). The mechanism accounting for such a recurrence pattern is unclear. It has classically been attributed to local recurrence of treatment-resistant cells. However, accumulating evidence suggests that additional mechanisms exist that involve the migration of tumor or tumor stem cells from other brain regions to tumor bed. VEGFs are well-known mitogens and can be up-regulated after RT. Here, we examine the effect of irradiation-induced VEGF on glioma cell motility.Materials and methodsU251 and LN18 cell lines were used to generate irradiated-conditioned medium (IR-CM). At 72 h after irradiation, the supernatants were harvested. VEGF level in IR-CM was quantified by ELISA, and expression levels for VEGF mRNA were detected by RT-PCR. In vitro cancer cell motility was measured in chambers coated with/without Matrigel and IR-CM as a cell motility enhancer and a VEGF antibody as a neutralizer of VEGF bioactivity. Immunoblots were performed to evaluate the activity of cell motility-related kinases. Proliferation of GBM cells after treatment was measured by flow cytometry.ResultsIrradiation increased the level of VEGF mRNA that was mitigated by pre-RT exposure to Actinomycin D. U251 glioma cell motility (migration and invasion) was enhanced by adding IR-CM to un-irradiated cells (174.9 ± 11.4% and 334.2 ± 46% of control, respectively). When we added VEGF antibody to IR-CM, this enhanced cell motility was negated (110.3 ± 12.0% and 105.7 ± 14.0% of control, respectively). Immunoblot analysis revealed that IR-CM increased phosphorylation of VEGF receptor-2 (VEGFR2) secondary to an increase in VEGF, with a concomitant increase of phosphorylation of the downstream targets (Src and FAK). Increased phosphorylation was mitigated by adding VEGF antibody to IR-CM. There was no difference in the mitotic index of GBM cells treated with and without IR-CM and VEGF.ConclusionsThese results indicate that cell motility can be enhanced by conditioned medium from irradiated cells in vitro through stimulation of VEGFR2 signaling pathways and suggest that this effect involves the secretion of radiation-induced VEGF, leading to an increase in glioma cell motility.

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Untitled

Cited by 61 publications

References 56 publications

Reduced Expression of the Hyaluronan and Proteoglycan Link Proteins in Malignant Gliomas

Reduced Expression of the Hyaluronan and Proteoglycan Link Proteins in Malignant Gliomas

Three-dimensional tissue culture based on magnetic cell levitation

Post-radiation increase in VEGF enhances glioma cell motility in vitro

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