chapter  12
26 Pages

Bioelectricty of Cancer: Voltage-Gated Ion Channels and Direct-Current Electric Fields

Cancer, the leading cause of death in the Western world, results from abnormal expression of genes. Such abnormality can be genetic, involving mutations in proto-oncogenes or tumor suppressor genes, and their heterogeneous accumulation, leading to uncontrolled growth, as in primary tumorigenesis. In the majority of cancers, however, the changes are epigenetic; i.e., it is the abnormal expression levels of otherwise normal genes that lead to cells losing their normal controlled behavior. Epigenetic changes result from hypo/ hypermethylation of DNA, leading to dysregulation of gene expression levels or patterns (Hanahan and Weinberg, 2000). Importantly, metastasis-spread of cells from the primary neoplasm ultimately to form secondary tumors-is what causes the majority (>90%) of cancer-

Introduction ....................................................................................................... 267 Expression of Voltage-Gated Ion Channels in Cancer Cells and Tissues: Invasiveness vs. Proliferation, and CELEX Hypothesis ................................... 271 Functional Contribution of Ion Channel Activity to the Cancer Process .......... 274

Effects of Downregulating VGSC Expression/Activity ............................... 275 Effects of Upregulating VGSC Expression/Activity .................................... 276

Regulation of Ion Channel Expression: Association with Mainstream Cancer Mechanisms .......................................................................................... 277 Response of Cancer Cells to Direct-Current Electric Fields ............................ 279 Tissue Electrolytes and Bioimpedance ............................................................. 282 Future Perspectives and Clinical Potential ........................................................ 283 Acknowledgments and Dedication ................................................................... 284 References ......................................................................................................... 284

related deaths (Nguyen and Massague, 2007; Hunter et al., 2008). Metastasis is a complex, multistage process in which cancer cells (1) disassociate from each other and detach from the extracellular matrix, (2) migrate through the basement membrane and invade local tissue, (3) enter the blood or lymph circulation (in which the survival of the circulating tumor cells is rate limiting), (4) reattach at a distant site and extravasate, and (5) form secondary tumors after proliferation and induction of angiogenesis (Figure 12.1; Fidler, 2002a, 2002b, 2003; Hunter et al., 2004; Bacac and Stamenkovic, 2007). Importantly, primary tumorigenesis and metastasis can be controlled by separate sets of molecular and cellular factors (Hanahan and Weinberg, 2000; Welch et al., 2000, 2004, 2006). Thus, at least eleven metastasis suppressor genes have been identišed that do not affect primary tumorigenesis (Berger et al., 2004; Weigelt et al., 2005; Vaidya and Welch, 2007). Furthermore, metastatic potential can be “preprogrammed” and modulated progressively by dynamic response to the local microenvironment (Fidler, 2003; Hunter, 2004; Hunter et al., 2008). The independence (at least, partial) of primary vs. secondary tumorigenesis is consistent with the apparent absence of an identišable primary tumor in a subset of metastatic disease cases.