Abstract

• This paper explores how natural bioelectric signals—generated by ion channels and pumps to create voltage gradients (Vmem) across cell membranes—govern cell behavior, tissue patterning, and regeneration, and how their disruption may lead to cancer.
• Cancer is presented not only as a genetic disease but also as a disorder of cellular “geometry” and communication, where misregulated bioelectric cues contribute to abnormal growth.
• Changes in the resting membrane potential (either depolarization or hyperpolarization) can trigger cascades that induce tumor formation or, conversely, suppress it.
• The concept of the morphogenetic field is central, proposing that tissues maintain their structure through collective bioelectric patterns, which when disrupted, result in cancer.

Introduction

• Traditional cancer models emphasize genetic mutations; however, this paper highlights that abnormal bioelectric signals also play a crucial role in misdirecting cell behavior.
• Cells normally cooperate to form organized tissues, but when bioelectric signaling is disrupted, this coordinated “traffic” is lost—leading to disorganized growth similar to a traffic jam.
• The idea of a morphogenetic field is introduced to describe how cells receive positional and developmental cues, and how its disruption may underlie tumorigenesis.

Bioelectricity as an Instructive Component of the Microenvironment

• Cells use ion channels and pumps to generate bioelectric signals, creating voltage gradients (Vmem) that influence cell migration, differentiation, and proliferation.
• These signals act like a recipe for tissue formation: slight alterations in the “ingredients” (ion flows) can lead to major changes in the final tissue structure.
• Such electrical cues are essential for proper communication among cells, ensuring that the tissue “blueprint” is followed during development and repair.

Spatio-Temporal Gradients of Vmem as Instructive Patterning Cues

• Dynamic gradients of Vmem provide cells with positional information, instructing them where to move and how to differentiate during development and regeneration.
• Experimental adjustments to these voltage patterns can reprogram tissue architecture—much like fine-tuning cooking conditions to achieve a specific texture or flavor.
• This demonstrates that bioelectric signals are a key layer of the regulatory network that governs tissue organization.

Bioelectric Gradients in Cancer at the Cell Level

• Cancer cells often exhibit abnormal depolarization (a less negative membrane potential), which serves as an early marker for neoplasia.
• Specific ion channels may act as oncogenes, promoting unchecked proliferation and cell migration.
• When the normal bioelectric “instructions” are lost, cells no longer adhere to proper tissue geometry, contributing to tumor formation.

Resting Potential: A Statistical Dynamics View

• The resting membrane potential is best understood as a collective property emerging from many ion channels—comparable to how gas pressure arises from countless molecular collisions.
• This statistical approach shows that even small shifts in the balance of ion flows can lead to significant changes in tissue patterning.
• Thus, cancer may result from the cumulative effect of many subtle bioelectric disruptions.

Bioelectrical Regulation of Cancer In Vivo

• In vivo studies using voltage-sensitive dyes reveal that regions of abnormal depolarization can be detected before visible tumor formation.
• These bioelectric signatures offer potential as early diagnostic tools, much like a thermometer indicating a fever before other symptoms appear.
• This method may help pinpoint pre-cancerous areas and define tumor margins during surgical procedures.

Depolarization of Specific Cells Induces Metastatic Phenotype at a Distance

• Selective depolarization of a small subset of “instructor” cells can non-cell-autonomously trigger a metastatic behavior in distant cells.
• This effect is mediated by serotonin, which translates the electrical change into biochemical signals that alter gene expression in target cells.
• Analogy: It’s like flipping a switch in one room that sets off an alarm system in another, far-removed part of a building.

Hyperpolarization Inhibits Oncogene-Induced Tumorigenesis

• Forcing cells into a hyperpolarized state (a more negative Vmem) can counteract tumor formation, even when oncogenes are present.
• This protective effect is linked to enhanced uptake of molecules such as butyrate, which inhibit enzymes (HDACs) that promote cell division.
• The process can be viewed as following a precise recipe: a controlled hyperpolarization sets off a chain reaction that slows down or stops uncontrolled cell growth.

Cancer: A Disease of Geometry?

• The paper argues that cancer may be viewed as a disruption of the normal geometric organization of tissues.
• Healthy tissues maintain a precise spatial arrangement, while cancer cells lose their positional “instructions” and grow in a disorganized manner.
• Metaphor: Think of a well-coordinated orchestra suddenly playing out of sync— the loss of harmony results in chaos, akin to tumor formation.

Normalization of Cancer by Developmental and Regenerative Patterning

• Studies indicate that placing cancer cells into an embryonic or regenerative environment can reprogram them to adopt normal behavior.
• This “normalization” shows that even malignant cells can be redirected to follow proper tissue organization if given the right bioelectric cues.
• Such findings open the door to therapeutic strategies that aim to restore the correct bioelectric environment rather than simply killing cancer cells.

Explanations Above the Single-Cell Level

• The paper emphasizes that cancer is a problem of multicellular organization, not just individual cell malfunction.
• Properties of tissues and organs emerge from interactions between many cells, much like the wetness of water is a property that arises only in bulk.
• A systems-level perspective is crucial for developing more effective prevention and treatment strategies that target intercellular communication.

Future Prospects/Speculations

• The authors discuss future research directions, including using advanced techniques like optogenetics to precisely control Vmem in vivo.
• Understanding the “bioelectric code” may lead to innovative therapies that can reset or “reboot” the normal tissue patterning program in cancer.
• Integrating bioelectric, genetic, and epigenetic data is seen as a promising path toward comprehensive models of tissue organization and cancer treatment.

Conclusion and Summary

• Cancer is redefined as not solely a genetic anomaly but as a disruption of bioelectrical communication and tissue geometry.
• Manipulating membrane potentials offers a novel strategy for early detection and intervention in cancer.
• The paper calls for a systems-level approach that considers bioelectric signals as central to both normal development and disease.

Acknowledgments

• The authors dedicate their work to pioneers in bioelectric research and acknowledge support from various grants and institutions.

— End of English Summary —

摘要

• 本文探讨了由离子通道和泵产生的自然生物电信号——在细胞膜上形成电压梯度（Vmem）的过程——如何调控细胞行为、组织模式形成及再生，并阐明其失调可能导致癌症。
• 作者认为癌症不仅是基因突变的结果，也是细胞“几何结构”及相互通信紊乱的疾病，生物电信号的错误传递在其中起关键作用。
• 细胞静息电位的改变（去极化或超极化）可触发一系列信号通路，从而诱导肿瘤形成或反过来抑制其发展。
• 文章提出形态发生场的概念，即细胞通过集体生物电模式保持组织结构，若该模式被破坏，则可能引发癌症。

引言

• 传统癌症理论侧重于基因突变，而本文强调生物电信号在细胞间沟通和组织发育中的重要性。
• 正常情况下，细胞协同工作形成有序组织，但当生物电信号失调时，这种协调性丧失，类似于交通堵塞中车辆各自为政。
• 文中引入了形态发生场的概念，描述细胞如何接收位置信息及发育指令，其失调可能正是肿瘤发生的根源。

生物电作为微环境中的指导性因素

• 细胞利用离子通道和泵产生生物电信号，在膜上形成Vmem，这些信号对细胞迁移、分化和增殖起重要作用。
• 这些信号就像是烹饪食谱中的调味料：微小的离子流变化可能导致组织结构的显著改变。
• 生物电信号确保了细胞间的正常交流，从而维持组织的正确蓝图。

时空Vmem梯度作为指导性模式线索

• 动态的Vmem梯度为细胞提供位置信息，指导细胞如何迁移和分化以形成有序组织。
• 实验显示，通过调控这些电压梯度，可以重新编程组织结构，就像调整烹饪时间和温度以达到理想口感一样。
• 这证明了生物电信号在调控组织形态中的关键作用。

细胞层面上的生物电梯度与癌症

• 癌细胞常显示出异常去极化（电位较少负），这可以作为早期肿瘤发生的标志。
• 某些离子通道可能充当癌基因，促进细胞无限增殖和迁移。
• 当正常的生物电“指令”丢失时，细胞无法维持正常的组织结构，从而导致肿瘤形成。

静息电位：统计动力学的视角

• 作者认为静息电位应被视为许多离子通道集体行为的结果，类似于气体分子碰撞形成的压力。
• 这一观点表明，即使是微小的离子流变化，也可能对整体组织模式产生深远影响。
• 因此，癌症可能正是由许多细微生物电失调累积而成的。

体内生物电调控癌症

• 体内研究利用电压敏感染料显示，异常去极化区域在肉眼可见肿瘤形成前就已出现。
• 这些生物电特征可作为早期诊断工具，就如同温度计提前预示发烧一样。
• 这种方法有望帮助定位癌前病变区域，并在手术时明确肿瘤边界。

特定细胞去极化诱导远程转移性表型

• 选择性去极化一小部分“指导细胞”可以非直接地诱发远处细胞呈现转移性行为。
• 这一过程通过血清素信号介导，将电信号转化为改变目标细胞基因表达的化学信号。
• 比喻：就像开启一个房间的灯开关引发远处警报系统一样。

超极化抑制致癌基因诱导的肿瘤形成

• 强制细胞保持超极化状态（更负的Vmem）能够抑制肿瘤形成，即使致癌基因已激活。
• 这种效应与促进抗肿瘤分子（如丁酸）的吸收有关，丁酸能抑制促进细胞增殖的酶（HDACs）。
• 这一过程如同按照防止食物过熟的精确配方操作，逐步降低细胞分裂速率。

癌症：几何疾病？

• 文章提出，癌症可以看作是组织几何结构失调的结果，当细胞失去正常的空间位置信息时，就会出现肿瘤。
• 正常细胞像一个协调的团队共同维持结构，而癌细胞则丧失了这种整体协调性。
• 比喻：就像一个协奏乐团突然失去了节奏和协调，导致整个音乐作品变得混乱一样。

通过发育和再生模式重塑癌症

• 实验证据显示，将癌细胞置于胚胎或再生环境中，可以重新编程其行为，使之融入正常组织结构。
• 这种“正常化”效应表明，即使是恶性细胞，也有可能被重新引导回正常的组织模式。
• 这一发现为通过激活发育信号来治疗癌症提供了新思路。

超越单个细胞层面的解释

• 本文强调，癌症应视为多细胞组织间相互作用失调的问题，而非单个细胞的问题。
• 组织和器官的特性源自细胞间复杂的互动，就如同水的“湿润”性质只有在分子集合时才出现。
• 这种系统性观点有助于发展更有效的预防和治疗策略。

未来展望/猜想

• 作者展望未来，将开发新技术（如光遗传学）来精确控制体内的Vmem，从而更好地理解生物电代码。
• 解码生物电信号有望引领出创新治疗方法，通过“重启”正常的组织模式来抗击癌症。
• 整合生物电、基因及表观遗传数据将有助于构建全面的组织模型，为癌症治疗提供新的思路。

结论与总结

• 本文重新定义了癌症，认为它不仅仅是基因失调的结果，更是生物电信号和组织几何失调的综合体现。
• 生物电信号在正常发育、再生及肿瘤抑制中发挥着核心作用。
• 通过操控Vmem，可以为早期癌症检测和创新治疗提供新途径。
• 文章强调采用系统性方法，以生物电信号为核心，来理解和治疗癌症的重要性。

致谢

• 作者将本文献给生物电研究的先驱，并感谢各资助机构和研究团队的支持。

— 结束中文摘要 —