Depolarization of a broadly distributed cell population in the Xenopus tadpole leads to upregulation of Sox10 and SLUG and induces a phenotype similar to metastatic melanoma: the pigment cells (melanocytes)

Resting voltage potential in non-excitable cells is an important regulator of cellular properties such as proliferation, migration and shape (Blackiston et al., 2009; Sundelacruz et al., 2009). Moreover, endogenous bioelectric signals (patterns of resting potential in all tissues) encode a set of morphogenetic cues that provide patterning control during regeneration (Levin, 2007; Levin, 2009), development (Adams, 2008; Levin, 2012a) and wound healing (Nuccitelli, 2003; McCaig et al., 2005; McCaig et al., 2009). Thus, ion flows and the resulting voltage gradients are highly relevant to the understanding of cancer as a developmental disorder and to the prediction and control of neoplastic cell behaviors (Rubin, 1985; Huang et al., 2009; Levin, 2012b). A relationship between cancer and the bioelectric properties of host tissue was suggested long ago on the basis of physiological measurements (Burr et al., 1938; Burr, 1940; Cone, 1971). Interestingly, membrane voltage (Vmem) analysis in many different mammalian cell types reveals that proliferative potential is correlated with unique ranges of Vmem: quiescent cells tend to be hyperpolarized, whereas highly plastic cells such as embryonic cells, adult stem cells and tumors cells are depolarized (Binggeli and Weinstein, 1986; Levin, 2007). The relationship between resting potential and proliferative plasticity is not merely correlative: Vmem is a causal factor in the control of proliferation and differentiation. For example, prolonged depolarization induces mature central nervous system neurons to re-enter mitosis and causes fibroblasts to overproliferate (Cone, 1971; Cone and Tongier, 1971), and also prevents stem cells from differentiating (Sundelacruz et al., 2008). Modern work using molecular genetics methods has linked several ion channel and pump genes to cancer (Saito et al., 1998; Pardo et al., 1999; Pei et al., 2003; Kunzelmann, 2005; Stühmer et al., 2006; Brackenbury et al., 2008; Becchetti, 2011), and small molecule compounds targeting ion channels have been suggested as candidates for cancer drugs (Arcangeli et al., 2009; Arcangeli et al., 2012). Not surprisingly, the normal expression patterns of a number of ion channels are altered in tumors (Schönherr, 2005; Fiske et al., 2006), and ion channel loci are starting to be identified as oncogenes in microarray studies of several cancer types (Pei et al., 2003; Onkal and Djamgoz, 2009; House et al., 2010; Roepke et al., 2010). Thus, an understanding of the roles of ion flow in cancer initiation and tumor progression is of high importance for basic biology and medicine. During the early stages of tumor formation, Vmem is a key regulator of the cell cycle and determines the proliferative state of many different kinds of cells (Blackiston et al., 2009). Depolarization of a broadly distributed cell population in the Xenopus tadpole leads to upregulation of Sox10 and SLUG and induces a phenotype similar to metastatic melanoma: the pigment cells (melanocytes)