Bioelecteric detection and control of tumor growth in Xenopus laevis.

摘要

Most current cancer studies focus on biochemical signaling factors and gene transcription networks implicated in cell proliferation, differentiation, migration, and apoptosis. Motivated by the known role of endogenous bioelectric cues in regulating pattern formation, and the possibility that cancer reveals a loss of morphogenetic control, we examined steady-state transmembrane potential (Vmem) as an important parameter by which tumorigenesis can be detected and controlled. Microinjection of mRNA encoding canonical tumor inducers (Gli1, Xrel3, KRAS and p53Thr248) in Xenopus laevis embryos results in the development of tumor foci; using fluorescent membrane voltage reporter dyes, we defined a physiological signature by which prospective tumor sites could be specifically detected before the tumors became morphologically apparent, revealing depolarization as an early step in neoplastic transformation. Moreover, we demonstrated that the relatively depolarized nature of putative tumor sites is a functionally important (instructive) parameter: misexpression of hyperpolarizing ion transporter mRNA's partially rescued the phenotype. Reduction of tumor incidence from canonical oncogenic inducers by forcing a more normal (polarized) bioelectric state is thus not only a promising approach to tumor normalization but highlights a novel control pathway for induction of cancer in somatic cells. Strikingly, the effect also occurs non-cell-autonomously - tumors can be suppressed by artificially hyperpolarizing cells at considerable distance from the site of oncogene misexpression. The suppression of tumorigenesis could also be achieved by hyperpolarization using native CLIC1 chloride channels, suggesting a treatment modality not requiring gene therapy. We identified butyrate and histone deacetylase-mediated mechanisms of tumor suppression, and demonstrated a role for gap junctional communication in oncogene-mediated tumorigenesis. These data reveal Vmem as a powerful, tractable regulator of cancer and suggest the existence of novel long-range mechanisms by which bioelectric state of the host environment controls cell behavior.