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Cited by 137Glioma Diagnosis and TreatmentMicrobial Inactivation MethodsElectromagnetic Fields and Biological Effects

The DOI matches its Crossref record; 58 of the 58 references it cites were found in a registry or an index; none of the 11 sources its claims cite is checked for support yet.

Tumor treating fields increases membrane permeability in glioblastoma cells

Open access
Chang, Edwin, Patel, Chirag B., Pohling, Christoph, Young, Caroline, Song, Jonathan, Flores, Thomas Anthony, Zeng, Yitian, Joubert, Lydia-Marie, Arami, Hamed, Natarajan, Arutselvan, Sinclair, Robert, Gambhir, Sanjiv S.·2018·Cell Death Discovery
DOI 10.1038/s41420-018-0130-xPMC PMC6281619
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Abstract

Glioblastoma is the most common yet most lethal of primary brain cancers with a one-year post-diagnosis survival rate of 65% and a five-year survival rate of barely 5%. Recently the U.S. Food and Drug Administration approved a novel fourth approach (in addition to surgery, radiation therapy, and chemotherapy) to treating glioblastoma; namely, tumor treating fields (TTFields). TTFields involves the delivery of alternating electric fields to the tumor but its mechanisms of action are not fully understood. Current theories involve TTFields disrupting mitosis due to interference with proper mitotic spindle assembly. We show that TTFields also alters cellular membrane structure thus rendering it more permeant to chemotherapeutics. Increased membrane permeability through the imposition of TTFields was shown by several approaches. For example, increased permeability was indicated through increased bioluminescence with TTFields exposure or with the increased binding and ingress of membrane-associating reagents such as Dextran-FITC or ethidium D or with the demonstration by scanning electron microscopy of augmented number and sizes of holes on the cellular membrane. Further investigations showed that increases in bioluminescence and membrane hole production with TTFields exposure disappeared by 24 h after cessation of alternating electric fields thus demonstrating that this phenomenom is reversible. Preliminary investigations showed that TTFields did not induce membrane holes in normal human fibroblasts thus suggesting that the phenomenom was specific to cancer cells. With TTFields, we present evidence showing augmented membrane accessibility by compounds such as 5-aminolevulinic acid, a reagent used intraoperatively to delineate tumor from normal tissue in glioblastoma patients. In addition, this mechanism helps to explain previous reports of additive and synergistic effects between TTFields and other chemotherapies. These findings have implications for the design of combination therapies in glioblastoma and other cancers and may significantly alter standard of care strategies for these diseases.

Overview

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Written from the paper’s full text.

TL;DR

Tumor treating fields (TTFields) increase plasma membrane permeability in glioblastoma cells, allowing greater uptake of small molecules and chemotherapeutics. This effect is reversible after TTFields cessation and appears specific to cancer cells in preliminary comparisons with normal human fibroblasts.

Key findings

  • TTFields (4 V/cm, 200 kHz, 0.5–24 h) significantly increased bioluminescence in luciferase-expressing U87-MG/eGFP-fLuc cells as early as 30 min and through 24 h (p < 0.0001, two-way ANOVA), without significantly increasing eGFP fluorescence.
  • Uptake of Dextran-FITC was significantly increased for 4 kDa (p < 0.0001) and 20 kDa (p < 0.01) dextrans, but not for 50 kDa dextran (p = 0.26, not significant).
  • SEM showed TTFields-exposed U87-MG cells had more holes ≥51.8 nm² (53.5 ± 19.1 vs. 23.9 ± 11.0, p = 0.0002) and larger average hole size (240.6 ± 91.7 nm² vs. 129.8 ± 31.9 nm², p = 0.0005) than unexposed cells; normal human PCS-201 fibroblasts showed no significant change.
  • TTFields increased 5-ALA uptake/PpIX fluorescence in U87-MG cells at 6 h (p = 0.047) and 24 h (p = 0.011), and in U87-MG/PCS-201 co-cultures (p < 0.001); the tumor-to-fibroblast PpIX ratio increased at 24 h (p = 0.043). Effects on bioluminescence, PpIX fluorescence, Dextran-FITC fluorescence, and SEM holes were attenuated after 24 h off TTFields.

Methods

  • Cell lines: patient-derived GBM2 and GBM39, commercial U87-MG, murine KR158B astrocytoma, and normal human PCS-201 fibroblasts; some lines were engineered to express firefly, Renilla, or GFP-fusion luciferases.
  • TTFields were applied in vitro using the inovitro system at 200 kHz (1–4 V/cm) for 0.5–72 h, with reversibility experiments after 24 h off TTFields; readouts included bioluminescence imaging, fluorescence imaging for Ethidium D, Dextran-FITC, and 5-ALA/PpIX, and scanning electron microscopy.
  • Statistical analysis used PRISM 7.0; normally distributed data were analyzed by Student’s t-test or ANOVA, non-normal data by non-parametric tests such as Mann–Whitney U, with alpha = 0.05 and post-hoc corrections for multiple comparisons.

Limitations

  • The paper states that results could not be confirmed in an animal model of glioblastoma because a practical device delivering TTFields to rodent brain does not yet exist.
  • The paper states that work focused on glioblastoma cells using 200 kHz TTFields because FDA approval exists only for glioblastoma and only at this frequency.
  • Evident from the text: experiments used unsynchronized cells, and the normal-fibroblast comparison is described as preliminary; the study is in vitro and does not establish clinical efficacy or blood-brain barrier effects.

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Integrity signals

Registry

Crossref · 10.1038/s41420-018-0130-x

Cites

58 of 58 references verified0 citation errors · 0 not checkable

Statistics

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Figures

Fig. 1 a Schematic showing classical view of the alteration of the mitotic spindle during mitosis by TTFields that results in cancer cell death. b Schematic showing an alternative effect of TTFields on modulating the integrity and thus the permeability of cancer cellular membranes. 5-ALA, 5-aminolevulinic acid, Ethidium D, ethidium bromide, FITC, fluorescein isothiocyanate, pk, peak, TTFields, tumor treating fields
Fig. 1 a Schematic showing classical view of the alteration of the mitotic spindle during mitosis by TTFields that results in cancer cell death. b Schematic showing an alternative effect of TTFields on modulating the integrity and thus the permeability of cancer cellular membranes. 5-ALA, 5-aminolevulinic acid, Ethidium D, ethidium bromide, FITC, fluorescein isothiocyanate, pk, peak, TTFields, tumor treating fieldsCC BY · PubMed Central
Fig. 2 Increased bioluminescence signal in U87-MG/eGFP-fLuc cells exposed to TTFields as shown by: a Representative panel of bioluminescent imaging (BLI) scans as a function of time in TTFields vs. no TTFields conditions. b Temporal quantification of BLI data in a. Significant difference (***p < 0.001) in plot between no TTFields and TTFields. Effect of TTFields on eGFP fluorescence in U87-MG/eGFP-fLuc cells as shown by c time course of representative panels for TTFields-exposed vs. TTFields-unexposed U87-MG/eGFP-fLuc and d temporal quantification of fluorescence data in c. Significant difference (***p < 0.001) in plot between no TTFields and TTFields. e Effect of TTFields on the fLuc bioluminescence (fLuc-BLI) over eGFP fluorescence (eGFP-FL) ratio for U87-MG/eGFP-fLuc cells as a function of length of TTFields exposure and f effect of TTFields exposure vs. non-exposure on the fLuc-BLI/eGFP-FL ratio as a function of TTFields exposure time (hours). For both e and f, there is a significant difference in ratio (***p < 0.001) between TTFields exposed and TTFields non-exposed. Two-way ANOVA analysis and n = 3 experiments per data point in each panel (b, d, e and f)
Fig. 2 Increased bioluminescence signal in U87-MG/eGFP-fLuc cells exposed to TTFields as shown by: a Representative panel of bioluminescent imaging (BLI) scans as a function of time in TTFields vs. no TTFields conditions. b Temporal quantification of BLI data in a. Significant difference (***p < 0.001) in plot between no TTFields and TTFields. Effect of TTFields on eGFP fluorescence in U87-MG/eGFP-fLuc cells as shown by c time course of representative panels for TTFields-exposed vs. TTFields-unexposed U87-MG/eGFP-fLuc and d temporal quantification of fluorescence data in c. Significant difference (***p < 0.001) in plot between no TTFields and TTFields. e Effect of TTFields on the fLuc bioluminescence (fLuc-BLI) over eGFP fluorescence (eGFP-FL) ratio for U87-MG/eGFP-fLuc cells as a function of length of TTFields exposure and f effect of TTFields exposure vs. non-exposure on the fLuc-BLI/eGFP-FL ratio as a function of TTFields exposure time (hours). For both e and f, there is a significant difference in ratio (***p < 0.001) between TTFields exposed and TTFields non-exposed. Two-way ANOVA analysis and n = 3 experiments per data point in each panel (b, d, e and f)CC BY · PubMed Central
Fig. 3 a Increased uptake of Ethidium D in U87-MG cells treated with TTFields, compared to the no TTFields condition (***p < 0.001). The effect of TTFields on the binding and uptake of Dextran-FITC of varying molecular weights in U87-MG cells. b A representative panel of Dextran-FITC fluorescence at 1 h incubation for 4, 20, and 50 kDa Dextran-FITC. Fluorescence scale bar shown on right. Impact of TTFields on the time course of Dextran-FITC uptake, c 4 kDa Dextran-FITC (***p < 0.001), d 20 kDa Dextran-FITC (**p < 0.01), and e 50 kDa Dextran-FITC (p = 0.26, not significant), compared to that of no TTFields. All statistical comparisons were based upon 2-way ANOVA analyses with each data point represented by n = 3 experiments. APC, allophycocyanin, Ethidium D, ethidium bromide, FITC, fluorescein isothiocyanate
Fig. 3 a Increased uptake of Ethidium D in U87-MG cells treated with TTFields, compared to the no TTFields condition (***p < 0.001). The effect of TTFields on the binding and uptake of Dextran-FITC of varying molecular weights in U87-MG cells. b A representative panel of Dextran-FITC fluorescence at 1 h incubation for 4, 20, and 50 kDa Dextran-FITC. Fluorescence scale bar shown on right. Impact of TTFields on the time course of Dextran-FITC uptake, c 4 kDa Dextran-FITC (***p < 0.001), d 20 kDa Dextran-FITC (**p < 0.01), and e 50 kDa Dextran-FITC (p = 0.26, not significant), compared to that of no TTFields. All statistical comparisons were based upon 2-way ANOVA analyses with each data point represented by n = 3 experiments. APC, allophycocyanin, Ethidium D, ethidium bromide, FITC, fluorescein isothiocyanateCC BY · PubMed Central
Fig. 4 Effect of TTFields on 5-aminolevulinic acid (5-ALA) uptake as shown. a representative protoporphyrin IX (PpIX) fluorescence panel for TTFields-unexposed vs. TTFields-exposed U87-MG cells after 6 and 24 h of exposure. Scale bar on right used for both 6 h and 12 h post-exposure data. b Quantitation of images in a showed significant increase in PpIX signals in TTFields exposed cells compared to no TTFields, at both 6 h (p = 0.047) and 24 h (p = 0.01) time points. All monovariant statistical comparisons between no TTFields vs. TTFields samples done by Student’s t-test for n = 3 experiments per time point. c, d Effect of TTFields on U87-MG glioblastoma cells co-cultured with PCS-201 fibroblast cells. c Representative fluorescent panels of 5-ALA uptake (and subsequent PpIX fluorescence, Ex = 558 nm, Em = 583 nm) for no TTFields (top row) vs. TTFields (bottom row) conditions. Duration of exposures are 2, 6, and 24 h. d Quantification of time course of PpIX accumulation (and thus accumulation of fluorescent flux as expressed as photons/s) in the glioblastoma-fibroblast co-culture platform under TTFields exposed vs. unexposed conditions (p < 0.001). Statistical analyses consisted of two-way ANOVA for no TTFields vs. TTFields conditions, and n = 3 experiments per time point. Schematic of co-culture platform is shown in Supplemental Figure S4
Fig. 4 Effect of TTFields on 5-aminolevulinic acid (5-ALA) uptake as shown. a representative protoporphyrin IX (PpIX) fluorescence panel for TTFields-unexposed vs. TTFields-exposed U87-MG cells after 6 and 24 h of exposure. Scale bar on right used for both 6 h and 12 h post-exposure data. b Quantitation of images in a showed significant increase in PpIX signals in TTFields exposed cells compared to no TTFields, at both 6 h (p = 0.047) and 24 h (p = 0.01) time points. All monovariant statistical comparisons between no TTFields vs. TTFields samples done by Student’s t-test for n = 3 experiments per time point. c, d Effect of TTFields on U87-MG glioblastoma cells co-cultured with PCS-201 fibroblast cells. c Representative fluorescent panels of 5-ALA uptake (and subsequent PpIX fluorescence, Ex = 558 nm, Em = 583 nm) for no TTFields (top row) vs. TTFields (bottom row) conditions. Duration of exposures are 2, 6, and 24 h. d Quantification of time course of PpIX accumulation (and thus accumulation of fluorescent flux as expressed as photons/s) in the glioblastoma-fibroblast co-culture platform under TTFields exposed vs. unexposed conditions (p < 0.001). Statistical analyses consisted of two-way ANOVA for no TTFields vs. TTFields conditions, and n = 3 experiments per time point. Schematic of co-culture platform is shown in Supplemental Figure S4CC BY · PubMed Central
Fig. 5 Scanning electron micrograph (SEM) comparison of plasma membrane holes in glioblastoma cells unexposed or exposed to TTFields. a Representative SEM images of a U87-MG/eGFP-fLuc cell unexposed to TTFields for 3 days with sparse holes in the plasma membrane. b Representative SEM images of a U87-MG/eGFP-fLuc cell exposed to TTFields for 3 days demonstrate more holes and of larger size in the plasma membrane, compared to that of cells not exposed to TTFields (Wilcoxon rank-sum analysis). c Quantification and comparison between TTFields unexposed and exposed cells of the number and size of holes with area ≥ 51.8 nm2 (equivalent to a 4-nm radius circle, or 9 pixels2 on the 60,000× magnification images) within a 500 nm-radius circular region of interest. The minimum hole size cut-off was based on the 3.3 and 5.0 nm Stokes radii of 20 kDa and 50 kDa Dextran-FITCs, respectively. From left to right, magnification levels in a and b are 2,000× (black scale bar 10 µm), 20,000× (black scale bar 1 µm), and 60,000× (black scale bar 200 nm) and final panel column on the extreme right, where yellow scale bar represents 200 nm scale. Yellow arrows point to representative holes on cellular membranes. Coverslips from three experiments per condition were used, and at least 5 cells per coverslip were analyzed for hole count and size, in a double-blind manner. Qualitative comparison of changes to the plasma membrane in cells seeded at higher density for 24 h of TTFields exposure vs. no TTFields exposure is shown in Supplemental Figure S9
Fig. 5 Scanning electron micrograph (SEM) comparison of plasma membrane holes in glioblastoma cells unexposed or exposed to TTFields. a Representative SEM images of a U87-MG/eGFP-fLuc cell unexposed to TTFields for 3 days with sparse holes in the plasma membrane. b Representative SEM images of a U87-MG/eGFP-fLuc cell exposed to TTFields for 3 days demonstrate more holes and of larger size in the plasma membrane, compared to that of cells not exposed to TTFields (Wilcoxon rank-sum analysis). c Quantification and comparison between TTFields unexposed and exposed cells of the number and size of holes with area ≥ 51.8 nm2 (equivalent to a 4-nm radius circle, or 9 pixels2 on the 60,000× magnification images) within a 500 nm-radius circular region of interest. The minimum hole size cut-off was based on the 3.3 and 5.0 nm Stokes radii of 20 kDa and 50 kDa Dextran-FITCs, respectively. From left to right, magnification levels in a and b are 2,000× (black scale bar 10 µm), 20,000× (black scale bar 1 µm), and 60,000× (black scale bar 200 nm) and final panel column on the extreme right, where yellow scale bar represents 200 nm scale. Yellow arrows point to representative holes on cellular membranes. Coverslips from three experiments per condition were used, and at least 5 cells per coverslip were analyzed for hole count and size, in a double-blind manner. Qualitative comparison of changes to the plasma membrane in cells seeded at higher density for 24 h of TTFields exposure vs. no TTFields exposure is shown in Supplemental Figure S9CC BY · PubMed Central
Fig. 6 Scanning electron micrographs (SEM) of normal human PCS-201 cells seeded at low density (5,000 cells per 13 mm glass coverslip, see Supplemental Figure S1). The cells were grown under standard tissue culture conditions (37 oC, 95% O2, 5% CO2). Non-TTFields-exposed cells (a) were left under those conditions for the duration of the study. Other cells (b) were exposed to TTFields for 72 h. c Quantification and comparison between TTFields unexposed and exposed cells of the number and size of holes with area ≥ 51.8 nm2 (equivalent to a 4-nm radius circle, or 9 pixels2 on the 60,000× magnification images) within a 500 nm-radius circular region of interest. The minimum hole size cut-off was based on the 3.3 nm and 5.0 nm Stokes radii of 20 kDa and 50 kDa Dextran-FITCs, respectively. There was no significant difference in the number or size of holes between the TTFields unexposed and exposed normal human PCS-201 cells (Wilcoxon rank-sum analysis). From left to right, magnification levels in a and b are 2,000× (black scale bar 10 µm), 20,000× (black scale bar 1 µm), and 60,000× (black scale bar 200 nm) and final panel column on the extreme right where yellow scale bar represents 200 nm scale. Yellow arrows point to representative holes on cellular membranes. Coverslips from three experiments per condition were used, and at least 5 cells per coverslip were analyzed for hole count and size, in a double-blind manner
Fig. 6 Scanning electron micrographs (SEM) of normal human PCS-201 cells seeded at low density (5,000 cells per 13 mm glass coverslip, see Supplemental Figure S1). The cells were grown under standard tissue culture conditions (37 oC, 95% O2, 5% CO2). Non-TTFields-exposed cells (a) were left under those conditions for the duration of the study. Other cells (b) were exposed to TTFields for 72 h. c Quantification and comparison between TTFields unexposed and exposed cells of the number and size of holes with area ≥ 51.8 nm2 (equivalent to a 4-nm radius circle, or 9 pixels2 on the 60,000× magnification images) within a 500 nm-radius circular region of interest. The minimum hole size cut-off was based on the 3.3 nm and 5.0 nm Stokes radii of 20 kDa and 50 kDa Dextran-FITCs, respectively. There was no significant difference in the number or size of holes between the TTFields unexposed and exposed normal human PCS-201 cells (Wilcoxon rank-sum analysis). From left to right, magnification levels in a and b are 2,000× (black scale bar 10 µm), 20,000× (black scale bar 1 µm), and 60,000× (black scale bar 200 nm) and final panel column on the extreme right where yellow scale bar represents 200 nm scale. Yellow arrows point to representative holes on cellular membranes. Coverslips from three experiments per condition were used, and at least 5 cells per coverslip were analyzed for hole count and size, in a double-blind mannerCC BY · PubMed Central
Fig. 7 Study showing the reversibility of TTFields’ effects on bioluminescence activity of U87-MG/eGFP-fLuc cells. Cells were subjected to the conditions of: (1) standard, control tissue culture settings of 37oC, 95% O2, 5% CO2 and no exposure to TTFields, (2) 24 h of TTFields exposure, and (3) 24 h of TTFields exposure followed by additional 24 h of no TTFields exposure. All experimental conditions were done in triplicate and statistical analysis calculated via 2-way ANOVA. NS stands for not significant. a Representative panel of bioluminescent imaging (BLI) scans as a function of the three aforementioned conditions (i.e., no TTFields, TTFields (24 h), TTFields (24 h) followed by no TTFields (24 h)) and b quantification of BLI data in a. BLI, bioluminescent imaging, eGFP, enhanced green fluorescence protein, fLuc, firefly luciferase
Fig. 7 Study showing the reversibility of TTFields’ effects on bioluminescence activity of U87-MG/eGFP-fLuc cells. Cells were subjected to the conditions of: (1) standard, control tissue culture settings of 37oC, 95% O2, 5% CO2 and no exposure to TTFields, (2) 24 h of TTFields exposure, and (3) 24 h of TTFields exposure followed by additional 24 h of no TTFields exposure. All experimental conditions were done in triplicate and statistical analysis calculated via 2-way ANOVA. NS stands for not significant. a Representative panel of bioluminescent imaging (BLI) scans as a function of the three aforementioned conditions (i.e., no TTFields, TTFields (24 h), TTFields (24 h) followed by no TTFields (24 h)) and b quantification of BLI data in a. BLI, bioluminescent imaging, eGFP, enhanced green fluorescence protein, fLuc, firefly luciferaseCC BY · PubMed Central

Verification

Claims the paper makes

41 Own result · 17 Own interpretation · 7 Not checked yet · 6 Own method

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Show all 50 claims

  • It may state two separate claims as one. 17
  • Probably not a substantial claim. 8
21 of 21

  • The paper relies on this without support.

    The PCS-201 fibroblasts used are representative of normal human cells for assessing whether TTFields effects are cancer-specific.

    “In contrast to U87-MG cells, TTFields did not significantly alter the size nor the number of holes in normal human fibroblast cells (Fig. 6).”

  • The paper relies on this without support.

    The membrane holes observed by SEM are not artifacts of sample preparation and reflect actual holes in living cell membranes.

    “Finally, we present scanning electron microscopy (SEM) data that demonstrate an increase in the number and size of holes in glioblastoma cell membranes caused by TTFields exposure.”

  • The paper relies on this without support.

    This is the first study to report the effects of TTFields on cancer cellular membrane integrity.

    “To our knowledge, this is the first study to report the effects of TTFields on cancer cellular membrane integrity.”

  • The paper relies on this without support.

    TTFields exert their maximal antiproliferative effect on dividing cells.

    “TTFields exert their maximal antiproliferative effect on dividing cells”
4 of 4

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Citations

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Research works printed but not linked: 6

  1. Diego UoC-S. SRX2006411: GBM39 EC naive. 2016. https://www.ncbi.nlm.nih.gov/sra/SRX2006411[accn]
  2. JoVE Science Education Database. Basic Methods in Cellular and Molecular Biology (Passaging Cells, JoVE, Cambridge, MA, 2018).
  3. Strober, W. in Current Protocols in Immunology (John Wiley and Sons, New York, 2001), Appendix 3: Appendix3A.
  4. Giladi, M. et al. Mitotic spindle disruption by alternating electric fields leads to improper chromosome segregation and mitotic catastrophe in cancer cells. Sci. Rep. 5, 18046 (2015). · DOI · Paper page
  5. Pubchem. Molecular weight of firefly d-Luciferin. 2017. https://pubchem.ncbi.nlm.nih.gov/compound/D-Luciferin
  6. Pubchem. Molecular weight of coelentrazine. 2017. https://pubchem.ncbi.nlm.nih.gov/compound/2762722

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Metadata

Authors
Chang, E., Patel, C. B., Pohling, C., Young, C., Song, J., Flores, T. A., Zeng, Y., Joubert, L.-M., Arami, H., Natarajan, A., Sinclair, R., & Gambhir, S. S.
Affiliations
  • Stanford Medicine (US)
  • Stellenbosch University (ZA)
Corresponding author
Gambhir, Sanjiv S.
ORCID
Venue
Cell Death Discovery
Publisher
Springer Science and Business Media LLC
Published
2018-12-05
Volume
4
Issue
1
Pages
113-113
ISSN
2058-7716 (ISSN-L)
DOI
10.1038/s41420-018-0130-x
PMC
PMC6281619
OpenAlex
W2902560780
Cited by
137
References
57
Citations by year
2026: 9 · 2025: 13 · 2024: 26 · 2023: 25 · 2022: 24 · 2021: 21 · 2020: 17 · 2019: 2
FWCI
5.67
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Death Discovery (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • Ben and Catherine Ivy Foundation
  • Ludwig Institute for Cancer Research
  • Novocure
  • National Cancer Institute (T32CA009695)
  • Stanford Cancer Institute
Topics
  • Health Sciences › Medicine › Oncology › Glioma Diagnosis and Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Microbial Inactivation Methods
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biophysics › Electromagnetic Fields and Biological Effects
Keywords
tumor treating fields, glioblastoma, membrane permeability, AC electric field, 5-aminolevulinic acid, chemotherapy delivery, combination therapy, bioluminescence

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