The multistep transition from a normal to a malignant cellular phenotype is often termed “somatic evolution” caused by accumulating random mutations. Here, we propose an alternative model in which the initial genetic state of a cancer cell is the result of mutations that occurred throughout the lifetime of the host. However, these mutations are not carcinogenic because normal cells in multicellular organism cannot ordinarily evolve. That is, proliferation and death of normal cells are controlled by local tissue constraints typically governed by nongenomic information dynamics in the cell membrane. As a result, the cells of a multicellular organism have a fitness that is identical to the host, which is then the unit of natural selection. Somatic evolution of a cell can occur only when its fate becomes independent of host constraints. Now, survival, proliferation, and death of individual cells are dependent on Darwinian dynamics. This cellular transition from host‐defined fitness to self‐defined fitness may, consistent with the conventional view of carcinogenesis, result from mutations that render the cell insensitive to host controls. However, an identical state will result when surrounding tissue cannot exert control because of injury, inflammation, aging, or infection. Here, all surviving cells within the site of tissue damage default to self‐defined fitness functions allowing them to evolve so that the mutations accumulated over the lifetime of the host now serve as the genetic heritage of an evolutionary unit of selection. Furthermore, tissue injury generates a new ecology cytokines and growth factors that might promote proliferation in cells with prior receptor mutations. This model integrates genetic and nongenetic dynamics into cancer development and is consistent with both clinical observations and prior experiments that divided carcinogenesis to initiation, promotion, and progression steps.

中文翻译：

---

整合致癌过程中体细胞进化的遗传和非遗传驱动因素：双翼模型。


从正常细胞表型到恶性细胞表型的多步转变通常被称为由随机突变累积引起的“体细胞进化”。在这里，我们提出了一种替代模型，其中癌细胞的初始遗传状态是宿主一生中发生的突变的结果。然而，这些突变并不致癌，因为多细胞生物中的正常细胞不能正常进化。也就是说，正常细胞的增殖和死亡由局部组织约束控制，通常由细胞膜中的非基因组信息动态控制。结果，多细胞生物体的细胞具有与宿主相同的适应性，这就是自然选择的单位。只有当细胞的命运变得独立于宿主的限制时，细胞的体细胞进化才会发生。现在，单个细胞的生存、增殖和死亡取决于达尔文动力学。与传统的致癌观点一致，这种从宿主定义的适应度到自我定义的适应度的细胞转变可能是由于使细胞对宿主控制不敏感的突变造成的。然而，当周围组织因损伤、炎症、衰老或感染而无法发挥控制作用时，就会出现相同的状态。在这里，组织损伤部位内的所有幸存细胞都默认具有自定义的适应功能，使它们能够进化，从而使宿主一生中积累的突变现在成为选择进化单位的遗传遗产。此外，组织损伤会产生新的生态细胞因子和生长因子，可能会促进先前受体突变的细胞增殖。 该模型将遗传和非遗传动力学整合到癌症发展中，并且与临床观察和先前将癌发生分为起始、促进和进展步骤的实验一致。