Gatenby Robert A, Avdieiev Stanislav, Tsai Kenneth Y, Brown Joel S
Cancer Biology and Evolution Program Moffitt Cancer Center Tampa FL USA.
Evol Appl. 2020 May 13;13(7):1651-1659. doi: 10.1111/eva.12973. eCollection 2020 Aug.
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.
从正常细胞表型到恶性细胞表型的多步骤转变通常被称为由累积随机突变引起的“体细胞进化”。在此，我们提出一种替代模型，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，这些突变并非致癌性的，因为多细胞生物中的正常细胞通常不会进化。也就是说，正常细胞的增殖和死亡受局部组织限制的控制，而这种限制通常由细胞膜中的非基因组信息动态调控。因此，多细胞生物的细胞具有与宿主相同的适应性，宿主于是成为自然选择的单位。只有当细胞的命运变得独立于宿主限制时，细胞的体细胞进化才会发生。现在，单个细胞的存活、增殖和死亡取决于达尔文动力学。这种从宿主定义的适应性到自我定义的适应性的细胞转变，可能如致癌作用的传统观点所述，是由使细胞对宿主控制不敏感的突变导致的。然而，当周围组织由于损伤、炎症、衰老或感染而无法施加控制时，也会产生相同的状态。在这里，组织损伤部位所有存活的细胞默认采用自我定义的适应性功能，从而使它们能够进化，这样宿主一生中积累的突变现在就成为了一个进化选择单位的遗传遗产。此外，组织损伤会产生一种新的生态环境，其中的细胞因子和生长因子可能会促进具有先前受体突变的细胞增殖。该模型将遗传和非遗传动态整合到癌症发展过程中，并且与将致癌作用分为启动、促进和进展步骤的临床观察和先前实验结果一致。
