Department of Biological Sciences, Neuroscience Solutions to Cancer Research Group, Imperial College London, Sir Alexander Fleming Building, South Kensington Campus, London, SW7 2AZ, UK
* Author for correspondence (e-mail: m.djamgoz{at}imperial.ac.uk)
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Summary |
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Key words: Galvanotaxis, Ca2+, Direct-current electric fields, Metastatic disease, Na+ channel
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Introduction |
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Endogeneous dcEFs play a significant role in major biological processes such as embryogenesis, wound healing and tissue regeneration (reviewed by Nuccitelli, 1988). TEP values vary depending on the physiological condition or the pathophysiological state of the tissue. For example, in cystic fibrosis, which is associated primarily with impaired Cl- transport across epithelial membranes, the TEP of the nasal airway epithelium is hyperpolarized (51 mV in cystic fibrosis patients, compared with 15 mV in normal nasal airway epithelium) (Hofmann et al., 1997
).
A major cellular effect of dcEFs is galvanotaxis, which is directional movement towards the cathode or the anode. Application of in vitro dcEF strengths comparable with those detected in vivo produces galvanotaxis in a variety of cultured cells. In most cases, cells move towards the cathode; for example, bovine corneal epithelial cells (Zhao et al., 1996), bovine aortic vascular endothelial cells (Li and Kolega, 2002
), human retinal pigment epithelial cells (Sulik et al., 1992
), human keratinocytes (Sheridan et al., 1996
), amphibian neural crest cells (Cooper and Keller, 1984
), C3H/10T1/2 mouse embryo fibroblasts (Onuma and Hui, 1985
), fish epidermal cells (Cooper and Shliwa, 1986
) and metastatic rat prostate cancer cells (Djamgoz et al., 2001
). However, some cell types move towards the anode; for example, human granulocytes (Rapp et al., 1988
), rabbit corneal endothelial cells (Chang et al., 1996
), human vascular endothelial cells (HUVECs) (Zhao et al., 2004
) and metastatic human breast cancer cells (Fraser et al., 2002
). Although human dermal melanocytes were recently reported to be insensitive to an external dcEF of 100 mV/mm (Grahn et al., 2003
), this might have been due to these cells having a higher threshold (Onuma and Hui, 1988
). We should also note that species and/or cell subtype differences might affect galvanotaxis. For example, HUVECs move towards the anode (Zhao et al., 2004
), whereas bovine aortic vascular endothelial cells show a cathodal response (Li and Kolega, 2002
).
In this Commentary, we discuss the subcellular mechanisms by which dcEFs could change the intracellular milieu, in particular the intracellular Ca2+ concentration, [Ca2+]i, and thus induce galvanotaxis. We then examine the possible role of galvanotaxis in cancer metastasis.
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Cellular mechanisms of galvanotaxis |
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The importance of Ca2+
In most cells studied, galvanotaxis is thought to depend on changes in [Ca2+]i. This is consistent with the initial response to dcEFs being fast (see below) and hence is likely to involve a `small' molecule. Measurements of [Ca2+]i in mouse embryo fibroblasts, using the Ca2+-sensitive photoprotein aequorin, show that application of a dcEF produces a significant overall [Ca2+]i increase (up to mM), which is maintained throughout exposure to the field (Onuma and Hui, 1988). Ca2+ channel blockers, such as Co2+ or D600, or removal of extracellular Ca2+, can block the dcEF-induced rise in [Ca2+]i (Onuma and Hui, 1988
) and, in most cases, this inhibits galvanotaxis without influencing the basic ability of the cell to move (Nuccitelli et al., 1993
). dcEF stimulation also more than doubles [Ca2+]i in a rat osteoblast-like cell line (Wang et al., 1998
). Moreover, note that Ca2+ influx induced by various factors, including membrane depolarization, has a role in cellular contraction (see below) in hepatic stellate cells (Bataller et al., 2001
), pulmonary artery smooth muscle (Zhang et al., 1997
) and skeletal muscle cells (Mickleson and Louis, 1996
). The commonly seen cathodal galvanotaxis of cells can be explained if one assumes that, as a consequence of the dcEF, a rise in [Ca2+]i in a given part of the cell causes contraction of that side whereas the opposite occurs at the other side. This should bring about a `push-pull' movement (Cooper and Keller, 1984
). Such Ca2+-dependent cellular contraction/protrusion could involve at least two different mechanisms (Horwitz and Parsons, 1999
) (Table 1), the most obvious being actin polymerization/depolymerization and actomyosin contractility.
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Note that in some cell types, such as mouse NIH 3T3 fibroblasts (Brown and Loew, 1994) and certain frog spinal neurites, the response to dcEFs is not always sensitive to extracellular Ca2+ (Palmer et al., 2000
). Interestingly, however, the galvanotactic response of another mouse fibroblast cell line, C3H/10T1/2, does require extracellular Ca2+ (Onuma and Hui, 1988
). The reason(s) for this difference is not clear at present but probably involves differences in the experimental conditions. In particular, the different concentrations of fetal calf serum used might have affected the expression of ion channels (Ding and Djamgoz, 2004
) and/or the different surfaces could have altered the electrotactic response (Sheridan et al., 1996
). Nevertheless, Ca2+ sensitivity does suggest a potential galvanotactic mechanism in the majority of cells where it is evident.
Actin polymerization/depolymerization
Elongation of actin filaments, usually at the leading edge of the cell (Chan et al., 1998), is the main driving force for cell movement. The mechanism involves generation of free barbed ends of cortical actin filaments by gelsolin- and/or cofilin-induced severing. A reduction in [Ca2+]i releases gelsolin from these barbed ends (Condeelis, 2001
), which could thus promote polymerization, thereby causing protrusion of that part of the cell (Onuma and Hui, 1988
). Although the mechanisms responsible for actin dynamics at the rear of migrating cells are still not well understood, [Ca2+]i might be increased, resulting in depolymerization of actin (Wehrle-Haller and Imhof, 2003
; Small et al., 1998
). Externally applied dcEFs transiently increase the total amount of filamentous actin in the cell. The lamellipodia projecting towards the cathode become selectively enriched in filamentous actin in these cells (Li and Kolega, 2002
; Zhao et al., 2002b
), which indicates that actin polymerization is indeed an important aspect of galvanotaxis.
Actomyosin contractility
Myosin II is the most common molecular motor of muscle and non-muscle cells and is regulated by [Ca2+]i (Somlyo and Somlyo, 2000). Myosin light chain kinase (MLCK), found in differentiated smooth muscle and non-muscle cells, is Ca2+/calmodulin-dependent and phosphorylates the regulatory light chain of myosin II. This phosphorylation stimulates the actin-activated myosin ATPase and is thought to play a major role in cell contraction (Stull et al., 1998
; Goeckeler and Wysolmerski, 1995
). Myosin disassembly follows a transient increase in [Ca2+]i (Rees et al., 1989
), and Ca2+ triggers contraction of non-muscle bile canaliculi in freshly isolated monolayer cultures of rat hepatocytes (Watanabe and Phillips, 1984
). Although it is not clear whether actin polymerization/depolymerization and actomyosin-based mechanisms have the same [Ca2+]i requirement (i.e. respond to the same quantitative changes in [Ca2+]i), both should displace the cell in the same direction (towards the cathode) in a dcEF, along the axis of a high to low [Ca2+]i gradient. In such a model, there could be some redistribution of intracellular Ca2+ as `Ca2+ waves' (Perret et al., 1999
) (Fig. 1B).
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Other effects
The change in [Ca2+]i should also affect cell adhesion (Table 1). To move, the cell must attach where it is protruding and detach where it retracts (Libotte et al., 2001; Gerisch et al., 1999
). Changes in [Ca2+]i could cause these effects (Hendey and Maxfield, 1993
). Indeed, an increase in [Ca2+]i is responsible for rear-margin detachment during the movement of keratocytes (Lee et al., 1999
). There should thus be a tendency for the cell to detach and attach where [Ca2+]i rises and falls, respectively. Such changes would be consistent with the net direction of movement. Ca2+ influx could also have several secondary effects, such as activation of Ca2+-dependent K+ channels (Schwindt and Crill, 1995
) and Ca2+/calmodulin-dependent kinases (CaMKs), which could also affect migration (Kobayashi et al., 1999
).
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dcEF-mediated direct regulation of [Ca2+]i |
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Influx through voltage-gated Ca2+ channels
If VGCCs are present, membrane depolarization (on the cathodal side) should open them and allow Ca2+ influx, which would then tend to cause the cell to move towards the anode in the opposite direction to the effect of passive Ca2+ influx alone (Fig. 1C). The net movement, if any, would then depend upon the balance of the two opposing forces. Application of `large' voltage pulses across keratocytes causes Ca2+ influx through VGCCs (Brust-Mascher and Webb, 1998). Several other excitable and non-excitable cell types respond similarly, including myeloma cells, osteoclasts, astrocytes and fibroblasts (Rink and Merritt, 1990; Cho et al., 1999
). In several cases, Ca2+ channel blockers reduce galvanotaxis (e.g. Brust-Mascher and Webb, 1998; Trollinger et al., 2002
). Experiments on frog myoblasts confirmed that the orientation of these cells in response to dcEFs depends on the presence of Ca2+ in the extracellular medium and that application of the general VGCC blocker Co2+ suppresses the responses completely (McCaig and Dover, 1989
). In human keratinocytes, galvanotaxis can be blocked by Ni2+ and Sr2+, which also inhibit VGCCs (Trollinger et al., 2002
). The effect of another Ca2+ channel blocker, verapamil, is not consistent (Brust-Mascher and Webb, 1998; Trollinger et al., 2002
); however, this might be owing to its complex action involving other ion channels (Fraser et al., 2000
). Interestingly, Sr2+ specifically blocks the directed migration of the cells yet the speed of motility remains the same. This suggests that these parameters are controlled by separate mechanisms (Trollinger et al., 2002
).
Internal Ca2+ stores
dcEFs might stimulate the release of Ca2+ from intracellular stores. As already noted, they can induce propagated intracellular Ca2+ waves (Perret et al., 1999), which normally require interplay between Ca2+ influx and Ca2+ released from internal stores (Bootman et al., 2001
; Himpens et al., 1999
). Indeed, in LNCaP cells and fish keratocytes, thapsigargin, which depletes internal Ca2+ stores, blocks the response to dcEFs (Perrett et al., 1999; Brust-Mascher and Webb, 1998). Inositol (1,4,5)-trisphosphate [Ins(1,4,5)P3] can also release Ca2+ from intracellular stores and produce oscillatory changes in [Ca2+]i, including waves (Berridge, 1993
; Dawson, 1997
). Neomycin, an antagonist of phosphoinositide signalling, inhibits the response of chondrocytes to dcEFs (Chao et al., 2000
). Similar experiments on embryonic muscle cells showed that galvanotaxis is not restored even in the presence of a 16-fold increase in the level of extracellular Ca2+ (McCaig and Dover, 1991
).
Mechanosensitive channels
Additional secondary rises in [Ca2+]i could occur by mechanosensitive (e.g. stretch-activated) cation channels (Lee et al., 1999). Indeed, Gd3+, which is a general blocker of mechanosensitive channels, suppressed galvanotaxis of human keratinocytes (Trollinger et al., 2002
).
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The role of voltage-gated Na+ channels |
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The highly metastatic human breast cancer MDA-MB-231 cell line is also galvanotactic, but the cells migrate anodally (Fraser et al., 2002). Application of TTX greatly suppresses the directionality of this response of the MDA-MB-231, which is consistent with the involvement of VGSCs (Fraser et al., 2002
).
How VGSCs control galvanotaxis is not well understood, but several possibilities exist (Fig. 2). First, Na+ influx through VGSCs could increase [Ca2+]i locally by inhibiting Ca2+ exchange across the plasmalemma (Blaustein and Lederer, 1999) and/or alter the release and uptake of Ca2+ from intracellular stores through disruption of normal pH-regulating mechanisms (Ishibashi et al., 1999
). Second, the Na+ influx could activate protein kinase A (PKA) to phosphorylate cytoskeletal components (Liu et al., 2001
; Senter et al., 1995
). Third, VGSCs could interact directly with the cytoskeleton (Komada and Soriano, 2002
) or calmodulin (Herzog et al., 2003
). In particular, the ß subunit is necessary for cytoskeletal linkage and could also function as a cell adhesion molecule mediating interaction with the ECM, cell migration and aggregation (Malhotra et al., 2000
; Isom, 2002
).
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Thus, a variety of mechanisms might link VGSCs and/or intracellular Na+ with galvanotaxis (Fig. 2). Interestingly, directional migration and patterned growth of neurons in vivo is controlled by VGSC activity (Dubin et al., 1986; Catalano and Shatz, 1998
; Meyer, 1982
; Penn et al., 1998
; Shatz, 1990
). However, it is not known whether these phenomena involve endogenous dcEFs.
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The influence of surface charge |
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Other mechanisms: growth factors and protein kinases |
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Short-term and long-term responses to dcEFs |
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Rat prostate cancer cell lines (Djamgoz et al., 2001), human keratinocytes (Pullar et al., 2001
), amphibian neural crest cells (Cooper and Keller, 1984
) and human corneal epithelial cells (Zhao et al., 1997
) show no sign of habituation. However, in the case of A. proteus, cells subjected to a dcEF for 5-10 minutes react to field reversal 10 times more quickly than they did initially, which can be viewed as sensitization (Korohoda et al., 2000
). Analysis of the responses of Mat-LyLu cells indicate that, although an initial galvanotactic reaction to an applied dcEF occurs within 30 seconds, steady state is not achieved for 30 minutes (Siwy et al., 2003
). Such long-term responses could involve translocation by electrophoresis of proteins involved in galvanotaxis (Jaffe, 1977
; Brown and Loew, 1994
), or changes in enzyme activity and gene expression (Fang et al., 1999
). Interestingly, fast and slow components of the responses to dcEFs might interact in the same cell. For example, the dcEF-induced asymmetrical distribution of epidermal growth factor receptors (EGFRs; or other growth factor receptors) in the cell membrane, and associated EGF signalling, could further affect galvanotactic reactions by modulating VGSC expression and/or activity (e.g. Toledo-Aral et al., 1995
) (Y. Ding, Cellular studies of ionic activity in prostate cancer metastasis and pain signalling, PhD Thesis, University of London, 2002).
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Metastatic disease |
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We compared the effects of external dcEFs on two prostate cancer cell lines of markedly different metastatic potential: Mat-LyLu (strongly metastatic) and AT-2 (weakly metastatic) cells (Isaacs et al., 1986). Mat-LyLu cells move towards the cathode, as noted earlier, whereas AT-2 cells migrate in the opposite direction (Djamgoz et al., 2001
). Galvanotaxis of the Mat-LyLu cells depends on the activity of VGSCs, which are expressed specifically in highly metastatic cells (Grimes et al., 1995
). By contrast, VGSC activity plays no role in the galvanotactic reaction of AT-2 cells, which probably involves voltage-gated K+ channel (VGPC) activity since it is suppressed by verapamil (Djamgoz et al., 2001
).
Cancer cell galvanotaxis could be important in vivo. The rat prostate has a TEP of 10 mV, which corresponds to a gradient of
500 mV/mm (Szatkowski et al., 2000
). One can therefore imagine the following scenario. Early in metastasis, when the epithelial ducts are intact, epithelial cells expressing functional VGSCs (i.e. with the potential to metastize) tend to migrate into the lumen and be detectable in semen or urine (Couture et al., 1980
; Barren et al., 1998
; Bockmann et al., 2001
). However, as metastasis progressed, the ducts would deform, the TEP would disappear and galvanotaxis would slow down and might even reverse, which would encourage invasion of the surrounding tissue (Djamgoz et al., 2001
). Furthermore, circulating metastatic cells would be subject to the endothelial potential (Revest et al., 1993
) and this could similarly influence intra/extravasation, a potentially crucial step (Wyckoff et al., 2000
). Note that TEP changes could be further influenced by alterations in the tight junctional coupling of epithelial cells (Tobioka et al., 2002
; Kominsky et al., 2003
) and, therefore, might be more complex.
Other cells might also undergo galvanotaxis in this context. Endothelial cells themselves might be galvanotactic since they possess functional ion channels, including VGSCs (Chang et al., 1996), and are associated with endogenous dcEFs in the form of transendothelial potentials and/or tissue field potentials (Revest et al., 1994
). Indeed, two studies have shown that bovine and human endothelial cells are galvanotactic (Li and Kolega, 2002
; Zhao et al., 2004
). An intriguing question is whether endothelial galvanotaxis is involved in angiogenesis, a process of fundamental physiological and pathophysiological importance (Papetti and Herman, 2002
). Interestingly, application of dcEF to HUVECs stimulates VEGF production (Zhao et al., 2004
), which is known to induce angiogenesis in vivo (Kanno et al., 1999
).
Another important cell type in cancer is tumour-infiltrating lymphocytes, which can be a significant prognostic determinant (Nzula et al., 2003; Marincola et al., 2003
). Galvanotaxis might be involved in intra/extravasation of lymphocytes since these possess a variety of ion channels, including VGSCs (Cahalan et al., 2001
), and there is an endothelial potential difference in areas that infiltrate (e.g.
25 mV in bullfrog cornea) (Graves et al., 1975
).
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Possible clinical applications |
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There are also therapeutic implications. Electrotherapy for adenocarcinoma could work in two ways. First, since malignant cells are strongly galvanotactic, one could `draw them out' of the diseased gland by applying small dc voltages across the epithelium. In the case of the prostate gland, this would be possible by insertion of an `active' electrode into the urethra, which would be similar to the surgical procedure used in trans-urethral resection of the prostate (TURP), and a reference electrode nearby. Electrotherapy might also be applicable to breast cancer, exploiting the methodology already developed for breast lavaging (e.g. Gray et al., 2000). Second, assuming that endogeneous TEPs facilitate galvanotaxis in vivo, it might be possible to suppress cell migration by reducing TEPs by using inhibitors of the ion pumps and exchangers that generate them.
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Conclusions and future perspectives |
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Acknowledgments |
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