The Role of Fascin in the Migration and Invasiveness = of Malignant Glioma Cells

Journal=20 List > Neoplasia=20 > v.1= 0(2);=20 Feb 2008

PubMed=20 articles by:

Hyun Hwang, J.

Smith, C.

Salhia, B.

Rutka, = J.

Neoplasia. = 2008 February; = 10(2):=20 149=E2=80=93159.

PMCID:=20 PMC2244690

The Role of Fascin in the Migration and = Invasiveness=20 of Malignant Glioma Cells 1

Jeong Hyun=20 Hwang,^*^=E2=80=A0 Christian A = Smith,^=E2=80=A0 Bodour=20 Salhia,^=E2=80=A1 and James T Rutka^=E2=80=A0

^*Department of Neurosurgery, = School of=20 Medicine, Kyungpook National University, Daegu, South Korea

^=E2=80=A0The Arthur and Sonia = Labatt Brain Tumor=20 Research Center, The Hospital for Sick Children, The University of = Toronto, Toronto, Ontario, Canada

^=E2=80=A1The Translational = Genomics Research=20 Institute, Phoenix, AZ, USA

Address all correspondence to: James T. = Rutka, MD,=20 PhD, Division of Neurosurgery, Suite 1503, The Hospital for Sick = Children,=20 555 University Avenue, Toronto, Ontario, Canada M5G 1X8. E-mail: = james.rutka/at/sickkids.ca

Received October 11, 2007; Revised = November 28,=20 2007; Accepted November 28, 2007.

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"=20 = src=3D"http://www.pubmedcentral.nih.gov/corehtml/pmc/pmcgifs/square.gif" = border=3D0>Abstract

Introduction

Material and=20 Methods

Results

Discussion

References

Abstract

Malignant glioma is the most common = primary=20 brain tumor, and its ability to invade the surrounding brain = parenchyma is=20 a leading cause of tumor recurrence and treatment failure. Whereas = the=20 molecular mechanisms of glioma invasion are incompletely = understood, there=20 is growing evidence that cytoskeletal-matrix interactions = contribute to=20 this process. Fascin, an actin-bundling protein, induces parallel = actin=20 bundles in cell protrusions and increases cell motility in = multiple human=20 malignancies. The role of fascin in glioma invasion remains = unclear. We=20 demonstrate that fascin is expressed in a panel of human malignant = glioma=20 cell lines, and downregulation of fascin expression in glioma cell = lines=20 by small interfering RNA (siRNA) is associated with decreased = cellular=20 attachment to extracellular matrix (ECM) and reduced migration. = Using=20 immunofluorescence analysis, we show that fascin depletion results = in a=20 reduced number of filopodia as well as altered glioma cell shape. = In=20 vitro invasiveness of U251, U87, and SNB19 glioma cells was = inhibited=20 by fascin siRNA treatment by 52.2%, 40.3%, and 23.8% respectively. = Finally, we show a decreased invasiveness of U251-GFP cells by = fascin=20 knockdown in an ex vivo rat brain slice model system. This is the = first=20 study to demonstrate a role for fascin in glioma cell morphology,=20 motility, and invasiveness.

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Abstract

"=20 = src=3D"http://www.pubmedcentral.nih.gov/corehtml/pmc/pmcgifs/square.gif" = border=3D0>Introduction

Material and=20 Methods

Results

Discussion

References

Introduction

Malignant gliomas are the most common primary brain tumors [1].=20 Currently, surgery and radiation therapy followed by treatment = with=20 temozolomide is the treatment protocol of choice for patients with = glioblastoma multiforme [2,3].=20 However, despite advanced multimodal treatment, the median life = expectancy=20 for patients with glioblastoma multiforme is approximately 14 = months with=20 less than 5% of patients alive at 5 years after diagnosis [4,5].=20 Although systemic metastases of malignant gliomas are relatively = rare, the=20 highly infiltrative nature of glioma cells that invade into = surrounding=20 brain parenchyma is a major cause of treatment failure and tumor=20 recurrence [6,7].=20 Glioma invasion is a multifactorial process consisting of glioma = cell=20 interactions with normal cellular constituents such as astrocytes, = neurons, and endothelial cells, interactions with the = extracellular matrix=20 (ECM), proteolysis of ECM components, and migration [8].

To migrate, glioma cells must modify their shape and rigidity = to=20 interact with the surrounding environment [9].=20 Typically, a migrating glioma cell will remodel its cytoskeleton = to form=20 cellular protrusions and focal adhesions at the leading edge, and = generate=20 tensile forces to move the cell body forward. Cellular protrusions = known=20 as filopodia are considered essential processes in cell migration = because=20 they function as sensors of the external microenvironment and as = plasma=20 membrane extensions that form initial contacts with the ECM. The=20 rearrangement of actin microfilaments into strong parallel actin = bundles=20 within or near filopodia is a key component of the migration = process [10=E2=80=9313].=20 Reorganization of the actin microfilamentous system has previously = been=20 associated with alterations in glioma morphology and invasiveness = [14].

Several actin-binding proteins have been described including = =CE=B1-actinin,=20 tropomyosin, fimbrin, villin, and fascin [11].=20 Fascin is a key actin-bundling protein that provides rigidity to=20 filopodial bundles [13,15].=20 Fascin was first isolated from sea urchin egg extracts [16],=20 and then identified in Drosophila [17]=20 and in human B-lymphocytes [18].=20 Fascin has been shown to be expressed at high levels in the brain, = ovary,=20 and testis [19].=20 In the brain, fascin expression has been localized to neurons, = glial=20 cells, and endothelial cells [19=E2=80=9322].=20 Fascin colocalizes with filopodia, microspikes, lamellopodia, and = stress=20 fibers [20,23].=20 Additionally, fascin has been shown to localize to lamellipodia = and=20 filopodia in growth cones of cultured neurons [12,18].=20 These findings suggest that fascin may play an important role in = the=20 formation of actin-based structures, such as filopodia and = lamellipodia,=20 and in the migratory behavior of cells.

Fascin expression is increased in different types of cancers = including=20 breast, lung, ovary, esophagus, kidney, and colon [24=E2=80=9333].=20 In addition, high fascin expression has been observed in many = transformed=20 cells and carcinoma cell lines [15,24,26,29,34].=20 Cancer cells expressing high levels of fascin exhibit morphologic=20 characteristics, such as increased membrane protrusions and = migration=20 ability. However, little is known about the role of fascin in = human brain=20 tumors. Recently, two studies reported the relationship between = fascin=20 expression and human gliomas [35,36].=20 Both studies demonstrate that an increase in fascin expression is=20 associated with increasing tumor grade in glial tumors. To date, = no=20 studies have examined the consequences of fascin manipulations in=20 experimental glioma cell systems. Accordingly, to determine if = fascin=20 plays a role in the migratory capacity of glioma cells, we have = used small=20 interfering RNAs (siRNA) to suppress the expression of fascin in = glioma=20 cells. Here we report our results on fascin knockdown on glioma = cell=20 proliferation, adhesion, migration, and invasivenevess in = vitro=20 and in an ex vivo rat brain slice model = system.

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Abstract

Introduction

"=20 = src=3D"http://www.pubmedcentral.nih.gov/corehtml/pmc/pmcgifs/square.gif" = border=3D0>Material and=20 Methods

Results

Discussion

References

Material and Methods

Cell Culture and Extracellular=20 Matrix

The permanent, well-characterized human glioma cell = lines=20 U251, U87, SNB19, U138, T98, and U118 were received from the = American Type=20 Culture Collection (Manassas, VA). The U343 cell line was obtained = from=20 Brain Tumor Research Center, University of California (San = Francisco, CA).=20 U251-GFP, a glioma cell line stably expressing green fluorescence = protein=20 (GFP), was provided by Michael Berens (The Translational Genomics = Research=20 Institute, Phoenix, AZ). Glioma cells were maintained in = Dulbecco's=20 modified Eagle's medium (DMEM) supplemented with 10% fetal bovine = serum=20 (FBS) and cultured at 37=C2=B0C, 5% CO₂ in a humidified = chamber.=20 Normal human astrocytes were purchased from Clonetics (East = Rutherford,=20 NJ) and maintained in ABM media containing 3% FBS, 0.1% ascorbic = acid,=20 0.5% recombinant human epidermal growth factor, 0.1% GA-1000, = 0.25%=20 insulin, and 1% l-glutamine (all from Clonetics). The human ECM = proteins=20 laminin, vitronectin, fibronectin, and collagen type IV were = obtained from=20 Sigma (St. Louis, MO).

Small Interfering RNA = Preparation and=20 Transfections

Small interfering RNA (siRNA) duplexes specific = for=20 Fascin1 were designed according to Elbashir et al. [37].=20 Two different Fascin siRNA sequences were used: Fs1, corresponding = to 113=20 to 133 bp after the start codon of the Fascin1 gene = (5=E2=80=B2=20 GCAGCCTGAAGAAGAAGCA), and Fs2, corresponding to 1340 to 1360 bp = after the=20 start codon of the Fascin1 gene (5=E2=80=B2 = CTCCTGTGGACTTCTTCTTTT). The=20 21-nt RNA was purchased from Eurogentec (San Diego, CA) in = deprotected and=20 desalted forms. As a control for off-target effects caused by RNA=20 interference, nontargeting siRNA, designed to have at least four=20 mismatches to any human and mouse species, was used (Dharmacon, = Lafayette,=20 CO). Transient transfections of siRNA (50 nM final concentration) = against=20 Fascin1 were carried out using Lipofectamine 2000 (Invitrogen, = Carlsbad,=20 CA). Cells were plated at 60% confluency in DMEM containing 10% = serum=20 without antibiotics and transfections were carried out 24 hours = later.=20 Lipofectamine 2000 was diluted in serum-free DMEM for 5 minutes = and the=20 siRNA was diluted in serumfree DMEM. The two mixtures were = combined and=20 incubated for 20 minutes at room temperature to enable = transfection=20 complex formation. The complexes were subsequently added to the = cells.=20 Transfections with Lipofectamine 2000 alone served as controls. = Maximal=20 depletion was achieved by day 3 after transfection, and cells were = assayed=20 at 72 hours after transfection. Fascin expression was determined = by=20 western blot analysis using an anti-human fascin monoclonal = antibody=20 (1:1000; DakoCytomation, Carpinteria, CA).

Western Blot = Analysis

Total cell=20 lysates were prepared in a lysis buffer (50 mM Tris pH 7.4, 1% = Triton=20 X-100, 2 mM EDTA, 150 mM NaCl) with a cocktail of protease = inhibitors=20 (Roche Diagnostics, Basel, Switzerland). Lysates were cleared by=20 centrifugation and mixed with SDS sample buffer containing Tris pH = 6.8, 2%=20 SDS, glycerol and =CE=B2-mercaptoethanol. The protein = concentration was=20 estimated by Lowry method using DC Protein Assay Kit (Bio-Rad, = Hercules,=20 CA) and 10 =C2=B5g of protein extracts were separated by SDS-PAGE, = and=20 transferred to polyvinyldifluoride membranes (Millipore, Bedford, = MA). The=20 membranes were subsequently blocked with 5% skim milk in TBS-T (50 = mM Tris=20 pH 7.5, 150 mM NaCl, and 0.1% Tween 20) for 1 hour at room = temperature and=20 incubated overnight at 4=C2=B0C with the primary antibodies = described above. A=20 monoclonal antibody against the human transferrin receptor = (1:1000; Zymed,=20 South San Francisco, CA) was used on the same blot and served as a = loading=20 control. The membranes were subsequently incubated at room = temperature for=20 1 hour with horseradish peroxidase-linked goat anti-mouse IgG = (Bio-Rad,=20 Hercules, CA) and analyzed using Western Blotting Luminol Reagent=20 (PerkinElmer Life Sciences, Boston, MA).

Cell Viability Assay

Cell = viability=20 was determined using the colorimetric MTS assay. Cells transiently = transfected with two different siRNA oligonucleotides were = trypsinized,=20 counted and resuspended in DMEM with 10% FBS at 6 hours after=20 transfection. The cells were plated in 96-well dishes at a density = of 5000=20 cells/well and were allowed to adhere overnight. Cells were = transfected=20 with Lipofectamine 2000-complexed fascin siRNA or nontargeting = siRNA.=20 Cells were tested in quadruplicate with MTS=20 = [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl= )-2H-tetrazolium,=20 inner salt (Promega, Madison, WI)] to assess cell viability at 24 = and 72=20 hours after transfection. The MTS assay was performed according to = the=20 manufacturer's instructions. MTS coupled with an electron-coupling = reagent=20 (phenazine ethosulfate) was added to each well of cells and = incubated at=20 37=C2=B0C in a humidified chamber for 1 hour. Absorbance of the = reaction was=20 measured at 490 nm using a microtiter plate reader (VersaMax; = Molecular=20 Devices Corp., Sunnyvale, CA). The quantity of formazan product, = as=20 measured by absorbance, is directly proportional to the number of = living=20 cells. Absorbance was plotted as a percentage of the control = value. All=20 experiments were repeated in triplicate and repeated three = independent=20 times.

Cell Attachment Assay

The = cell=20 attachment assay was performed as described previously [37,38]=20 with modifications. Ninety-six-well plates were incubated at = 4=C2=B0C overnight=20 with different ECM proteins (laminin and fibronectin at 10 = =C2=B5g/ml, collagen=20 type IVat 50 =C2=B5g/ml, and vitronectin at 1 =C2=B5g/ml). The = unbound sites were=20 blocked with 0.1% BSA in PBS for 1 hour at 37=C2=B0C. Control = dishes were=20 prepared by blocking with BSA alone. Glioma cells were detached,=20 resuspended in serum-free medium at 72 hours after transfection, = then=20 plated at 5 x 10⁴ cells/well on ECM protein- or = BSA-coated=20 plates. The cells were allowed to adhere for 3 hours at 37=C2=B0C = and 5%=20 CO₂ in a humidified chamber. Unattached cells were = removed by=20 washing with PBS three times, and the remaining cells were fixed = with 4%=20 paraformaldehyde and stained with 0.5% crystal violet. The excess = stain=20 was washed away with water then air-dried overnight. The crystal = violet=20 bound to the attached cells was solubilized with 1% SDS and the = absorbance=20 of each well was measured at 595 nm using a microtiter plate = reader=20 (Molecular Devices Corp.). All experiments were repeated three = times with=20 five replicates.

Cell Migration Assay

Cell = migration=20 assays were performed using the microliter-scale radial monolayer = assay as=20 described previously [6,14,39,40].=20 Briefly, 10-well Teflon-coated slides (CSM Inc., Phoenix, AZ) were = coated=20 with different ECM proteins and 0.1% BSA as described above. Cells = transfected with siRNA for Fascin1 or nontargeting oligonucleotide = were=20 collected 24 hours after transfection and seeded through a cell=20 sedimentation manifold (CSM Inc.) at 3000 cells/well to establish = a=20 circular confluent monolayer, 1 mm in diameter, at the center of = the=20 substrate-coated well. Photographs were taken 16 hours after = plating and a=20 circle of best-fit circumscribing the cells was drawn. The cells = were=20 allowed to migrate for a 24-hour period, and another circle = circumscribing=20 the newly migrated cells was made. The average migration rate was=20 calculated as the change in the diameter of the circle = circumscribing the=20 cell population over a 24-hour period (micrometers per 24 hours).=20 Photomicrographs were taken with an inverted microscope (Leica DM = IRE2;=20 Leica Microsystems, Bannokburn, IL) and analyzed using image = analysis=20 software (Scion Image, Frederick, MD). All experiments were = repeated in=20 five replicates and experiments were repeated three times.

Cell Invasion Assay

A cell = invasion=20 assay was carried out using modified Boyden Chambers consisting of = Transwell-precoated Matrigel membrane filter inserts with 8 = =C2=B5m pores in=20 24-well tissue culture plates (BD Biosciences, Bedford, MA) as = described=20 previously [40].=20 Two days after transfection with siRNA, 4 x 10⁴ cells = were=20 plating onto the top of the chamber in DMEM with 5% FBS and the = bottom=20 chamber was filled with DMEM containing 20% FBS as a = chemoattractant.=20 After 24 hours of incubation in a 5% CO₂ humidified = chamber at=20 37=C2=B0C, noninvading cells were removed by wiping the upper = surface of the=20 membrane with a cotton swab, and the filter membrane was fixed = with 4%=20 paraformaldehyde and stained with 0.5% crystal violet. The degree = of=20 invasion was quantified by counting the cells that had migrated = through=20 the membrane in at least six random fields (total magnification, = x200) per=20 filter. Experiments were repeated three times in triplicate.

Ex Vivo Brain Slice Invasion=20 Assay

The ex vivo rat brain slice model system was = modified=20 from the organotypic culture methods reported previously [40=E2=80=9343].=20 Briefly, the brain tissue was prepared from 4-week-old male Wistar = rats=20 (Charles River Laboratories Inc., Wilmington, MA). After = administration of=20 isoflurane anesthesia, the cerebrum was removed and cut vertically = to the=20 base in 400-=C2=B5m sections using a tissue slicer (EMS 4000; = Electron=20 Microscopy Science, Hatfield, PA). The brain slices were = transferred to=20 the upper chamber of a transwell insert and placed on top of the = 0.4-=C2=B5m=20 micropore polycarbonate filter (BD Biosciences) in a six-well = tissue=20 culture plate. The brain slices were incubated at least 24 hours = before=20 cell seeding at 37=C2=B0C and 5% CO₂ in a humidified = chamber in DMEM=20 with 10% FBS, 100 U/ml penicillin, 100 =C2=B5g/ml streptomycin, = and 2.5 =C2=B5g/ml=20 amphotericin B. Three days after transfection with siRNA, U251-GFP = cells=20 were trypsinized and resuspended in serum-free medium to 2 x=20 10⁸ cells/ml, and 10⁵ glioma cells (0.5 = =C2=B5l transfer=20 volume) were placed on the center of the putamen. The cells were = allowed=20 to invade into the brain slice for 72 hours. Six brain slices were = used in=20 each experiment. To quantitate glioma cell invasion, the brain = slice was=20 fixed overnight in 4% paraformaldehyde at 4=C2=B0C, and = fluorescent imaging was=20 taken at 10x magnification using an inverted laser confocal = microscope=20 (LSM 510 META; Carl Zeiss Inc., Thronwood, NY). To assess the = depth of=20 invasion in control and fascin siRNA. transfected cell = populations, serial=20 sections were obtained every 10 =C2=B5m downward from the top = surface to the=20 bottom of the slice after 72 hours. The LSM 510 software (Carl = Zeiss Inc.)=20 was used to calculate the total area of GFP-stained cells in each = section=20 and the extent of glioma cell invasion was defined as the depth of = penetration (in =C2=B5m) after 72 hours to which the invading = cells penetrated=20 the brain slice as described previously [40].=20 The animal protocol described here was approved by the = Institutional=20 Animal Care Committee. All experiments were repeated three times.

Immunofluorescence and Confocal = Microscopy

Cells transfected by siRNA were plated onto = coverslips=20 precoated with laminin (10 =C2=B5g/ml) 24 hours after = transfection. At 72 hours=20 after transfection, cells were washed three times with PBS and = fixed with=20 4% paraformaldehyde for 10 minutes and permeabilized for 5 minutes = with=20 0.5% Triton X-100 in PBS at room temperature. Nonspecific binding = was=20 blocked by 1% BSA in PBS for 1 hour at room temperature. = Subsequently,=20 cells were incubated with an anti-fascin monoclonal antibody = (1:200;=20 DakoCytomation) for 1 hour. After washing, cells were then = incubated with=20 Alexa Fluor 488. (Molecular Probes, Eugene, OR) conjugated goat = anti-mouse=20 IgG secondary antibodies for 30 minutes at room temperature. For = double=20 labeling with F-actin, cells were coincubated with Texas Red-X = phalloidin=20 (1:50 dilution; Molecular Probes). A Zeiss Axiovert 200M Spinning = Disk=20 confocal microscope (Carl Zeiss Inc.) installed with a Hamamatsu=20 Back-Thinned EM-CCD camera (Hamamatsu, Bridgewater, NJ) was used = to=20 visualize fluorescence.

Statistical Analyses

Data = are=20 expressed as mean =C2=B1 standard error (SE). Statistical analyses = were=20 performed with Student's t test and Mann-Whitney U test. = A=20 P value of < .05 was considered statistically = significant.

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Abstract

Introduction

Material and=20 Methods

"=20 = src=3D"http://www.pubmedcentral.nih.gov/corehtml/pmc/pmcgifs/square.gif" = border=3D0>Results

Discussion

References

Results

Fascin Expression in Glioma = Cell Lines=20 and Fascin Silencing by siRNA Transfection

Western blot = analysis was=20 performed on all the different glioma cell lines including U138, = T98,=20 U251, U87, SNB19, U343, and U118 as well as normal human = astrocytes. All=20 glioma cells tested and normal human astrocytes showed fascin = expression=20 (Figure=20 1A). Of the cell glioma cell lines examined, we = selected=20 three, U251, U87, and SNB19, for further study as they were = comparable in=20 terms of fascin expression levels and were well characterized = previously=20 in terms of in vitro growth kinetics.

Figure=20 1

Expression of=20 fascin protein in glioma cell lines and fascin knockdown by = siRNA.=20 (A) Western blot analysis of fascin expression in = astrocytoma cell=20 lines and normal human astrocytes. (B) Fascin expression = following=20 transfection with siRNA for fascin1=20 (more ...)

Fascin knockdown was achieved following transient transfection = with two=20 different fascin siRNA duplexes (Figure=20 1B). In all experiments, a nontargeting = oligonucleotide was=20 used to exclude nonspecific off-target effects of RNA = interference. Fascin=20 knockdown was observed following 24 hours after siRNA = transfection, and=20 reached maximum depletion at 72 hours after transfection (Figure=20 1C). Therefore, subsequent experiments such as = adhesion,=20 migration, invasion, and immunofluorescent studies were performed = 72 hours=20 after transfection to analyze the functional effects of fascin=20 depletion.

Fascin Downregulation and = Glioma Cell=20 Viability

An MTS cell viability assay was used to examine the = effects=20 of fascin knockdown on glioma cells. At 72 hours after = transfection, cell=20 viability was unaffected in U251 and SNB19 glioma cells, and = minimally=20 affected in U87 cells (13% decrease in cell viability compared to=20 untransfected and nontargeting siRNA controls) (data not shown).

Fascin Knockdown Reduces = Filopodia=20 Formation in Glioma Cells

Immunofluorescence was used to = examine the=20 effects of fascin knockdown on cell morphology. Cells were seeded = on=20 laminin-coated coverslips given that previous studies have shown = laminin=20 to be the most permissive ECM substrate for glioma cell motility = [6,44].=20 Fascin localized to the perinuclear cytoplasm and actin-rich = membrane=20 ruffles at the leading edge (Figure=20 2). SNB19 and U251 cells showed well-organized lamellipodia. = Filopodia=20 were also observed at the leading edge especially in SNB19 glioma = cells.=20 In contrast to untransfected cells, we observed a decrease in the=20 formation of membrane ruffles in fascin-depleted SNB19 and U251 = glioma=20 cells. U87 cells changed cell shape somewhat from typical spindle = form of=20 untransfected cells to more polygonal appearances after fascin = knockdown.=20 Following fascin knockdown, there was a significant reduction in = filopodia=20 formation especially for U87 and SNB19 glioma cells (Figure=20 3). Filopodia that remained after fascin depletion were of = shorter=20 length when compared to controls.

Figure=20 2

Morphology of=20 glioma cells following fascin siRNA transfection. After = siRNA=20 transfection, cells were plated on laminin-precoated = coverslips for=20 immunofluorescence. Cells were labeled with Texas Red-X = phalloidin=20 for F-actin. Fascin was labeled with anti-fascin=20 (more ...)

Figure=20 3

Inhibition of=20 filopodia formation by fascin knockdown. Cells were seeded = on=20 laminin-coated coverslips after fascin siRNA transfection. = Actin=20 filaments were labeled with Texas Red-X phalloidin. Arrows = show=20 filopodial bundles from cell edge in untransfected=20 (more ...)

Fascin Elimination Decreases = Glioma Cell=20 Adhesion

Given that filopodial formation was significantly = inhibited=20 following fascin knockdown, and that filopodia play an important = role in=20 cell-ECM adhesion, we predicted that fascin depletion may affect = glioma=20 cell adhesion. To determine the effects of fascin knockdown on = cell-ECM=20 adhesion, we used different purified ECM macromolecules as = substrates for=20 glioma adhesion. Glioma cell lines studied demonstrated different=20 affinities for adhering to ECM macromolecules. In general, glioma = cell=20 adhesion was greatest in all cell lines examined when laminin and = collagen=20 type IV were used as substrates. Glioma cell adhesion to = vitronectin and=20 fibronectin was similar to that of BSA in all three glioma cell = lines (Figure=20 4). The ability of the glioma cell lines to adhere to the = different=20 ECM substrates was strongly inhibited by fascin knockdown (Figure=20 4). These data suggest that, in addition to loss of filopodia = by=20 fascin knockdown, glioma cells demonstrate a decreased adhesive = capacity=20 when compared to controls. In addition, the data indicate that=20 fascin-dependent adhesion is not attributable to a single ECM=20 macromolecule, as the percentage inhibition of adhesion due to = siRNA is=20 similar across all substrates examined.

Figure=20 4

The = effects of=20 fascin knockdown on glioma cell adhesion to ECM. (A) U251, = (B) U87,=20 and (C) SNB19 cells were plated and allowed to adhere for 3 = hours on=20 different ECM substrates at 72 hours after transfection with = fascin=20 siRNA. After washing, crystal violet=20 (more ...)

Fascin Elimination Decreases = Migration in=20 Glioma Cells

To determine if fascin plays a role in glioma = cell=20 migration, radial migration assays were performed with different = purified=20 ECM macromolecules over a 24-hour period. Similar to the results = observed=20 in the adhesion study, the migration rate of all three glioma cell = lines=20 was enhanced on ECM substrates. After fascin knockdown, all three = glioma=20 cell lines showed a significant decrease in migration rate; the = migration=20 rate of U251 was decreased on laminin, collagen type IV, and = vitronectin=20 by 47.0% (P < .01), 24.7% (P < .01), and = 16.3%=20 (P < .05), respectively; U87 migration rate was = decreased on=20 laminin and collagen type IV by 47.9% (P < .01) and = 24.2%=20 (P < .01), respectively; the migration rate of SNB19 = was=20 decreased on laminin, collagen type IV, vitronectin, and = fibronectin by=20 49.8% (P < .01), 39.7% (P < .01), 28.2%=20 (P < .01), and 28.0% (P < .01) by fascin=20 knockdown, respectively (Figure=20 5).

Figure=20 5

The = effects of=20 fascin knockdown on glioma cell migration using = microliter-scale=20 radial migration assay. (A) U251, (B) U87, and (C) SNB19 = cells were=20 transfected with siRNA and seeded through a cell = sedimentation=20 manifold to establish a circular confluent=20 (more ...)

Fascin Knockdown Decreases = Invasion=20 Ability in Glioma Cells In Vitro and Ex = Vivo

Given=20 that there is a role for fascin in migration and adhesion, we = examined the=20 effect of fascin knockdown on glioma cell invasion. The = invasiveness of=20 U251, U87 and SNB19 cells was decreased following fascin depletion = compared to untransfected cells by 52.2% (mean =C2=B1 SE, 31.8 = =C2=B1 3.5=20 vs 66.5 =C2=B1 5.9 cells/field; P < .01), = 40.3% (47.7 =C2=B1=20 3.6 vs 79.9 =C2=B1 7.1 cells/field; P < .01), = and 23.8%=20 (47.9 =C2=B1 2.9 vs 62.9 =C2=B1 4.7 cells/field; = P < .01),=20 respectively. Nontargeting siRNA transfection had no demonstrable = effect=20 on the rate of invasion in all three glioma cell lines (Figure=20 6).

Figure=20 6

Matrigel = invasion=20 assay after fascin elimination. (A) Modified Boyden chamber = with=20 Matrigel-precoated membrane filter insert was used to = measure in=20 vitro invasiveness. After 24 hours of incubation, the = cells=20 that migrated through the membrane were stained,=20 (more ...)

For the ex vivo rat brain slice model system, we first = demonstrated that fascin expression was suppressed in U251-GFP = cells using=20 fascin siRNA (Figure=20 7A). After 72 hours of incubation on the brain = slices, the=20 depth of invasion of fascin-depleted U251-GFP cells was decreased = (74.2 =C2=B1=20 3.5 =C2=B5m/72 hours) compared to control cells (94.4 =C2=B1 4.4 = =C2=B5m/72 hours;=20 P < .01; Figure=20 7, B and C).

Figure=20 7

Ex = vivo=20 invasion assay. (A) Western blot analysis demonstrates = fascin=20 knockdown in U251-GFP cells following siRNA transfection (B) = Rat=20 brain slice model system was used to measure ex = vivo=20 invasiveness. Cells transfected by fascin siRNA were=20 transplanted=20 (more ...)

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Abstract

Introduction

Material and=20 Methods

Results

"=20 = src=3D"http://www.pubmedcentral.nih.gov/corehtml/pmc/pmcgifs/square.gif" = border=3D0>Discussion

References

Discussion

In this study, we have shown that the actin-bundling protein, = fascin,=20 is expressed in normal human astrocytes and permanent glioma cell = lines.=20 Previously, we demonstrated that fascin is expressed in white = matter and=20 cortex of normal brain. Interestingly, fascin expression increased = with=20 increasing grade of astrocytoma [35,36].=20 In the current study, when fascin is downregulated by siRNA, there = is an=20 associated decrease in glioma cell adhesion, migration, and in = vitro invasion. Taken together, these results suggest a role = for=20 fascin in glioma invasiveness. Whereas the mechanism by which = fascin=20 knockdown reduces glioma invasion is not entirely elucidated, we=20 hypothesize that suppression of fascin may alter the assembly of=20 cytoskeletal proteins, in particular actin microfilaments, in = filopodia at=20 the leading edge of motile cells causing a reduction in cell = adhesion and=20 migration.

Fascin is principally expressed in neural and mesenchymal = derivatives=20 during embryogenesis [45].=20 In the adult organism, fascin expression is highly tissue- and = cell=20 type-specific. For example, fascin is expressed at high levels in = the=20 nervous system, especially in neurons, glial cells, and vascular=20 endothelial cells [19=E2=80=9322,46].

Fascin functions in two major forms of actin-based structures: = cortical=20 cell protrusions that mediate cell interactions with ECM or other = cells=20 and migration; and cytoplasmic microfilamentous bundles that = contribute to=20 cell architecture and intracellular movements [13].=20 Fascin is a key filopodial bundling protein and has a central role = in the=20 formation and protrusion of filopodia [13,15].=20 Vignjevic et al. [15]=20 determined that fascin activity is essential to filopodial = dynamics and=20 proposed that fascin imparts rigidity to the forming filopodia to=20 efficiently push the membrane forward.

High-level expression of fascin has been observed in several = types of=20 human neoplasms, such as cancer of colon [26,29,33],=20 breast [24],=20 lung [27],=20 kidney [32],=20 ovary [30],=20 cervix [47],=20 and esophagus [28,31].=20 In node-negative invasive hereditary breast carcinomas, fascin is=20 frequently expressed in BRCA1-associated tumors [48].=20 Zhang et al. [49]=20 observed that breast cancer metastasis suppressor, BRMS1, = expression downregulates fascin expression in ovarian carcinoma. = Recently,=20 fascin has been regarded as a potential biomarker of early stage = cancer=20 [31].=20 Furthermore, high fascin expression correlated with lymph node or = distant=20 metastasis in cancers of colon, kidney, and esophagus, and played = a role=20 as an independent marker of poor prognosis [27=E2=80=9329,31=E2=80=9333,50].

Two previous studies have examined the expression of fascin in = human=20 gliomas. Peraud et al. [35]=20 reported fascin expression in a panel of human gliomas and = observed an=20 increase in fascin expression with increasing tumor grade. Roma = and=20 Prayson [36]=20 performed immunohistochemical analysis in gliomas including 90=20 glioblastomas. They also observed that the higher-grade tumors = expressed a=20 greater degree of fascin staining than did the lower-grade tumors. = Based=20 on these immunohistochemical data, it has been concluded that = fascin=20 expression is correlated with higher-grade malignancy in human = glial=20 tumors.

Overexpression of fascin is associated with increased cellular=20 proliferation in different cancers including non-small cell lung=20 adenocarcinoma [27],=20 colon carcinoma [26],=20 and esophageal squamous cell carcinoma [31].=20 Downregulation of fascin using RNAi resulted in suppression of = cell=20 proliferation in esophageal carcinoma cells [34].

Jawhari et al. [26]=20 transfected human colon adenocarcinoma cells with a fascin cDNA = and showed=20 that fascin overexpression leads to increased dynamic cell = protrusions,=20 increased focal contacts formation, increased motility, and = increased=20 invasiveness. In contrast, downregulation of fascin using RNAi in=20 esophageal carcinoma cells resulted in significantly reduced = cellular=20 motility and invasive properties [28,34].=20 These data support our observations in human glioma cells.

Previous reports have shown that the fascin-actin interaction = is=20 affected by extracellular cues [13,20].=20 Certain ECM components induce bundling of actin by fascin, whereas = others=20 produce inhibitory effects. Adams [21]=20 reported that cells exposed to thrombospondin-1 and tenascin-C = activate=20 stable formation of fascin-containing protrusions in fibroblasts, = whereas=20 cells that attach to fibronectin or vitronectin show only = transient=20 cellular protrusions. It is conceivable that differential = phosphorylation=20 of fascin by ECM substrates contributes to these observations. On = a=20 molecular basis, the actin-binding activity of fascin is inhibited = by=20 phosphorylation of residue Ser-39 by protein kinase C=CE=B1 = (PKC=CE=B1) [51,52].=20 Cohan et al. [12]=20 observed that treatment with the PKC activator,=20 12-O-tetradecanoylphorbol-13-acetate, resulted in loss of = all=20 actin bundles from growth cones in Helisoma. Recently, = Vignjevic=20 et al. [15]=20 demonstrated that dephosphorylation of Ser-39 determined = filopodial=20 formation in mouse melanoma cells. The constitutively active = fascin mutant=20 S39A increased the number and length of filopodia, = whereas the=20 inactive S39E mutant did not.

Several previous reports have demonstrated that fascin = silencing is=20 associated with changes in cellular process formation. Stable = fascin siRNA=20 transfection of esophageal carcinoma cells led to a decrease in = filopodia=20 formation by immunofluorescence analysis [28]=20 and electron microscopy [34].=20 Vignjevic et al. [15]=20 showed that fascin depletion leads to a reduction in the number of = filopodia with the remaining filopodia demonstrating abnormal = morphology=20 with waxy and loose actin bundle organization. Our study with = human glioma=20 cells corroborates the results of these previous studies.

In attempts to clarify the mechanism by which the elimination = of fascin=20 can lead to a reduction in cellular adhesion and migration, Wong = et al.=20 [53]=20 showed that ectopic constitutive expression of fascin disrupted = the=20 dexamethasone-induced localization of occludin and =CE=B2-catenin = to peripheral=20 cell membranes. Interestingly, Vignjevic et al. [54]=20 showed recently that =CE=B2-catenin/T cell factor signaling can = transactivate=20 the fascin1 promoter in human colon carcinoma cells. Xie = et al.=20 [34]=20 demonstrated that the effect of fascin on cell invasiveness = correlated=20 with the activation of matrix metalloproteinase-2 and -9, and = confirmed=20 that fascin downregulation is associated with a decrease in = =CE=B2-catenin and=20 c-erbB-2 expression. Grothey et al. [24]=20 have suggested that transcriptional upregulation of fascin in = human tumors=20 is dependent on overexpression of c-erbB-2/HER-2. However, the = role of=20 c-erbB-2 in malignant gliomas is not clear. In one study, 80% of=20 glioblastoma cells showed expression of c-erbB-2/HER-2 [55],=20 whereas in another study overexpression of c-erbB-2/HER-2 was = detected in=20 only 15% of glioblastoma tumor specimens [56].

In summary, fascin depletion in glioma cells results in = decreased=20 filopodial formation and decreased migration suggesting that = fascin plays=20 a key role in glioma invasiveness. The molecular mechanisms by = which=20 fascin interacts with actin and other cytoskeletal proteins to = alter=20 glioma cell motility, the use of a stable fascin knockdown system = in=20 vivo, and the development of pharmacological inhibitors of = fascin=20 will be instrumental in furthering our understanding of the role = of ascin=20 dynamics in human malignant gliomas.

Footnotes

¹This work was = supported by a=20 grant from the Canadian Institutes of Health Research (CIHR; = MOP-74610)=20 and was supported by Brainchild, the Wiley Fund, and the Laurie = Berman=20 Fund for Brain Tumor Research. J. T. Rutka was supported as a = Scientist of=20 the CIHR. B. Salhia was supported by a Restracomp fellowship from = The=20 Hospital for Sick Children and by a Canada Graduate Scholarship = Award from=20 the CIHR.

Top

Abstract

Introduction

Material and=20 Methods

Results

Discussion

"=20 = src=3D"http://www.pubmedcentral.nih.gov/corehtml/pmc/pmcgifs/square.gif" = border=3D0>References

<= /TD>

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Articles=20 from Neoplasia (New = York,=20 N.Y.) are provided here courtesy of
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i < len; i++)=0A= {=0A= if (elmnts.item(i).className.indexOf(className, " ") = !=3D -1)=0A= {=0A= elmnts.item(i).innerHTML =3D innerHTML;=0A= unObscuredEmails[className] =3D true=0A= =0A= }=0A= }=0A= }=0A= }=0A= catch(e){=0A= }=0A= }=0A= =0A= //=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=0A= function pubMedDbLinkSubmit(control) {=0A= try{=0A= if (control.pubmedOption) =0A= control =3D control.pubmedOption=0A= if (control.options)=0A= location.href =3D = control.options[control.options.selectedIndex].value;=0A= }=0A= catch(e){}=0A= return false;=0A= }=0A= ------=_NextPart_000_0008_01C87AC9.26E13E10 Content-Type: application/octet-stream Content-Transfer-Encoding: quoted-printable Content-Location: http://www.ncbi.nlm.nih.gov/corehtml/jsutils/utils.1.js // $Id: utils.1.js,v 1.12 2008/01/14 14:44:06 sponomar Exp $=0A= var utils=3D{=0A= KeyCode_TAB:9,=0A= KeyCode_DELETE:46,=0A= KeyCode_BACKSPACE:8,=0A= KeyCode_LEFT_ARROW:37,=0A= KeyCode_RIGHT_ARROW:39,=0A= KeyCode_HOME:36,=0A= KeyCode_END:35,=0A= KeyCode_PAGE_UP:33,=0A= KeyCode_PAGE_DOWN:34,=0A= KeyCode_UP_ARROW:38,=0A= KeyCode_DOWN_ARROW:40,=0A= KeyCode_ESC:27,=0A= KeyCode_ENTER:13,=0A= KeyCode_SPACE:32,=0A= KeyCode_SHIFT_KEY:16,=0A= KeyCode_CTRL_KEY:17,=0A= KeyCode_ALT_KEY:18,=0A= KeyCode_LEFT_MS_WINDOWS_KEY:91,=0A= KeyCode_RIGHT_MS_WINDOWS_KEY:92,=0A= KeyCode_MS_MENU_KEY:93,=0A= isObject: function(a) { return (a && typeof a =3D=3D 'object'); 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" + sText;=0A= else=0A= obj.innerHTML+=3DsText;=0A= }=0A= },=0A= selectRange:function (oObj,iStart,iLength ) {=0A= if (!(oObj && oObj.value)) return;=0A= if (oObj.createTextRange) {=0A= var oRange=3DoObj.createTextRange();=0A= oRange.moveStart("character", iStart);=0A= oRange.moveEnd("character", iLength - oObj.value.length);=0A= oRange.select();=0A= } else if (oObj.setSelectionRange) {=0A= oObj.setSelectionRange(iStart,iLength);=0A= }=0A= oObj.focus();=0A= },=0A= getSelection:function() {=0A= var text =3D "";=0A= if (window.getSelection) {=0A= text+=3Dwindow.getSelection();=0A= } else if (document.getSelection) {=0A= text+=3Ddocument.getSelection();=0A= } else if (document.selection){=0A= text+=3Ddocument.selection.createRange().text;=0A= }=0A= return text;=0A= },=0A= getPlural:function x_Plural(iN,sSuffix) {=0A= if (undefined=3D=3DsSuffix) {=0A= return (iN > 1 ? "s" : "");=0A= } else if ("y" =3D=3D sSuffix) {=0A= return (iN > 1 ? "ies" : "");=0A= } else {=0A= return (iN > 1 ? sSuffix + "s" : sSuffix);=0A= }=0A= },=0A= getPeriodToString:function(iDelta) {=0A= var x =3D "Error, cannot convert '" + iDelta + "'";=0A= var sDir;=0A= iDelta=3DparseInt(iDelta);=0A= if (iDelta<0) {=0A= sDir =3D " before";=0A= iDelta=3D-iDelta;=0A= } else=0A= sDir =3D " ago";=0A= var iS=3DparseInt(iDelta/1000);=0A= var iM,iH,iD;=0A= if (iS<60) {=0A= x =3D iS + " second" + this.getPlural(iS);=0A= } else {=0A= iM=3DparseInt(iS/60);=0A= if (iM<60) {=0A= x =3D iM + " minute" + this.getPlural(iM);=0A= } else {=0A= iH=3DparseInt(iM/60);=0A= if (iH<24) {=0A= iM=3DiM-iH *60;=0A= x =3D iH + " hour" + this.getPlural(iH) + " and " + iM + " minute" + = this.getPlural(iM);=0A= } else {=0A= iD=3DparseInt(iH/24);=0A= iH-=3DiD *24;=0A= x =3D iD + " day" + this.getPlural(iD) + " and " + iH + " hour" + = this.getPlural(iH);=0A= }=0A= }=0A= }=0A= return x+sDir;=0A= },=0A= addEvent_guid:1,=0A= addEvent:function (element,type,handler) {=0A= if (!handler.$$guid) handler.$$guid=3Dthis.addEvent_guid++;=0A= if (!element.events) element.events=3D{};=0A= var handlers=3Delement.events[type];=0A= if (!handlers) {=0A= handlers=3Delement.events[type]=3D{};=0A= if (element["on" + type]) {=0A= handlers[0] =3D element["on" + type];=0A= }=0A= }=0A= handlers[handler.$$guid]=3Dhandler;=0A= element["on" + type] =3D handleEvent;=0A= function handleEvent(event) {=0A= var returnValue=3Dtrue;=0A= event=3Devent || fixEvent(window.event);=0A= var handlers=3Dthis.events[event.type];=0A= for (var i in handlers) {=0A= this.$$handleEvent=3Dhandlers[i];=0A= if (this.$$handleEvent(event)=3D=3D=3Dfalse) {=0A= returnValue=3Dfalse;=0A= }=0A= }=0A= return returnValue;=0A= };=0A= function fixEvent(event) {=0A= event.preventDefault=3DfixEvent.preventDefault;=0A= event.stopPropagation=3DfixEvent.stopPropagation;=0A= return event;=0A= };=0A= fixEvent.preventDefault=3Dfunction() {=0A= this.returnValue=3Dfalse;=0A= };=0A= fixEvent.stopPropagation=3Dfunction() {=0A= this.cancelBubble=3Dtrue;=0A= };=0A= return handler.$$guid;=0A= },=0A= removeEvent:function (element,type,handler) {=0A= if (element.events && element.events[type]) {=0A= delete element.events[type][handler.$$guid];=0A= return handler.$$guid;=0A= }=0A= return null;=0A= },=0A= preventDefault:function(e) {=0A= if (e.preventDefault) e.preventDefault();=0A= else window.event.returnValue=3Dfalse;=0A= },=0A= getRelatedTarget:function(e) {=0A= if (!e) var e=3Dwindow.event;=0A= if (e.relatedTarget) return e.relatedTarget;=0A= else if (e.toElement) return e.toElement;=0A= else if (e.fromElement) return e.fromElement;=0A= },=0A= getTargetObj:function(eEvent) {=0A= var oTarget;=0A= var e=3DeEvent || window.event;=0A= if (e=3D=3Dnull) return null;=0A= if (e.srcElement=3D=3Dnull) oTarget=3De.target;=0A= else oTarget=3De.srcElement;=0A= while (oTarget && oTarget.nodeType !=3D1) oTarget=3DoTarget.parentNode;=0A= return oTarget;=0A= },=0A= printObj:function (oObj,iLevel) {=0A= var s =3D "";=0A= var sIdent =3D "";=0A= if (!iLevel) iLevel=3D0;=0A= for (var i=3D0;i";=0A= }=0A= return s;=0A= },=0A= jsLoader:{=0A= oLoaded:[],=0A= sBase:"",=0A= load:function (aScripts) {=0A= var oS =3D document.getElementsByTagName("script");=0A= for (var j=3D0;j");=0A= this.oLoaded.push(sNewSrc);=0A= }=0A= }=0A= }=0A= },=0A= insertInHtml:function(text,obj) {=0A= if (document.all) {=0A= obj.innerHTML+=3Dtext;=0A= } else {=0A= var range=3Ddocument.createRange();=0A= range.setStartAfter(obj);=0A= var docFrag=3Drange.createContextualFragment(text);=0A= obj.appendChild(docFrag);=0A= }=0A= },=0A= replaceInHtml:function(text,obj) {=0A= if (document.all) {=0A= obj.innerHTML=3Dtext;=0A= } else {=0A= while (obj.hasChildNodes()) obj.removeChild(obj.firstChild);=0A= var range=3Ddocument.createRange();=0A= range.setStartAfter(obj);=0A= var docFrag=3Drange.createContextualFragment(text);=0A= obj.appendChild(docFrag);=0A= }=0A= }=0A= };=0A= String.prototype.trimSpaces=3Dfunction(trimMode) {=0A= var targetString=3Dthis;=0A= var iPos=3D0;=0A= if (!trimMode) trimMode=3D0;=0A= if (trimMode=3D=3D0|| trimMode=3D=3D1) {=0A= if (targetString.charAt(iPos)=3D=3D" ") {=0A= while(targetString.charAt(iPos)=3D=3D" ") iPos++;=0A= targetString=3DtargetString.substr(iPos);=0A= }=0A= }=0A= iPos=3DtargetString.length-1;=0A= if (trimMode=3D=3D0|| trimMode=3D=3D2) {=0A= if (targetString.charAt(iPos) =3D=3D " ") {=0A= while(targetString.charAt(iPos) =3D=3D " ") iPos--;=0A= targetString=3DtargetString.substr(0,iPos+1);=0A= }=0A= }=0A= return targetString;=0A= }=0A= function $() {=0A= var elements=3Dnew Array();=0A= for (var i=3D0;i0) {=0A= var W=3DoMetadata.aView[0].W * oThis.fScale;=0A= for = (oThis.iScaleIndex=3D0;oThis.iScaleIndex