Cell-cell communication in carcinogenesis.
Cell-cell communication in carcinogenesis.
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DOI：
10.2741/a275
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发表时间：
1998-02
期刊：
影响因子：
--
通讯作者：
J. Trosko;R. Ruch
中科院分区：
文献类型：
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作者：
J. Trosko;R. Ruch
为了解释人类单个正常细胞转化为侵袭性和转移性癌细胞的复杂致癌过程，本综述整合了许多实验结果、流行病学观察及其相关的假设/理论。所有癌症通常被认为是细胞对身体细胞外信号作出适当反应的能力的稳态调节破坏的结果，细胞外信号触发细胞内信号转导机制，调节组织内细胞之间的间隙连接细胞间通讯。这三种形式的细胞通讯的正常稳态控制决定是否：（a）细胞保持静止（Go）； (b) 进入细胞增殖期； (c) 被诱导分化； (d) 致力于细胞凋亡；或者（e）如果它已经分化，它可以自适应地响应。在从单细胞生物到多细胞生物的进化过程中，出现了新的细胞/生物学功能，即细胞增殖的控制（“接触抑制”）、各种组织的定向干细胞分化过程的出现以及程序性细胞死亡或凋亡的需要。有趣的是，癌细胞已被表征为以下细胞： (a) 源自干细胞样细胞； (b) 没有控制细胞生长的能力或没有接触抑制的能力； (c) 在正常条件下不能终末分化； (d) 正常条件下细胞凋亡的能力发生改变。在从单细胞生物到多细胞生物的进化转变过程中，许多新基因似乎伴随着这些新的细胞功能。这些新基因之一是编码膜相关蛋白通道（间隙连接）的基因，该通道在耦合细胞之间允许离子和小分子量分子的被动转移。一个由十多个高度进化保守的基因（连接蛋白基因）组成的家族，编码连接蛋白。一个细胞中这些连接蛋白的六聚体单位（连接子）与邻近细胞中相应的连接子偶联以连接细胞质。这用于同步组织内细胞的代谢或电紧张功能。实体组织内的大多数正常细胞都具有功能性间隙连接细胞间通讯 (GJIC)（独立细胞除外，例如红细胞、中性粒细胞和几种（如果不是全部）干细胞）。另一方面，实体组织的癌细胞似乎具有功能失调的同源或异源 GJIC。因此，在癌细胞与其正常亲本细胞之间的许多差异中，致癌过程涉及从具有GJIC功能的正常细胞向GJIC缺陷细胞的转变。该综述探讨了 GJIC 如何在转录、翻译或翻译后水平上被内源性或外源性化学物质或癌基因和肿瘤抑制基因瞬时或稳定地调节。并以间隙连接作为促进细胞/组织稳态的生物结构，成为“干细胞”学说、“分化疾病学说”、“起始/促进/进展”概念、癌变的先天与培育概念、癌变的突变/表观遗传学说、癌基因/抑癌基因的癌变学说的整合者。在此背景下，产生了对癌症预防和癌症治疗的影响。
To explain the complex carcinogenic process by which a single normal cell in human beings can be converted to an invasive and metastatic cancer cell, a number of experimental findings, epidemiological observations and their associated hypothesis/theories have been integrated in this review. All cancers have been generally viewed as the result of a disruption of the homeostatic regulation of a cell's ability to respond appropriately to extra-cellular signals of the body which trigger intra-cellular signal transducting mechanisms which modulate gap junctional intercellular communication between the cells within a tissue. Normal homeostatic control of these three forms of cell communication determines whether: (a) the cell remains quiescent (Go); (b) enters into the cell proliferation phase; (c) is induced to differentiate; (d) is committed to apoptose; or (e) if it is already differentiated, it can adaptively respond. During the evolution from single cell organisms to multicellular organisms, new cellular/biological functions appeared, namely, the control of cell proliferation ("contact inhibition"), the appearance of the process of differentiation from committed stem cells of the various tissues and the need for programmed cell death or apoptosis. Interestingly, cancer cells have been characterized as cells: (a) having been derived from a stem-like cell; (b) without their ability to control cell growth or without the ability to contact inhibit; (c) which can not terminally differentiate under normal conditions; and (d) having altered ability to apoptosis under normal conditions. During that evolutionary transition from the single cell organism to the multicellular organism, many new genes appeared to accompany these new cellular functions. One of these new genes was the gene coding for a membrane associated protein channel (the gap junction) which between coupled cells, allowed the passive transfer on ions and small molecular weight molecules. A family of over a dozen of these highly evolutionarily-conserved genes (the connexin genes) coded for the connexin proteins. A hexameric unit of these connexins in one cell (a connexon) couples with a corresponding connexon in a contiguous cell to join the cytoplasms. This serves to synchronize either the metabolic or electrotonic functions of cells within a tissue. Most normal cells within solid tissues have functional gap junctional intercellular communication (GJIC) (exceptions are free-standing cells such as red blood cells, neutrophils, and several, if not all, the stem cells). On the other hand, the cancer cells of solid tissues appear to have either dysfunctional homologous or heterologous GJIC. Therefore, among the many differences between a cancer cell and its normal parental cell, the carcinogenic process involves the transition from a normal, GJIC-competent cell to one that is defective in GJIC. The review examines how GJIC can be either transiently or stably modulated by endogenous or exogenesis chemicals or by oncogenes and tumor suppressor genes at the transcriptional, translational, or posttranslational levels. It also uses the gap junction as the biological structure to facilitate cellular/tissue homeostasis to be the integrator for the "stem cell" theory, "disease of differentiation theory", "initiation/promotion/progression" concepts, nature and nurture concept of carcinogenesis, the mutation/ epigenetic theories of carcinogenesis, and the oncogene/ tumor suppressor gene theories of carcinogenesis. From this background, implications to cancer prevention and cancer therapy are generated.