Cellular microenvironment modulates the galvanotaxis of brain tumor initiating cells

Huang, Yu; Hoffmann, Gwendolyn A.; Wheeler, Benjamin J; Schiapparelli, Paula; Quiñones‐Hinojosa, Alfredo; Searson, Peter C.

doi:10.1038/srep21583

Cited by 40 publications

(55 citation statements)

References 60 publications

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“…3E); as we weakened the cathodic response mediated by sulfated GAGs, the mechanisms governing an anodic response dominated and cells migrated towards the anode. Interestingly, we have also previously observed that the galvanotaxis of BTICs can also be reversed by their surrounding microenvironment (Huang et al, 2016); galvanotaxis of BTICs switched from cathodic to anodic upon addition of poly-L-ornithine on top of a laminincoated substrate, similar to the galvanotropism of neurons reported previously (Movie 5 and Fig. S4) (Rajnicek et al, 1998).…”

Section: Discussionsupporting

confidence: 59%

Electrophoresis of cell membrane heparan sulfate regulates galvanotaxis in glial cells

Huang

Schiapparelli

Kozielski

et al. 2017

Journal of Cell Science

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Endogenous electric fields modulate many physiological processes by promoting directional migration, a process known as galvanotaxis. Despite the importance of galvanotaxis in development and disease, the mechanism by which cells sense and migrate directionally in an electric field remains unknown. Here, we show that electrophoresis of cell surface heparan sulfate (HS) critically regulates this process. HS was found to be localized at the anode-facing side in fetal neural progenitor cells (fNPCs), fNPCderived astrocytes and brain tumor-initiating cells (BTICs), regardless of their direction of galvanotaxis. Enzymatic removal of HS and other sulfated glycosaminoglycans significantly abolished or reversed the cathodic response seen in fNPCs and BTICs. Furthermore, Slit2, a chemorepulsive ligand, was identified to be colocalized with HS in forming a ligand gradient across cellular membranes. Using both imaging and genetic modification, we propose a novel mechanism for galvanotaxis in which electrophoretic localization of HS establishes cell polarity by functioning as a co-receptor and provides repulsive guidance through Slit-Robo signaling.

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Section: Discussionsupporting

confidence: 59%

Electrophoresis of cell membrane heparan sulfate regulates galvanotaxis in glial cells

Huang

Schiapparelli

Kozielski

et al. 2017

Journal of Cell Science

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“…These galvanotaxing cells also showed oriented ERK and Akt signaling that lined up with the EF and apparently was critical for directional migration (Yan et al 2009). Consistently, one study showed that the galvanotaxis of brain tumor initiating cells from three distinct GBM subtypes also depended upon the oriented activity of PI3K and ERK signaling (Huang et al 2016). Although these findings suggest galvanotaxis can promote the directed migration of tumor cells, data clearly suggest that the nature of the behavior including the anodal versus the cathodal effect is context-dependent and likely cell type -dependent.…”

Section: Galvanotaxismentioning

confidence: 66%

“…For example, changes in ECM deposition and organization simultaneously promote haptotaxis, alignotaxis, and durotaxis. Furthermore, a recent study showed that GBM galvanotaxis proceeds toward the anode on a poly-L-ornithine/laminin 2D surface but switches to a cathode bias when the tumor cells are assayed with a 3D hyaluronic acid and collagen gel (Huang et al 2016). This underscores the importance of using in vitro assays that can accurately model multiple aspects of the tumor microenvironment to gain a clear and accurate understanding of the role of directional migration of tumors in vivo.…”

Section: Conclusion and Outstanding Questions How Do Different Gradiementioning

confidence: 99%

“…Multiple studies have illustrated a correlation between the metastatic potential of a tumor cell and its sensitivity to galvanotaxis (Djamgoz et al 2001), including the galvanotaxis-mediated directional migration of prostate cancer cells (Djamgoz et al 2001), breast cancer (Fraser et al 2005), lung adenocarcinoma (Sun et al 2012), and glioblastoma cells (Huang et al 2016). Interestingly, although prostate, lung, and glioblastoma multiforme (GBM) tumor cells show cathodal galvanotaxis, the breast tumor cells migrate toward the anode, suggesting that different tumor microenvironments might contribute to EF-driven invasion.…”

Section: Galvanotaxismentioning

confidence: 99%

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Physical and Chemical Gradients in the Tumor Microenvironment Regulate Tumor Cell Invasion, Migration, and Metastasis

Oudin

Weaver

2016

Cold Spring Harb Symp Quant Biol

151

121

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Cancer metastasis requires the invasion of tumor cells into the stroma and the directed migration of tumor cells through the stroma toward the vasculature and lymphatics where they can disseminate and colonize secondary organs. Physical and biochemical gradients that form within the primary tumor tissue promote tumor cell invasion and drive persistent migration toward blood vessels and the lymphatics to facilitate tumor cell dissemination. These microenvironment cues include hypoxia and pH gradients, gradients of soluble cues that induce chemotaxis, and ions that facilitate galvanotaxis, as well as modifications to the concentration, organization, and stiffness of the extracellular matrix that produce haptotactic, alignotactic, and durotactic gradients. These gradients form through dynamic interactions between the tumor cells and the resident fibroblasts, adipocytes, nerves, endothelial cells, infiltrating immune cells, and mesenchymal stem cells. Malignant progression results from the integrated response of the tumor to these extrinsic physical and chemical cues. Here, we first describe how these physical and chemical gradients develop, and we discuss their role in tumor progression. We then review assays to study these gradients. We conclude with a discussion of clinical strategies used to detect and inhibit these gradients in tumors and of new intervention opportunities. Clarifying the role of these gradients in tumor evolution offers a unique approach to target metastasis.Tumors are highly heterogeneous and this feature compromises treatment efficacy and promotes tumor cell dissemination and metastasis to reduce patient survival. Tumor heterogeneity is driven in part by genetic alterations induced through genomic instability and maintained by the evolutionary selection of these genetically modified cells (Alizadeh et al. 2015). Epigenetic, transcriptional, and posttranslational modifications also contribute significantly to tumor cell diversity. Furthermore, cancer develops within a complex tissue microenvironment that itself fosters tumor heterogeneity through clonal selection as well as via epigenetic reprogramming and modifications of the tumor phenotype. The tumor microenvironment is composed of cellular constituents that include cells of the vasculature, infiltrating immune cells, and resident fibroblasts, adipocytes and nerves, and a noncellular component composed of diverse soluble factors and a highly variable and evolving insoluble extracellular matrix (ECM) (Joyce and Pollard 2009). The composition and organization of the tumor microenvironment vary significantly within and across tumors.One key feature of the noncellular microenvironment is the existence of local chemical and physical gradients that exert profound effects on the tumor phenotype, including its predilection to disseminate. In this regard, metastasis is facilitated by efficient local tumor cell invasion that is fostered by ECM and chemokine/cytokine/growth factor gradients which cooperate to promote the directional migration of the t...

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“…Myosin II is not needed for the 2D anodal migration, but is required for 3D cathodal migration. By contrast, PI3kinase regulates the 2D anodal response (Huang et al, 2016). …”

Section: Interaction Of Ef With Tissue Electroporation Galvanotaxismentioning

confidence: 99%

Low intensity transcranial electric stimulation: Safety, ethical, legal regulatory and application guidelines

Antal

Alekseichuk

Bikson

et al. 2017

Clinical Neurophysiology

898

728

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Low intensity transcranial electrical stimulation (TES) in humans, encompassing transcranial direct current (tDCS), transcutaneous spinal Direct Current Stimulation (tsDCS), transcranial alternating current (tACS), and transcranial random noise (tRNS) stimulation or their combinations, appears to be safe. No serious adverse events (SAEs) have been reported so far in over 18,000 sessions administered to healthy subjects, neurological and psychiatric patients, as summarized here. Moderate adverse events (AEs), as defined by the necessity to intervene, are rare, and include skin burns with tDCS due to suboptimal electrode-skin contact. Very rarely mania or hypomania was induced in patients with depression (11 documented cases), yet a causal relationship is difficult to prove because of the low incidence rate and limited numbers of subjects in controlled trials. Mild AEs (MAEs) include headache and fatigue following stimulation as well as prickling and burning sensations occurring during tDCS at peak-to-baseline intensities of 1–2 mA and during tACS at higher peak-to-peak intensities above 2 mA. The prevalence of published AEs is different in studies specifically assessing AEs vs. those not assessing them, being higher in the former. AEs are frequently reported by individuals receiving placebo stimulation. The profile of AEs in terms of frequency, magnitude and type is comparable in healthy and clinical populations, and this is also the case for more vulnerable populations, such as children, elderly persons, or pregnant women. Combined interventions (e.g., co-application of drugs, electrophysiological measurements, neuroimaging) were not associated with further safety issues. Safety is established for low-intensity ‘conventional’ TES defined as <4 mA, up to 60 min duration per day. Animal studies and modeling evidence indicate that brain injury could occur at predicted current densities in the brain of 6.3–13 A/m2 that are over an order of magnitude above those produced by tDCS in humans. Using AC stimulation fewer AEs were reported compared to DC. In specific paradigms with amplitudes of up to 10 mA, frequencies in the kHz range appear to be safe. In this paper we provide structured interviews and recommend their use in future controlled studies, in particular when trying to extend the parameters applied. We also discuss recent regulatory issues, reporting practices and ethical issues. These recommendations achieved consensus in a meeting, which took place in Göttingen, Germany, on September 6–7, 2016 and were refined thereafter by email correspondence.

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Cellular microenvironment modulates the galvanotaxis of brain tumor initiating cells

Cited by 40 publications

References 60 publications

Electrophoresis of cell membrane heparan sulfate regulates galvanotaxis in glial cells

Electrophoresis of cell membrane heparan sulfate regulates galvanotaxis in glial cells

Physical and Chemical Gradients in the Tumor Microenvironment Regulate Tumor Cell Invasion, Migration, and Metastasis

Low intensity transcranial electric stimulation: Safety, ethical, legal regulatory and application guidelines

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