Trosko J E, Ruch R J
Department of Pediatrics/Human Development, College of Human Medicine, Michigan State University, East Lansing 48824, USA.
Curr Drug Targets. 2002 Dec;3(6):465-82. doi: 10.2174/1389450023347371.
The development of the most efficacious strategy for the prevention and treatment of cancers is based on understanding the underlying mechanisms of carcinogenesis. This includes the knowledge that the carcinogenic process is a multi-step, multi-mechanism process and that no two cancers are alike, in spite of some apparent universal characteristics, such as their inability to have growth control, to terminally differentiate, to apoptose abnormally and to have an apparent extended or immortalized life span. The multi-step process, involving the "initiation" of a single cell via some irreversible process, with the clonal expansion of this initiated cell by suppressing growth control and inhibiting apoptosis (promotion step), leads to a situation whereby additional genetic and epigenetic events can take place (progression step) to confer the necessary phenotypes of invasiveness, and metasis (neoplastic stage). While it is clear that, in principle, prevention of each of these three steps is possible, in practical terms, while it would make sense to minimize the initiation step, one can never reduce this step to zero. On the other hand, since the promotion step is the rate-limiting step of carcinogenesis, intervening to block this step makes the most sense. Also, by understanding the ultimate biological function that confers growth control, terminal differentiation or apoptosis for cells, there is even some hope of treating some, but not all, malignant cells such that they can regain some ability to perform these vital cellular functions. Gap junctional intercellular communication (GJIC) has been speculated to be a necessary, if not sufficient, biological function of metazoan cells for the regulation of growth control, differentiation and apoptosis of normal progenitor cells. Normal, contact-inhibited fibroblast and epithelial cells have functional GJIC, while most, if not all, tumor cells have dysfunctional homologous or heterologous GJIC. Cancer cells are characterized by the lack of growth control, inability to terminally differentiate or apoptose under normal conditions and have extended or immortalized life spans. Chemical tumor promoters, growth factors and hormones have been shown to inhibit GJIC. Several oncogenes and anti-sense connexin genes have been shown to down-regulate GJIC function. Anti-oncogene drugs, anti-tumor promoting natural and synthetic chemicals, as well as GJIC-deficient neoplastic cells, transfected with various connexin genes, have been shown to re-gain GJIC and growth control with the loss of tumorigenicity. Therefore, the hypothesis for a rational approach to identify anti-tumor promoting chemopreventive drugs and anti-carcinogenic treatments is to use the prevention of the down regulation of GJIC by the tumor promoters and the restoration of GJIC in neoplastic cells. While previous and many current strategies for chemoprevention and therapy have been based on treating specific oncogene products or cell signalling mechanisms, as well as advance molecular modifications of older strategies, none have specifically used the prevention of GJIC by agents during the rate limiting step of carcinogenesis or the restoration of GJIC in neoplastic cells which are deficient in GJIC. Since there are multiple mechanisms by which GJIC is down regulated during the tumor promotion phase and since stable GJIC deficiencies in neoplastic cells can be the result of transcriptional, translational or posttranslational mechanisms, it should be clear there would not be one "golden bullet" approach to resolve either the chemoprevention or therapeutic approach. Even with the hypothesis that GJIC, which depends on the transcription of normal connexin genes, their normal translation, trafficking, assembly and function, it should be clear that cells with normal connexin genes and potentially normal GJIC might not have functional GJIC because of dysfunction of other defects in cancer cells, namely cell-adhesion or cell-matrix problems (both of which are necessary for GJIC to occur). In essence, if dietary or chemopreventive/therapy is to be effective, the strategy must either ameliorate the growth stimulatory effects of exogenous chemicals, growth factors or hormones, that trigger various mitogenic/anti-apoptotic signal transducing systems that inhibit GJIC.
制定最有效的癌症预防和治疗策略，其基础在于了解致癌作用的潜在机制。这包括认识到致癌过程是一个多步骤、多机制的过程，而且尽管存在一些明显的普遍特征，如无法进行生长控制、无法终末分化、异常凋亡以及具有明显延长或永生的寿命，但没有两种癌症是完全相同的。多步骤过程涉及通过某种不可逆过程使单个细胞“启动”，通过抑制生长控制和抑制凋亡使这个启动细胞进行克隆扩增（促进步骤），从而导致一种情况，即额外的遗传和表观遗传事件可以发生（进展步骤），赋予侵袭性和转移（肿瘤阶段）所需的表型。虽然原则上显然有可能预防这三个步骤中的每一个，但实际上，虽然将启动步骤降至最低是有意义的，但永远无法将这一步骤降至零。另一方面，由于促进步骤是致癌作用的限速步骤，干预以阻断这一步骤最有意义。此外，通过了解赋予细胞生长控制、终末分化或凋亡的最终生物学功能，甚至有希望治疗一些（但不是全部）恶性细胞，使其能够重新获得执行这些重要细胞功能的一些能力。间隙连接细胞间通讯（GJIC）被推测是后生动物细胞调节正常祖细胞生长控制、分化和凋亡所必需的生物学功能，即便不是充分条件。正常的、接触抑制的成纤维细胞和上皮细胞具有功能性GJIC，而大多数（如果不是全部）肿瘤细胞具有功能失调的同源或异源GJIC。癌细胞的特征是缺乏生长控制，在正常条件下无法终末分化或凋亡，并且具有延长或永生的寿命。化学肿瘤促进剂、生长因子和激素已被证明可抑制GJIC。几种癌基因和反义连接蛋白基因已被证明可下调GJIC功能。已证明反癌基因药物、抗肿瘤促进的天然和合成化学物质，以及用各种连接蛋白基因转染的GJIC缺陷肿瘤细胞，能够重新获得GJIC并恢复生长控制，同时丧失致瘤性。因此，识别抗肿瘤促进化学预防药物和抗癌治疗的合理方法的假设是，利用肿瘤促进剂预防GJIC下调，并使肿瘤细胞中的GJIC恢复。虽然以前和许多当前的化学预防和治疗策略基于治疗特定的癌基因产物或细胞信号传导机制，以及对旧策略的先进分子修饰，但没有一种策略专门利用在致癌作用的限速步骤中通过药物预防GJIC，或在GJIC缺陷的肿瘤细胞中恢复GJIC。由于在肿瘤促进阶段GJIC下调有多种机制，而且肿瘤细胞中稳定的GJIC缺陷可能是转录、翻译或翻译后机制的结果，显然不存在一种“万灵药”方法来解决化学预防或治疗方法。即使假设GJIC依赖于正常连接蛋白基因的转录、其正常翻译、运输、组装和功能，也应该清楚，具有正常连接蛋白基因和潜在正常GJIC的细胞可能由于癌细胞中的其他缺陷（即细胞粘附或细胞基质问题，这两者都是GJIC发生所必需的）功能失调而没有功能性GJIC。本质上，如果饮食或化学预防/治疗要有效，该策略必须要么改善外源化学物质、生长因子或激素的生长刺激作用，这些物质会触发各种抑制GJIC的促有丝分裂/抗凋亡信号转导系统。
