Biology Department and Tufts Center for Regenerative and Developmental Biology, Tufts University, 200 Boston Avenue, Medford, MA 02155, USA.
Phys Biol. 2012 Dec;9(6):065002. doi: 10.1088/1478-3975/9/6/065002. Epub 2012 Nov 29.
Cancer may result from localized failure of instructive cues that normally orchestrate cell behaviors toward the patterning needs of the organism. Steady-state gradients of transmembrane voltage (V(mem)) in non-neural cells are instructive, epigenetic signals that regulate pattern formation during embryogenesis and morphostatic repair. Here, we review molecular data on the role of bioelectric cues in cancer and present new findings in the Xenopus laevis model on how the microenvironment's biophysical properties contribute to cancer in vivo. First, we investigated the melanoma-like phenotype arising from serotonergic signaling by 'instructor' cells-a cell population that is able to induce a metastatic phenotype in normal melanocytes. We show that when these instructor cells are depolarized, blood vessel patterning is disrupted in addition to the metastatic phenotype induced in melanocytes. Surprisingly, very few instructor cells need to be depolarized for the hyperpigmentation phenotype to occur; we present a model of antagonistic signaling by serotonin receptors that explains the unusual all-or-none nature of this effect. In addition to the body-wide depolarization-induced metastatic phenotype, we investigated the bioelectrical properties of tumor-like structures induced by canonical oncogenes and cancer-causing compounds. Exposure to carcinogen 4-nitroquinoline 1-oxide (4NQO) induces localized tumors, but has a broad (and variable) effect on the bioelectric properties of the whole body. Tumors induced by oncogenes show aberrantly high sodium content, representing a non-invasive diagnostic modality. Importantly, depolarized transmembrane potential is not only a marker of cancer but is functionally instructive: susceptibility to oncogene-induced tumorigenesis is significantly reduced by forced prior expression of hyperpolarizing ion channels. Importantly, the same effect can be achieved by pharmacological manipulation of endogenous chloride channels, suggesting a strategy for cancer suppression that does not require gene therapy. Together, these data extend our understanding of the recently demonstrated role of transmembrane potential in tumor formation and metastatic cell behavior. V(mem) is an important non-genetic biophysical aspect of the microenvironment that regulates the balance between normally patterned growth and carcinogenesis.
癌症可能是由于正常指导细胞行为以满足机体模式需求的指令性信号的局部失效而引起的。非神经细胞中跨膜电压（V(mem)）的稳态梯度是指令性的、表观遗传信号，可调节胚胎发生和形态稳定修复过程中的模式形成。在这里，我们回顾了生物电信号在癌症中的作用的分子数据，并在非洲爪蟾模型中提出了新的发现，即微环境的生物物理特性如何促进体内癌症的发生。首先，我们研究了“指导”细胞中血清素信号引起的类黑色素瘤表型，“指导”细胞是一种能够在正常黑色素细胞中诱导转移表型的细胞群。我们发现，当这些指导细胞去极化时，除了诱导黑色素细胞发生转移表型外，血管模式也会被破坏。令人惊讶的是，只有很少的指导细胞需要去极化就会导致黑色素过度沉着表型的发生；我们提出了一个血清素受体拮抗信号的模型，解释了这种效应异常的全有或全无性质。除了全身去极化诱导的转移表型外，我们还研究了经典致癌基因和致癌化合物诱导的肿瘤样结构的生物电特性。接触致癌剂 4-硝基喹啉 1-氧化物（4NQO）会诱导局部肿瘤，但对整个身体的生物电特性有广泛（且可变）的影响。致癌基因诱导的肿瘤表现出异常高的钠含量，这是一种非侵入性的诊断方式。重要的是，去极化跨膜电位不仅是癌症的标志物，而且具有功能指导意义：通过强制表达超极化离子通道，可显著降低致癌基因诱导的肿瘤发生的易感性。重要的是，通过内源性氯离子通道的药理学操作可以达到相同的效果，这为癌症抑制提供了一种策略，而不需要基因治疗。总之，这些数据扩展了我们对最近证明的跨膜电位在肿瘤形成和转移细胞行为中的作用的理解。V(mem)是微环境中重要的非遗传生物物理方面，它调节正常模式生长和癌变之间的平衡。
