Tumor Treating Fields (TTFields) Hinder Cancer Cell Motility through Regulation of Microtubule and Actin Dynamics
Open accessAbstract
Tumor Treating Fields (TTFields) are noninvasive, alternating electric fields within the intermediate frequency range (100–300 kHz) that are utilized as an antimitotic cancer treatment. TTFields are loco-regionally delivered to the tumor region through 2 pairs of transducer arrays placed on the skin. This novel treatment modality has been FDA-approved for use in patients with glioblastoma and malignant pleural mesothelioma based on clinical trial data demonstrating efficacy and safety; and is currently under investigation in other types of solid tumors. TTFields were shown to induce an anti-mitotic effect by exerting bi-directional forces on highly polar intracellular elements, such as tubulin and septin molecules, eliciting abnormal microtubule polymerization during spindle formation as well as aberrant cleavage furrow formation. Previous studies have demonstrated that TTFields inhibit metastatic properties in cancer cells. However, the consequences of TTFields application on cytoskeleton dynamics remain undetermined. In this study, methods utilized in combination to study the effects of TTFields on cancer cell motility through regulation of microtubule and actin dynamics included confocal microscopy, computational tools, and biochemical analyses. Mechanisms by which TTFields treatment disrupted cellular polarity were (1) interference with microtubule assembly and directionality; (2) altered regulation of Guanine nucleotide exchange factor-H1 (GEF-H1), Ras homolog family member A (RhoA), and Rho-associated coiled-coil kinase (ROCK) activity; and (3) induced formation of radial protrusions of peripheral actin filaments and focal adhesions. Overall, these data identified discrete effects of TTFields that disrupt processes crucial for cancer cell motility.
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Written from the paper’s full text.
TL;DR
TTFields applied in vitro at low intensity (0.6 V/cm RMS, 200 kHz) reduce glioblastoma invasion and migration while altering microtubule directionality, activating GEF-H1/RhoA/ROCK, and reorganizing actin and focal adhesions. The proposed mechanism links TTFields-induced microtubule disruption to impaired cancer cell polarity and motility, without impairing leukocyte migration at 200 kHz.
Key findings
- TTFields (0.6 V/cm RMS, 200 kHz, 24 h) significantly reduced invasion in U-87 MG, A-172, LN-229, and LN-18 glioblastoma cells and decreased 3D spheroid dispersal of U-87 MG and A-172 cells.
- TTFields reduced cell migration velocity; bi-directional TTFields reduced directionality/linearity of migration, and perpendicular application to the leading edge produced the lowest average migration velocity, while uni-directional parallel application slowed velocity but increased directional persistence.
- TTFields reduced microtubule fluorescence intensity, induced perinuclear microtubule localization, reduced cell polarity and spread area, aligned microtubules with the electric field, and altered MTOC positioning; treated cells also showed increased focal adhesion size/number/peripheral distribution, a dense peripheral actin meshwork, and reduced detachment.
- TTFields induced transient RhoA activation at 3, 5, 10, 15, and 30 min, increased phosphorylation of GEF-H1 on Ser886, and increased ROCK activity; 200 kHz TTFields did not impair random or CCL19-induced migration of bone marrow-derived dendritic cells and splenic T cells.
Methods
- Human glioblastoma cell lines U-87 MG, A-172, LN-229, and LN-18 and lung adenocarcinoma lines H1299 and A549 were treated with TTFields using the inovitro/inovitro live systems; general treatment was 1.75 V/cm RMS at 150 kHz for lung adenocarcinoma and 200 kHz for glioblastoma, while invasion experiments used 0.6 V/cm RMS at 200 kHz for 24 h.
- Assays included modified Boyden chamber invasion, 3D spheroid dispersal, wound healing time-lapse microscopy, immunofluorescence/confocal microscopy, cellular detachment, RhoA G-LISA activation, ROCK activity, Western blotting, and leukocyte migration assays with BMDCs and splenic T cells from 5–7-week-old male C57BL/6 mice.
- Image analysis used FIJI/ImageJ, OpenCV, and the ibidi Chemotaxis and Migration tool; statistical analysis used GraphPad Prism with p < 0.05 considered significant.
Limitations
- Stated: the authors did not test the effect of TTFields on cytoskeletal architecture of non-cancerous cells, relying instead on clinical trial and animal safety data; they also note that the mechanism of microtubule alignment with TTFields remains theoretical and should continue to be investigated.
- Evident: the study is primarily in vitro, using cancer cell lines and isolated leukocyte migration assays, with no in vivo metastasis or tumor invasion model reported in this paper.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
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Claims the paper makes
0 of 24 cited sources checked · 0 supported · 0 flagged
- Findingown data
When TTFields were applied at 200 kHz, no differences were observed relative to control conditions in the number of leukocytes that relocated in random migration without CCL19 or due to CCL19-induced migration.
“When TTFields were applied at the optimal frequency of 200 kHz, no differences were observed relative to control conditions in the number of leukocytes that relocated in random migration (without CCL19) and due to CCL19-induced migration (Figure 5E,F).”
Quote in the paperSubstantial claim - Findingown data
Application of TTFields in parallel to the direction of the leading edge led to a reduction in cell polarity.
“Application of TTFields in parallel to the direction of the leading edge also led to a reduction in cell polarity (defined as the distance from cell nucleus to the center of mass; Figure 3D).”
Quote in the paperSubstantial claim - Findingown data
TTFields applied perpendicularly to the leading edge resulted in reduction in cell spread area.
“Moreover, TTFields applied perpendicularly to the leading edge resulted in reduction in the cell spread area (Figure 3B) and cellular polarity (Figure 3D), in addition to eliciting alignment of the microtubules in the direction of the electric field (Figure 3E).”
Quote in the paperSubstantial claim - Findingown data
No significant differences were observed in overall migration rates or leading edge velocity between cells treated with TTFields applied bi-directionally or uni-directionally in parallel with cell movement.
“No significant differences were observed in overall migration rates or leading edge velocity, as determined by calculation of the total distance that the cells moved from the edge of the cell-free gap toward the mid-center of the cell-free gap, as a function of time between cells treated with TTFields applied bi-directionally or uni-directionally in parallel with cell movement.”
Quote in the paperSubstantial claim - Findingown data
TTFields reduced the quantity of microtubules in cancer cells.
“In this study, we demonstrated that similar to the effects of TTFields on mitotic spindle microtubules, TTFields also reduced the quantity of microtubules and dictated the directionality of cancer migration.”
Quote in the paperSubstantial claim
- Findingown data
TTFields reduced cellular detachment from polystyrene in all TTFields-treated cancer cell lines compared with untreated control cells.
“TTFields reduced cellular detachment from polystyrene in all TTFields-treated cancer cell lines compared with untreated control cells (Figure 4A).”
Quote in the paperSubstantial claim - Findingown data
Significant differences in directionality were observed between cells treated with bi-directional versus uni-directional TTFields.
“Significant differences in directionality were also observed between cells treated with bi-directional versus uni-directional TTFields.”
Quote in the paperNot a substantial claim - Findingown data
TTFields applied perpendicularly to the leading edge elicited alignment of microtubules in the direction of the electric field.
“Moreover, TTFields applied perpendicularly to the leading edge resulted in reduction in the cell spread area (Figure 3B) and cellular polarity (Figure 3D), in addition to eliciting alignment of the microtubules in the direction of the electric field (Figure 3E).”
Quote in the paperSubstantial claim - Findingown data
Cells treated with TTFields applied perpendicularly to the leading edge showed the lowest average migration velocity.
“Consistent with these findings, cells that were treated with TTFields applied perpendicularly to the leading edge of cells showed the lowest average migration velocity (Figure 2E).”
Quote in the paperSubstantial claim - Findingown data
The velocity of cells treated with uni-directional TTFields was significantly slower than that of bi-directional TTFields application and control.
“The velocity of cells treated with uni-directional TTFields was shown to be significantly slower than that of bi-directional TTFields application and control (Figure 2J).”
Quote in the paperNot a substantial claim - Findingown data
TTFields-treated cells exhibited a dense meshwork of actin filaments around the entire cell periphery, resembling dorsal stress fibers and transverse actin arcs.
“Interestingly, F-actin staining revealed that while control cells were highly polarized, TTFields-treated cells exhibited a dense meshwork of actin filaments around the entire cell periphery, resembling the appearance of dorsal stress fibers and transverse actin arcs (Figure 4E).”
Quote in the paperSubstantial claim - Findingown data
In both directions, the intensity of fluorescence from labelled microtubules was significantly lower than in the control group.
“In both directions, the intensity of fluorescence collected from the labelled microtubules was significantly lower than what was observed in the control group (Figure 3C).”
Quote in the paperSubstantial claim - Findingown data
TTFields application significantly reduced cancer cell invasion compared with control conditions in all tested cell lines (U-87 MG, A-172, LN-229, LN-18) under 0.6 V/cm RMS, 200 kHz, for 24 h.
“TTFields application significantly reduced cancer cell invasion compared to control conditions in all tested cell lines (Figure 1B,C).”
Quote in the paperSubstantial claim - Findingown data
Cell migration velocity was significantly reduced when TTFields were applied perpendicular to the direction of cell movement compared with parallel application.
“Cell migration rate (velocity) was found to be significantly reduced when TTFields were applied perpendicular to the direction of cell movement (toward the gap) as compared to when the field direction of TTFields was applied in parallel to cellular movement (Figure 2D,E).”
Quote in the paperSubstantial claim - Findingown data
TTFields exposure significantly increased the activity levels of ROCK in treated cells.
“Subsequently, activation of ROCK, which mediates the downstream effects of RhoA on stress fibers and focal adhesions, was evaluated and showed that TTFields exposure significantly increased the activity levels of ROCK in treated cells (Figure 5D) [23].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [23] Amano, 1997, Formation of actin stress fibers and focal adhesions enhanced by Rho-kinase, Science source
Not checked in the free run.
- Findingown data
TTFields application promoted phosphorylation of GEF-H1 in A-172 and LN-229 cells.
“Consistent with the above hypothesis, TTFields application was demonstrated to promote phosphorylation of GEF-H1 (Figure 5C).”
Quote in the paperSubstantial claim - Findingown data
TTFields application induced a significant and transient increase in RhoA activity in A-172 and LN-229 cells.
“Results demonstrated that TTFields application induced a significant and transient increase in RhoA activity (Figure 5A,B).”
Quote in the paperSubstantial claim - Findingown data
Treated cancer cells adopted a more spread shape compared with control cells.
“Treated cancer cells adopted a more spread shape in comparison with control cells.”
Quote in the paperSubstantial claim - Findingown data
Significantly higher directionality was observed in cells treated with uni-directional TTFields applied in parallel to cell movement relative to bi-directional application.
“Interestingly, a significantly higher directionality (directional persistence) was observed in cells treated with uni-directional TTFields (applied in parallel to cell movement) relative to bi-directional application (Figure 2I).”
Quote in the paperNot a substantial claim - Findingown data
Application of TTFields in parallel to the direction of the leading edge induced perinuclear localization of microtubules.
“Microtubule staining and confocal fluorescence microscopy of cells at the wound edge revealed that application of TTFields in parallel to the direction of the leading edge induced perinuclear localization of the microtubules (Figure 3B).”
Quote in the paperSubstantial claim - Findingown data
No significant differences were observed in the overall accumulated distance between control cells and bi-directional TTFields-treated A-172 cells.
“No significant differences were observed in the overall accumulated distance between control cells and bi-directional application of TTFields to A-172 cells (Figure 2G).”
Quote in the paperNot a substantial claim - Findingown data
In F-actin staining, control cells were highly polarized.
“Interestingly, F-actin staining revealed that while control cells were highly polarized, TTFields-treated cells exhibited a dense meshwork of actin filaments around the entire cell periphery, resembling the appearance of dorsal stress fibers and transverse actin arcs (Figure 4E).”
Quote in the paperSubstantial claim - Findingown data
In cells exposed to TTFields, microtubules tend to align with the field.
“In addition, our data suggests that in cells exposed to TTFields, the microtubules tend to align with the field, further inhibiting the ability of cells to migrate freely.”
Quote in the paperSubstantial claim - Findingown data
TTFields applied perpendicularly to the leading edge resulted in reduction in cellular polarity.
“Moreover, TTFields applied perpendicularly to the leading edge resulted in reduction in the cell spread area (Figure 3B) and cellular polarity (Figure 3D), in addition to eliciting alignment of the microtubules in the direction of the electric field (Figure 3E).”
Quote in the paperSubstantial claim - Findingown data
TTFields application led to a significant reduction in cell migration velocity compared with untreated control cells in U-87 MG and A-172 wound healing assays.
“Application of TTFields led to a significant reduction in cell migration velocity compared with untreated control cells (Figure 2A,B; Supplementary Videos S1 [U-87 MG] and S2,S3 [A-172]).”
Quote in the paperSubstantial claim - Findingown data
TTFields dictated the directionality of cancer migration.
“In this study, we demonstrated that similar to the effects of TTFields on mitotic spindle microtubules, TTFields also reduced the quantity of microtubules and dictated the directionality of cancer migration.”
Quote in the paperSubstantial claim - Findingown data
TTFields application led to a significant decrease in the dispersal of both U-87 MG and A-172 spheroids in a 3D extracellular matrix model.
“We observed that TTFields application led to a significant decrease in the dispersal of both U-87 MG and A-172 cells in accordance with the observed effects in the modified Boyden chamber system (Figure 1D,E).”
Quote in the paperSubstantial claim - Findingown data
TTFields application does not impair leukocyte migration.
“In this study, we also demonstrated that TTFields application does not impair leukocyte migration; however, the integrity and function of the microtubule and actin cytoskeleton are critical for the function of many other healthy tissues.”
Quote in the paperSubstantial claim - Premisecitation
Induction of TTFields anti-mitotic effects requires electric field intensities above 1 V/cm RMS.
“Noteworthy, the duration of the invasion experiments and the applied electric fields intensities were shorter and lower than the duration and the intensities (above 1 V/cm RMS) required for induction of TTFields anti-mitotic effects [1,2].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [1] Kirson, 2004, Disruption of cancer cell replication by alternating electric fields, Cancer Res. source
Not checked in the free run.
- cites [2] Kirson, 2007, Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors, Proc. Natl. Acad. Sci. USA source
Not checked in the free run.
- Interpretationown data
TTFields application at 200 kHz did not impair random or chemoattractant-induced leukocyte migration.
“These results suggest that TTFields application at 200 kHz did not impair random or chemoattractant-induced leukocyte migration.”
Quote in the paperSubstantial claim - Interpretationown data
TTFields exposure potentiates cellular adherence of cancer cells.
“These results suggest that TTFields exposure potentiates cellular adherence of cancer cells.”
Quote in the paperSubstantial claim - Premisecitation
The field intensities at which electro-orientation of microtubules in solution occurs are at least three orders of magnitude higher than the field intensities of TTFields.
“However, the field intensities at which this occurs are at least three orders of magnitude higher than the field intensities of TTFields.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [35] Minoura, 2006, Dielectric measurement of individual microtubules using the electroorientation method, Biophys. J. source
Not checked in the free run.
- Interpretationreasoning
TTFields induce changes in microtubule and actin organization and dynamics, thereby disrupting processes important for polarity generation and motility in cancer cells.
“Together, these results propose a novel mechanism by which TTFields induce changes in microtubule and actin organization and dynamics, thereby disrupting processes important for polarity generation and motility in cancer cells.”
Quote in the paperSubstantial claim - Interpretationreasoning
Changes in microtubule organization led to increased activation of GEF-H1.
“These changes in microtubule organization also led to increased activation of GEF-H1, actuating the RhoA/ROCK signaling cascade and further inducing the formation of a dense meshwork of peripheral actin filaments and an increase in size and number of focal adhesions (Figure 6).”
Quote in the paperSubstantial claim - Interpretationreasoning
Cellular polarization is altered under TTFields application.
“Since cellular polarization is mainly determined by the location of the MTOC relative to the nucleus, these results suggest that cellular polarization is altered under TTFields application.”
Quote in the paperSubstantial claim - Interpretationreasoning
Increased activation of GEF-H1 actuates the RhoA/ROCK signaling cascade.
“These changes in microtubule organization also led to increased activation of GEF-H1, actuating the RhoA/ROCK signaling cascade and further inducing the formation of a dense meshwork of peripheral actin filaments and an increase in size and number of focal adhesions (Figure 6).”
Quote in the paperSubstantial claim - Interpretationreasoning
Activation of RhoA/ROCK signaling increases the size and number of focal adhesions.
“These changes in microtubule organization also led to increased activation of GEF-H1, actuating the RhoA/ROCK signaling cascade and further inducing the formation of a dense meshwork of peripheral actin filaments and an increase in size and number of focal adhesions (Figure 6).”
Quote in the paperSubstantial claim - Interpretationown data
The RhoA/ROCK signaling pathway is an essential component of signal transduction pathways linking TTFields-induced microtubule disruption to the induction of peripheral actin bundling and focal adhesion formation.
“Jointly, these data show that the RhoA/ROCK signaling pathway is an essential component of signal transduction pathways linking TTFields-induced microtubule disruption to the induction of peripheral actin bundling and focal adhesion formation.”
Quote in the paperSubstantial claim - Interpretationown data
Alignment of microtubules with the field further inhibits the ability of cells to migrate freely.
“In addition, our data suggests that in cells exposed to TTFields, the microtubules tend to align with the field, further inhibiting the ability of cells to migrate freely.”
Quote in the paperSubstantial claim - Interpretationreasoning
Activation of RhoA/ROCK signaling induces the formation of a dense meshwork of peripheral actin filaments.
“These changes in microtubule organization also led to increased activation of GEF-H1, actuating the RhoA/ROCK signaling cascade and further inducing the formation of a dense meshwork of peripheral actin filaments and an increase in size and number of focal adhesions (Figure 6).”
Quote in the paperSubstantial claim - Interpretationown data
TTFields application induces changes in microtubule organization leading to interference with the directionality and robustness of cancer cell migration.
“In this study, we report TTFields application induces changes in microtubule organization leading to interference with the directionality and robustness of cancer cell migration, with mechanistic consistency to other anti-microtubule agents and inhibitors of cancer cell invasion [11,12,13,14,15,16].”
Quote in the paperSubstantial claim - Premisecitation
Alignment of microtubules in low intensity DC electric fields has been observed in kinesin-propelled microtubule assays.
“Alignment of microtubules in low intensity DC electric fields has been observed in kinesin-propelled microtubule assays [36].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [36] Dekker, 2008, Microtubule curvatures under perpendicular electric forces reveal a low persistence length, Proc. Natl. Acad. Sci. USA source
Not checked in the free run.
- Premisecitation
Data from clinical trials and extensive safety studies in healthy animals have shown that TTFields are not associated with significant systemic toxicities.
“Although we have not tested the effect of TTFields on cytoskeletal architecture of non-cancerous cells, data from clinical trials and extensive safety studies in healthy animals have shown that TTFields are not associated with significant systemic toxicities [7,37].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [7] Mun, 2018, Tumor-Treating Fields: A Fourth Modality in Cancer Treatment, Clin. Cancer Res. source
Not checked in the free run.
- cites [37] Shi, 2020, Global post-marketing safety surveillance of Tumor Treating Fields (TTFields) in patients with high-grade glioma in clinical practice, J. Neurooncol. source
Not checked in the free run.
- Rests on an assumption: The integrity and function of the microtubule and actin cytoskeleton are critical for the function of many other healthy tissues.
- May combine two claims. 10
- Classified as probably not a substantial claim. 13
May combine two claims.
Findingown dataUntreated individual cancer cells moved along relatively straight, linear paths compared with bi-directional TTFields-treated cells, with significant differences in Euclidean distance and directionality.
“However, under control conditions (without TTFields), untreated individual cancer cells moved along in relatively straight, linear paths as compared with bi-directional TTFields-treated cells. This effect on cell migration patterns was indicated by significant differences in Euclidean distance (Figure 2H) and directionality (Figure 2I), which is defined as a measure of the straightness or linearit”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe frequency of cells with MTOC positioned between the leading edge and the nucleus was significantly lower in TTFields-treated cells, with posterior and centroid orientations being more prominent.
“However, the frequency of cells with this MTOC reorientation were significantly lower in TTFields-treated cells, with posterior (MTOC localized between the nucleus and the rear of the cell) and centroid orientations being more prominent.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataTTFields application resulted in a dramatic increase in focal adhesion size and numbers as well as peripheral distribution of adhesion sites.
“TTFields application was found to result in a dramatic increase in focal adhesion size and numbers as well as peripheral distribution of the adhesion sites (Figure 4B–D).”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationTTFields induce an anti-mitotic effect by exerting bi-directional forces on highly polar intracellular elements such as tubulin and septin, eliciting abnormal microtubule polymerization during spindle formation and aberrant cleavage furrow formation.
“TTFields were shown to induce an anti-mitotic effect by exerting bi-directional forces on highly polar intracellular elements, such as tubulin and septin molecules, eliciting abnormal microtubule polymerization during spindle formation as well as aberrant cleavage furrow formation.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [4] Wenger, 2018, A Review on Tumor-Treating Fields (TTFields): Clinical Implications Inferred from Computational Modeling, IEEE Rev. Biomed. Eng. source
Not checked in the free run.
- cites [5] Gera, N., Yang, A., Holtzman, T.S., Lee, S.X., Wong, E.T., and Swanson, K.D. (2015). Tumor treating fields perturb the localization of septins and cause aberrant mitotic exit. PLoS ONE, 10. source
Not checked in the free run.
- cites [6] Giladi, 2015, Mitotic Spindle Disruption by Alternating Electric Fields Leads to Improper Chromosome Segregation and Mitotic Catastrophe in Cancer Cells, Sci. Rep. source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationTTFields are typically delivered through two pairs of transducer arrays that generate perpendicular fields within the treated tumor.
“TTFields are typically delivered through two pairs of transducer arrays that generate perpendicular fields within the treated tumor [7].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [7] Mun, 2018, Tumor-Treating Fields: A Fourth Modality in Cancer Treatment, Clin. Cancer Res. source
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationPrevious studies have demonstrated that TTFields inhibit metastatic properties in cancer cells.
“Previous studies have demonstrated that TTFields inhibit metastatic properties in cancer cells [8,9,10].”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [8] Kirson, 2009, Alternating electric fields (TTFields) inhibit metastatic spread of solid tumors to the lungs, Clin. Exp. Metastasis source
Not checked in the free run.
- cites [9] Silginer, 2017, Biological activity of tumor-treating fields in preclinical glioma models, Cell Death Dis. source
Not checked in the free run.
- cites [10] Kim, 2016, Tumor treating fields inhibit glioblastoma cell migration, invasion and angiogenesis, Oncotarget source
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationTumor Treating Fields (TTFields) are noninvasive alternating electric fields in the intermediate frequency range (100-300 kHz) used as an antimitotic cancer treatment.
“Tumor Treating Fields (TTFields) are noninvasive, alternating electric fields within the intermediate frequency range (100–300 kHz) that are utilized as an antimitotic cancer treatment.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [1] Kirson, 2004, Disruption of cancer cell replication by alternating electric fields, Cancer Res. source
Not checked in the free run.
- cites [2] Kirson, 2007, Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors, Proc. Natl. Acad. Sci. USA source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationRhoA has been reported to serve as a key regulator of leukocyte differentiation and function.
“RhoA has been previously reported to serve as a key regulator of leukocyte differentiation and function [28].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [28] Bros, M., Haas, K., Moll, L., and Grabbe, S. (2019). RhoA as a Key Regulator of Innate and Adaptive Immunity. Cells, 8. source
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationGEF-H1 catalytic activity toward RhoA is downregulated through microtubule binding.
“GEF-H1 was of focus since its catalytic activity toward RhoA is downregulated through microtubule binding [24,27].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [24] Krendel, 2002, Nucleotide exchange factor GEF-H1 mediates cross-talk between microtubules and the actin cytoskeleton, Nat. Cell Biol. source
Not checked in the free run.
- cites [27] Ren, 1998, Cloning and characterization of GEF-H1, a microtubule-associated guanine nucleotide exchange factor for Rac and Rho GTPases, J. Biol. Chem. source
Not checked in the free run.
May combine two claims.
Interpretationown dataTTFields exposure hinders cancer cell migration, and a single-direction approach of applying TTFields orthogonal to the path of migration is more effective than parallel application.
“These results suggest that TTFields exposure hinders cancer cell migration and that a single-direction approach of applying TTFields orthogonal to the path of migration is more effective than parallel application.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataTTFields application results in radially oriented adhesions and complete re-organization of the actin cytoskeleton of treated cancer cells.
“These results suggest that TTFields application results in radially oriented adhesions and complete re-organization of the actin cytoskeleton of treated cancer cells.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationElectro-orientation of microtubules in solution in response to alternating electric fields has been reported.
“Electro-orientation of microtubules in solution in response to alternating electric fields has been reported [35].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [35] Minoura, 2006, Dielectric measurement of individual microtubules using the electroorientation method, Biophys. J. source
Not checked in the free run.
May combine two claims.
Interpretationown dataTTFields hinder the assembly of microtubules and dictate their directional assembly during cell movement.
“Collectively, these data support the findings that TTFields hinder the assembly of microtubules and dictate their directional assembly during cell movement.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationRhoA plays a central role in the regulation of stress fiber assembly and the induced formation of focal adhesions.
“The small GTPase RhoA plays a central role in the regulation of stress fiber assembly and the induced formation of focal adhesions [21,22].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [21] Leung, 1996, The p160 RhoA-binding kinase ROK alpha is a member of a kinase family and is involved in the reorganization of the cytoskeleton, Mol. Cell Biol. source
Not checked in the free run.
- cites [22] Ridley, 1992, The small GTP-binding protein rac regulates growth factor-induced membrane ruffling, Cell source
Not checked in the free run.
May combine two claims.
Interpretationown dataChanges in microtubule organization result in activation of GEF-H1 and lead to an increase in active RhoA, activation of ROCK, and consequent formation of focal adhesions and changes in actin cytoskeleton architecture.
“We show that these changes in microtubule organization result in activation of GEF-H1 and lead to an increase in the levels of active RhoA, activation of Rho-associated coiled-coil kinase (ROCK), and the consequent formation of focal adhesions and changes in actin cytoskeleton architecture.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationCCL19 promotes leukocyte recruitment and migration.
“CCL19 (chemoattractant), which promotes leukocyte recruitment and migration [30,31].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [30] Real, 2007, CCR7 ligands control basal T cell motility within lymph node slices in a phosphoinositide 3-kinase-independent manner, J. Exp. Med. source
Not checked in the free run.
- cites [31] Robbiani, 2000, The leukotriene C(4) transporter MRP1 regulates CCL19 (MIP-3beta, ELC)-dependent mobilization of dendritic cells to lymph nodes, Cell source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Study design and conductnone givenStandard cell phenotypes were checked and did not change over time.
“Standard cell phenotypes were checked and did not change over time.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenThe purity of T cell samples was validated by flow cytometry analysis using Mouse anti-CD3 antibody.
“The purity of each sample was validated by flow cytometry analysis using Mouse anti-CD3 antibody (clone 17A2, BioLegend).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataThe purity of dendritic cell samples was validated by flow cytometry analysis using Mouse anti-CD11c antibody.
“The purity of each sample was validated by flow cytometry analysis using Mouse anti-CD11c antibody (clone N418, BioLegend).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenIn immunofluorescence imaging, detectors Offset and Master Gain were kept constant, and the same laser power, pinhole, and pixel dwell time were set to maintain consistent conditions for all images being compared.
“Images were acquired using 8-bit digitization depth, while detectors Offset and Master Gain were kept constant. Also, the same laser power, pinhole, and pixel dwell time were set to maintain consistent conditions for all images being compared.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenAll animal studies were approved by the Novocure Internal Animal Care Committee, in accordance with the Technion-Israel Institute of Technology guidelines for the care of laboratory animals.
“All animal studies were approved by the Novocure Internal Animal Care Committee, in accordance with the Technion-Israel Institute of Technology guidelines for the care of laboratory animals.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
The consequences of TTFields application on cytoskeleton dynamics remain undetermined.
“However, the consequences of TTFields application on cytoskeleton dynamics remain undetermined.”
The paper relies on this without support.
The high propensity of glioblastoma cells to infiltrate and invade adjacent brain tissue remains a major obstacle to therapeutic disease management.
“The high propensity of glioblastoma cells to infiltrate and invade adjacent brain tissue remains as a major obstacle to therapeutic disease management.”
The paper relies on this without support.
The integrity and function of the microtubule and actin cytoskeleton are critical for the function of many other healthy tissues.
“however, the integrity and function of the microtubule and actin cytoskeleton are critical for the function of many other healthy tissues.”
The paper relies on this without support.
Cellular polarity is required for effective cancer cell motility.
“changes in actin organization and cellular polarity that is required for effective cancer cell motility.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The standard theory proposes that TTFields disrupt the mitotic spindle in actively dividing cells, leading to aberrant cellular division and eventual cellular death.
“The standard theory proposes a disruption of the mitotic spindle by TTFields in actively dividing cells, thereby leading to aberrant cellular division and eventual cellular death [8,84].”
From Permeabilizing Cell Membranes with Electric Fields (2021) · cites this paper as [84]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Wound-healing observation duration differs between Results and Methods
MinorThe Results say cell migration in the wound-healing assay was monitored for 24 hours, whereas the Methods say migration was observed for 14 hours.
“cell migration during TTFields application, utilizing the inovitro live system, was monitored using time-lapse microscopy for 24 h.”
“Migration was observed in time-lapse series for 14 h (Zeiss axio observer; per 10 objective; Carl Zeiss Microscopy GmbH, Jena, Germany).”
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- Authors
- Voloshin, T., Schneiderman, R. S., Volodin, A., Shamir, R. R., Kaynan, N., Zeevi, E., Koren, L., Klein-Goldberg, A., Paz, R., Giladi, M., Bomzon, Z., Weinberg, U., & Palti, Y.
- Affiliations
- Novocure Ltd., Topaz Building, MATAM Center, Haifa 31905, Israel
- Corresponding author
- Giladi, Moshe
- ORCID
- Venue
- Cancers
- Publisher
- MDPI AG
- Published
- 2020-10-17
- Volume
- 12
- Issue
- 10
- Pages
- 3016
- ISSN
- 2072-6694 (ISSN-L)
- PMC
- PMC7603026
- OpenAlex
- W3092664852
- Cited by
- 94
- References
- 39
- Citations by year
- 2026: 13 · 2025: 22 · 2024: 15 · 2023: 21 · 2022: 13 · 2021: 9 · 2020: 1
- FWCI
- 5.49
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cancers (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biophysics › Electromagnetic Fields and Biological Effects
- Keywords
- tumor treating fields, tumor cell motility, microtubule dynamics, actin dynamics, cytoskeleton, cell polarity, GEF-H1, RhoA, rocks, focal adhesions, glioblastoma, malignant pleural mesothelioma, antimitotic therapy, electric field treatment
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.
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