Hydrodynamic Cellular Volume Changes Enable Glioma Cell Invasion

Malignant gliomas are highly invasive brain tumors that currently lack effective treatment. Unlike other cancers, gliomas do not metastasize via the vasculature but invade surrounding brain solely along extracellular routes, primarily moving along the vasculature and nerve tracts. This study uses several model systems to visualize and quantitatively assess cell volume changes of human glioma cells invading within the brain's extracellular space of C.B.17 severe combined immunodeficient (scid) mice and tumor cells invading in a modified Boyden chamber using three-dimensional multiphoton and confocal time-lapse microscopy. Regardless of model system used to quantitatively assess volume changes, invading glioma cells maximally decreased their volume by 30–35%, a value that was independent of barrier and cell size. Through osmotic challenges, we demonstrate that the observed cellular volume changes during invasion represent the smallest achievable cell volume and require glioma cells to release all free unbound cytoplasmic water. Water osmotically follows the release of Cl− through ion channels and cotransporters and blockade of Cl− flux inhibits both volume changes and cell invasion. Hence, invading glioma cells use hydrodynamic volume changes to meet the spatial constraints imposed within the brain, using essentially all free, unbound cytoplasmic water to maximally alter their volume as they invade.

• Publication year

  2011

• Venue

  Journal of Neuroscience

• Publication date

  2011-11-23

• Fields of study

  Biology, Medicine, Engineering

• Identifiers
  DOI 10.1523/JNEUROSCI.3938-11.2011PMID 22114291PMCID PMC3253353
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Bradykinin Promotes the Chemotactic Invasion of Primary Brain Tumors

  2011cited by this paper
• Invasion of human glioma cells is regulated by multiple chloride channels including ClC-3.

  2010cited by this paper
• Inhibition of the Sodium-Potassium-Chloride Cotransporter Isoform-1 reduces glioma invasion.

  2010cited by this paper
• Molecular Interaction and Functional Regulation of ClC-3 by Ca2+/Calmodulin-dependent Protein Kinase II (CaMKII) in Human Malignant Glioma*

  2010cited by this paper
• Volume-activated chloride channels contribute to cell-cycle-dependent regulation of HeLa cell migration.

  2009cited by this paper
• Long-term, high-resolution imaging in the mouse neocortex through a chronic cranial window

  2009cited by this paper
• Chloride accumulation drives volume dynamics underlying cell proliferation and migration.

  2009cited by this paper
• Nkcc1 (Slc12a2) is required for the regulation of endolymph volume in the otic vesicle and swim bladder volume in the zebrafish larva

  2009cited by this paper
• ADAM-10-Mediated N-Cadherin Cleavage Is Protein Kinase C-α Dependent and Promotes Glioblastoma Cell Migration

  2009cited by this paper
• Cell migration in the normal and pathological postnatal mammalian brain.

  2009cited by this paper
• An Unexpected Role for Ion Channels in Brain Tumor Metastasis

  2008cited by this paper
• The interface between glial progenitors and gliomas

  2008cited by this paper
• Suppression of ClC-3 channel expression reduces migration of nasopharyngeal carcinoma cells.

  2008cited by this paper
• Cytoplasmic condensation is both necessary and sufficient to induce apoptotic cell death

  2008cited by this paper
• Expression and function of water channels (aquaporins) in migrating malignant astrocytes

  2007cited by this paper
• Long-term survival with glioblastoma multiforme.

  2007cited by this paper
• Extracellular glutamine is a critical modulator for regulatory volume increase in human glioma cells.

  2007cited by this paper
• Molecular targets of glioma invasion

  2007cited by this paper
• Kinetic Properties of Cl− Uptake Mediated by Na+-Dependent K+-2Cl− Cotransport in Immature Rat Neocortical Neurons

  2007cited by this paper
• Blockage of Volume-Activated Chloride Channels Inhibits Migration of Nasopharyngeal Carcinoma Cells

  2007cited by this paper
• Expression and function of calcium‐activated potassium channels in human glioma cells

  2006cited by this paper
• Relative contribution of chloride channels and transporters to regulatory volume decrease in human glioma cells.

  2005cited by this paper
• A role for ion channels in glioma cell invasion.

  2005cited by this paper
• Involvement of regulatory volume decrease in the migration of nasopharyngeal carcinoma cells

  2005cited by this paper
• Cl– channels are expressed in human normal monocytes: a functional role in migration, adhesion and volume change

  2004cited by this paper
• Molecular Mechanisms of Glioma Cell Migration and Invasion

  2004cited by this paper
• Cell volume regulation and swelling-activated chloride channels.

  2003cited by this paper
• Expression of Voltage-Gated Chloride Channels in Human Glioma Cells

  2003cited by this paper
• Adenovirus-mediated expression of antisense MMP-9 in glioma cells inhibits tumor growth and invasion

  2002cited by this paper
• Cloning and Characterization of Glioma BK, a Novel BK Channel Isoform Highly Expressed in Human Glioma Cells

  2002cited by this paper
• Volume-Activated Chloride Currents Contribute to the Resting Conductance and Invasive Migration of Human Glioma Cells

  2001cited by this paper
• Function and spatial distribution of ion channels and transporters in cell migration.

  2001cited by this paper
• Apoptosis, cell volume regulation and volume-regulatory chloride channels.

  2001cited by this paper
• Neurotechnique A Genetically Encoded Ratiometric Indicator for Chloride: Capturing Chloride Transients in Cultured Hippocampal Neurons

  2000cited by this paper
• Differential expression of volume‐regulated anion channels during cell cycle progression of human cervical cancer cells

  2000cited by this paper
• The role of ClC‐3 in volume‐activated chloride currents and volume regulation in bovine epithelial cells demonstrated by antisense inhibition

  2000cited by this paper
• A genetically encoded ratiometric indicator for chloride: capturing chloride transients in cultured hippocampal neurons.

  2000cited by this paper
• Regulation of Intracellular Chloride by Cotransporters in Developing Lateral Superior Olive Neurons

  1999cited by this paper
• Modulation of Glioma Cell Migration and Invasion Using Cl− and K+ Ion Channel Blockers

  1999cited by this paper
• Membrane-type 1 Matrix Metalloprotease (MT1-MMP) Enables Invasive Migration of Glioma Cells in Central Nervous System White Matter

  1999cited by this paper
• Regulation of intracellular chloride by cotransporters in developing lateral superior olive neurons.

  1999cited by this paper
• Overexpression of a transmembrane isoform of neural cell adhesion molecule alters the invasiveness of rat CNS-1 glioma.

  1998cited by this paper
• Use of chlorotoxin for targeting of primary brain tumors.

  1998cited by this paper
• Fibronectin-mediated cell migration promotes glioma cell invasion through chemokinetic activity

  1997cited by this paper
• Stimulation of glioma‐cell migration by laminin and inhibition by anti‐α3 and anti‐β1 integrin antibodies

  1996cited by this paper
• Stimulation of glioma-cell migration by laminin and inhibition by anti-alpha3 and anti-beta1 integrin antibodies.

  1996cited by this paper
• Migratory patterns of lac‐z transfected human glioma cells in the rat brain

  1995cited by this paper
• Determinants of human astrocytoma migration.

  1994cited by this paper
• The role of extracellular matrix in human astrocytoma migration and proliferation studied in a microliter scale assay

  1994cited by this paper
• CD44 mediates human glioma cell adhesion and invasion in vitro.

  1994cited by this paper
• The extracellular matrix of the central and peripheral nervous systems: structure and function.

  1988cited by this paper
• Properties and metabolism of the aqueous cytoplasm and its boundaries.

  1984cited by this paper
• Intracellular water and the cytomatrix: some methods of study and current views

  1984cited by this paper
• Heterogeneity of Genotypic and Phenotypic Characteristics of Fifteen Permanent Cell Lines Derived from Human Gliomas

  1981cited by this paper

• Log-linear scaling of TRPV4-KCNN4 transcripts tunes ROCK-dependent mechanotransduction in a DCIS progression model

  2026cites this paper
• Piezo1 is an essential player in volume regulation of human glioblastoma cells

  2025cites this paper
• Variations among glioblastoma cell lines in boron-mediated enhancement of cell killing by proton beams

  2025cites this paper
• Piezo1-related physiological and pathological processes in glioblastoma

  2025cites this paper
• Reciprocal interactions between glioma and tissue-resident cells fueling tumor progression.

  2025cites this paper
• Softness or Stiffness What Contributes to Cancer and Cancer Metastasis?

  2025cites this paper
• Ion channel expression and function in glioblastoma multiforme (GBM): pathophysiological mechanisms and therapeutic potential.

  2025cites this paper
• Cell crowding activates pro-invasive mechanotransduction pathway in high-grade DCIS via TRPV4 inhibition and cell volume reduction

  2025cites this paper
• Elastocapillary effects determine early matrix deformation by glioblastoma cell spheroids

  2024cites this paper
• On-chip fabrication of tailored 3D hydrogel scaffolds to model cancer cell invasion and interaction with endothelial cells

  2024cites this paper
• Emerging Lipid Targets in Glioblastoma

  2024cites this paper
• The role of disease state in confined migration

  2024cites this paper
• SKCa- and Kv1-type potassium channels and cancer: promising therapeutic targets ?

  2023cites this paper
• Cytoskeletal activation of NHE1 regulates mechanosensitive cell volume adaptation and proliferation

  2023cites this paper
• Hypoxia, Ion Channels and Glioblastoma Malignancy

  2023influential citation
• Models for evaluating glioblastoma invasion along white matter tracts.

  2023cites this paper
• Placenta and maternal endothelium during preeclampsia: Disruption of the glycocalyx explains increased inositol phosphoglycans and angiogenic factors in maternal blood.

  2023cites this paper
• Compression drives diverse transcriptomic and phenotypic adaptations in melanoma

  2023cites this paper
• SPAK-dependent cotransporter activity mediates capillary adhesion and pressure during glioblastoma migration in confined spaces

  2023cites this paper
• Potassium Ion Channels in Glioma: From Basic Knowledge into Therapeutic Applications

  2023cites this paper
• Paraptosis and tumor immunity.

  2022cites this paper
• Protein Condensation, Cellular Organization, and Spatiotemporal Regulation of Cytoplasmic Properties

  2022cites this paper
• Analysis of U87 glioma cells by dielectrophoresis

  2022cites this paper
• Rheological comparison between control and Dupuytren fibroblasts when plated in circular micropatterns using atomic force microscopy

  2022cites this paper
• Aberrant inactivation of SCNN1G promotes the motility of head and neck squamous cell carcinoma.

  2022cites this paper
• Organoid Models of Glioblastoma and Their Role in Drug Discovery

  2021cites this paper
• Potassium Channels in Cancer.

  2021cites this paper
• Using Zebrafish to Elucidate Glial-Vascular Interactions During CNS Development

  2021cites this paper
• A constriction channel analysis of astrocytoma stiffness and disease progression.

  2021cites this paper
• The influence of methylation status on a stochastic model of MGMT dynamics in glioblastoma: phenotypic selection can occur with and without a downshift in promoter methylation status.

  2021cites this paper
• Temporal manipulation of KCC3 expression in juvenile or adult mice suggests irreversible developmental deficit in HSMN/ACC.

  2021cites this paper
• Glioma invasion along white matter tracts: A dilemma for neurosurgeons.

  2021cites this paper
• Eukaryotic CRFK Cells Motion Characterized with Atomic Force Microscopy

  2021cites this paper
• Novel facets of glioma invasion.

  2021cites this paper
• Effectiveness of porous silicon nanoparticle treatment at inhibiting the migration of a heterogeneous glioma cell population

  2021cites this paper
• Role of NKCC1 Activity in Glioma K+ Homeostasis and Cell Growth: New Insights With the Bumetanide-Derivative STS66

  2020cites this paper
• Fishing for contact: Modeling perivascular glioma invasion in the zebrafish brain

  2020cites this paper
• TRPV4 activates the Cdc42/N-wasp pathway to promote glioblastoma invasion by altering cellular protrusions

  2020cites this paper
• Targeting Ion Channels for Cancer Treatment: Current Progress and Future Challenges.

  2020cites this paper
• LTP Induction Boosts Glutamate Spillover by Driving Withdrawal of Perisynaptic Astroglia

  2020cites this paper
• Glioma stem cells invasive phenotype at optimal stiffness is driven by MGAT5 dependent mechanosensing

  2020cites this paper
• Communication of Glioma Cells with Neuronal Plasticity: What is the underlying Mechanism?

  2020cites this paper
• Pressure sensing through Piezo channels controls whether cells migrate with blebs or pseudopods

  2020cites this paper
• Transferrin-targeted porous silicon nanoparticles reduce glioblastoma cell migration across tight extracellular space

  2020cites this paper
• Matrix protease production, epithelial-to-mesenchymal transition marker expression and invasion of glioblastoma cells in response to osmotic or hydrostatic pressure

  2020cites this paper
• A role for caveola‐forming proteins caveolin‐1 and CAVIN1 in the pro‐invasive response of glioblastoma to osmotic and hydrostatic pressure

  2020cites this paper
• Tumor Cell Invasion in Glioblastoma

  2020cites this paper
• NKCC1 involvement in the epithelial-to-mesenchymal transition is a prognostic biomarker in gliomas

  2020cites this paper
• Phenotypic selection through cell death: stochastic modelling of O-6-methylguanine-DNA methyltransferase dynamics

  2020cites this paper
• Bioelectric Control of Metastasis in Solid Tumors

  2019cites this paper
• Variations of elastic modulus and cell volume with temperature for cortical neurons.

  2019cites this paper
• Cancer-Associated Intermediate Conductance Ca2+-Activated K+ Channel KCa3.1

  2019cites this paper
• The Piezo channel is used by migrating cells to sense compressive load

  2019cites this paper
• Acetylcholine Receptor Activation as a Modulator of Glioblastoma Invasion

  2019cites this paper
• LTP induction drives remodeling of astroglia to boost glutamate escape from synapses

  2019cites this paper
• 2+ -activated K + channels modulate microglia affecting motor neuron survival in hSOD1 G93A mice”

  2019cites this paper
• Overlapping migratory mechanisms between neural progenitor cells and brain tumor stem cells

  2019cites this paper
• LTP Induction Boosts Glutamate Spillover by Driving Withdrawal of Astroglia

  2019cites this paper
• The unique invasiveness of glioblastoma and possible drug targets on extracellular matrix

  2019cites this paper
• Multivalent proteins rapidly and reversibly phase-separate upon osmotic cell volume change

  2019cites this paper
• P120-catenin dependent collective brain infiltration by glioma cell networks

  2019cites this paper
• Mécanotransduction des cellules souches de glioblastome dans un nouveau modèle de culture tridimensionnel : implication de la MGAT5 dans la perception de l'environnement mécanique

  2018cites this paper
• Antisecretory Factor–Mediated Inhibition of Cell Volume Dynamics Produces Antitumor Activity in Glioblastoma

  2018cites this paper
• Mesenchymal stem cell differentiation: Control by calcium‐activated potassium channels

  2018cites this paper
• NKCC1 promotes EMT‐like process in GBM via RhoA and Rac1 signaling pathways

  2018cites this paper
• Functional Roles of the Ca2+-activated K+ Channel, KCa3.1, in Brain Tumors

  2018cites this paper
• Piezo2 channel regulates RhoA and actin cytoskeleton to promote cell mechanobiological responses

  2018cites this paper
• Astroglia withdraw from potentiated synapses boosting inter-synaptic cross-talk

  2018cites this paper
• Role of Microenvironment in Glioma Invasion: What We Learned from In Vitro Models

  2018cites this paper
• Combating malignant astrocytes: Strategies mitigating tumor invasion.

  2018cites this paper
• Molecular Mechanisms of Glioma Cell Motility

  2017cites this paper
• Calcium-independent disruption of microtubule dynamics by nanosecond pulsed electric fields in U87 human glioblastoma cells

  2017cites this paper
• Molecular Biology of Human Brain Tumors

  2017cites this paper
• Cell volume change through water efflux impacts cell stiffness and stem cell fate

  2017cites this paper
• Bridging the gap: microfluidic devices for short and long distance cell-cell communication.

  2017cites this paper
• Systems biology of cellular membranes: a convergence with biophysics

  2017cites this paper
• The Molecular and Phenotypic Basis of the Glioma Invasive Perivascular Niche

  2017cites this paper
• NKCC1 Regulates Migration Ability of Glioblastoma Cells by Modulation of Actin Dynamics and Interacting with Cofilin

  2017influential citation
• CALCIUM MODULATORY EFFECTS OF CROCIN FROM SAFFRON (CROCUS SATIVUS L.) IN C6 GLIOMA CELLS

  2017influential citation
• KCa3.1 Channels and Glioblastoma: In Vitro Studies

  2017cites this paper
• Prognostic value of ion channel genes in Chinese patients with gliomas based on mRNA expression profiling

  2017cites this paper
• Molecular Determinants of Malignant Brain Cancers: From Intracellular Alterations to Invasion Mediated by Extracellular Vesicles

  2017cites this paper
• Developmentally regulated signaling pathways in glioma invasion

  2017cites this paper
• Relationship between Apparent Diffusion Coefficients and MR Spectroscopy Findings in High‐Grade Gliomas

  2017cites this paper
• The Warburg effect as an adaptation of cancer cells to rapid fluctuations in energy demand

  2017cites this paper
• Regulation of glioma migration and invasion via modification of Rap2a activity by the ubiquitin ligase Nedd4-1

  2017cites this paper
• Ion Channels in Cancer

  2016cites this paper
• Ion channels in control of pancreatic stellate cell migration

  2016cites this paper
• Quantitative analysis of U251MG human glioma cells invasion in organotypic brain slice co-cultures.

  2016cites this paper
• Plasticity of Cell Migration In Vivo and In Silico.

  2016cites this paper
• Seizures and gliomas — towards a single therapeutic approach

  2016cites this paper
• Anti-Neoplastic and Calcium Modulatory Action of Caffeic Acid Phenethyl Ester and Dasatinib in C6 Glial Cells: A Therapeutic Perspective.

  2016cites this paper
• Cl-out is a novel cooperative optogenetic tool for extruding chloride from neurons

  2016cites this paper
• A role for ion channels in perivascular glioma invasion

  2016cites this paper
• The Investigation of the Uptake of Interleukin-13 Conjugated Nanoparticles into Glioma Cells

  2016cites this paper
• Determination of the signaling pathways and subcellular targets in response to nanosecond pulsed electric fields

  2016cites this paper
• Calcium signaling orchestrates glioblastoma development: Facts and conjunctures.

  2016cites this paper
• Double Blockade of Glioma Cell Proliferation and Migration by Temozolomide Conjugated with NPPB, a Chloride Channel Blocker.

  2016cites this paper
• Role of ion channels in ionizing radiation-induced cell death.

  2015cites this paper
• Reconciling the discrepancies on the involvement of large-conductance Ca2+-activated K channels in glioblastoma cell migration

  2015cites this paper