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Cited by 231Ion channel regulation and functionIon Transport and Channel RegulationGlioma Diagnosis and Treatment

An Unexpected Role for Ion Channels in Brain Tumor Metastasis

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Sontheimer, Harald·2008·Experimental Biology and Medicine
DOI 10.3181/0711-mr-308PMC PMC2557067
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Abstract

Over the past two decades it has become apparent that essentially all living cells express voltage-activated ion channels. While the role of ion channels for electrical signaling between excitable cells is well known, their function in non-excitable cells is somewhat enigmatic. Research on cancer cells suggests that certain ion channels, K + channels in particular, may be involved in aberrant tumor growth and channel inhibitors often lead to growth arrest. An unsuspected role for K + and Cl − channels has now been documented for primary brain tumors, glioma, where the concerted activity of these channels promotes cell invasion and the formation of brain metastasis. Specifically, Ca 2+ -activated K + (BK) channels colocalize with ClC-3 Cl − channels to the invading processes of these tumor cells. Upon a rise in intracellular Ca 2+ , these channels activate and release K + and Cl − ions together with obligated water causing a rapid shrinkage of the leading process. This in turn facilitates the invasion of the cell into the narrow and tortuous extracellular brain spaces. The NKCC1 cotransporter accumulates intracellular Cl − to unusually high concentrations, thereby establishing an outward directed gradient for Cl − ions. This allows glioma cells to utilize Cl − as an osmotically active anion during invasion. Importantly, the inhibition of Cl − channels retards cell volume changes, and, in turn, compromises tumor cell invasion. These findings have led to the clinical evaluation of a Cl − channel blocking peptide, chlorotoxin, in patients with malignant glioma. Data from this clinical trial shows remarkable tumor selectivity for chlorotoxin. The experimental therapeutic was well tolerated and is now evaluated in a multi-center phase II clinical trial. A similar role for Cl − and K + channels is suspected in other metastatic cancers, and lessons learned from studies of gliomas may pave the way towards the development of novel therapeutics targeting ion channels.

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  • Modulating the Vm of malign tissues by adjusting the activities of various ion channels/transporters may provide a convenient clinical approach.

    “Considering the vast array of therapeutic drugs that target ion channels (Sontheimer, 2008; Stuhmer and Pardo, 2010; D'amico et al., 2013; Djamgoz and Onkal, 2013), modulating the Vm of malign tissues by adjusting the activities of varies ion channels/transporters may provide a convenient clinical approach.”

    From Membrane potential and cancer progression (2013) · cites this paper as Sontheimer, 2008

    The Abstract describes a chloride-channel-targeting experimental therapy in clinical trials for malignant glioma, supporting the possibility of treating cancer through ion channels. It does not establish a vast array of suitable therapeutic drugs or a convenient clinical approach based on modulating membrane potential; it says potassium channels remain elusive therapeutic targets because selective drugs are lacking. The membrane-potential proposal after the citations is the citing authors’ own conclusion. (LLM, conf=0.82)

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  • Cl− channels, which contribute to the depolarized Vm in glioma cells, enhance migration and invasion by permitting the release of K+, Cl−, and water at the leading edge, resulting in shrinkage and facilitating movement into tortuous extracellular spaces.

    “In agreement with this, Cl− channels, which contribute to the depolarized Vm in glioma cells, enhance migration and invasion by permitting the release of K+, Cl−, and water at the leading edge, resulting in shrinkage and facilitating movement into tortuous extracellular spaces (Soroceanu et al., 1999; Sontheimer, 2008; Habela et al., 2009; Schwab et al., 2012).”

    From Membrane potential and cancer progression (2013) · cites this paper as Sontheimer, 2008

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Cited by

Sorted by citations

Authors
Sontheimer, H.
Affiliations
University of Alabama at Birmingham (US)
Corresponding author
Sontheimer, Harald
ORCID
Sontheimer, Harald
Venue
Experimental Biology and Medicine
Publisher
Frontiers Media SA
Published
2008-07
Volume
233
Issue
7
Pages
779-791
ISSN
  • 0071-3384 (ISSN-L)
  • 1535-3702
  • 1535-3699
DOI
10.3181/0711-mr-308
PMC
PMC2557067
OpenAlex
W2064608326
Cited by
231
References
1
Citations by year
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FWCI
1.52
Type
journal article
Language
en
Open access
Licence
journals.sagepub.com/page/policies/text-and-data-mining-license (tdm)
Locations
  • Experimental Biology and Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (5r01ns031234-18)
  • National Cancer Institute (P50 CA97247, P50CA097247)
  • National Institute of Neurological Disorders and Stroke (R01-NS031234, NS36692, R01-NS--31234, R01NS052634, R01 NS-52634, R01NS036692)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
  • Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
Keywords
ion channels, brain metastases, glioma, calcium-activated potassium channels, BK channels, ClC-3 chloride channel, chloride channel blockers, chlorotoxin, tumor invasion, cell volume regulation, osmotic shrinkage, ion channel inhibitors
MeSH terms
Brain Neoplasms, Glioma, Humans, Ion Channels, Neoplasm Metastasis, Potassium Channels, Chloride Channels

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