Tubiana M
Centre Antoine Béclère, Faculté de Médecine, Paris.
Bull Acad Natl Med. 1998;182(1):19-29; discussion 29-31.
Carcinogenesis is a multi-step process and at least three stages can be distinguished: initiation, promotion and progression. Initiation is made up of events whereby an exogenous or endogenous carcinogen induces alterations in the genome of the cell; this results in a lesion that can be inherited and which confers upon that cell the potential for neoplastic growth. This is the result of activation of cellular proto-oncogenes into transforming oncogenes and/or the inactivation of the two alleles of tumor suppressor genes (anti-oncogenes). Although it is conceivable that a single event or a single lesion can initiate a cell it is probable that in most cases initiation is the consequence of a series of events since the different types of proto-oncogenes do not function independently of each other. The coordinated activation of more than one oncogene is generally required to confer the full potential for neoplastic growth. DNA repair and apoptosis play a critical role in carcinogenesis and the effectiveness of these mechanisms might be influenced by the dose and the time interval between individual events (dose rate). Epidemiological and experimental data show also the main role of cell proliferation after initiation. Proliferation influences the probability of DNA repair and contributes to further genomic alteration. Cell to cell interaction within a tissue participates in the control of cell proliferation and cell repair. The evolution of one initiated cell is not independent of the surrounding cells and disorganization of a tissue is a factor in carcinogenesis. Presently carcinogenesis appears to be a complex phenomenon which cannot be a adequately modelled. The linear no-threshold model has been used for the purpose of cancer prevention and legal norms, however it should be realized that its experimental and theoretical bases are debatable and that much recent data do not support them. Its predictions should therefore be considered with great caution. All efforts should be made in the future to build new models incorporating available epidemiological and fundamental data.
致癌作用是一个多步骤过程，至少可区分出三个阶段：启动、促进和进展。启动由外源性或内源性致癌物诱导细胞基因组改变的事件组成；这会导致一种可遗传的损伤，并赋予该细胞肿瘤性生长的潜能。这是细胞原癌基因激活转化为癌基因和/或肿瘤抑制基因（抗癌基因）的两个等位基因失活的结果。虽然可以想象单个事件或单个损伤就能启动一个细胞，但在大多数情况下，启动可能是一系列事件的结果，因为不同类型的原癌基因并非彼此独立发挥作用。通常需要多个癌基因的协同激活才能赋予肿瘤性生长的全部潜能。DNA修复和细胞凋亡在致癌作用中起关键作用，这些机制的有效性可能会受到单个事件之间的剂量和时间间隔（剂量率）的影响。流行病学和实验数据也表明启动后细胞增殖的主要作用。增殖影响DNA修复的概率，并导致进一步的基因组改变。组织内细胞间的相互作用参与细胞增殖和细胞修复的控制。一个启动细胞的演变并非独立于周围细胞，组织的紊乱是致癌作用的一个因素。目前，致癌作用似乎是一个复杂的现象，无法得到充分模拟。线性无阈值模型已被用于癌症预防和法律规范的目的，然而应该认识到其实验和理论基础存在争议，而且许多最新数据并不支持它们。因此，对其预测应极为谨慎地考虑。未来应尽一切努力构建纳入现有流行病学和基础数据的新模型。
