Carvalho João
CFisUC, Department of Physics, University of Coimbra, Coimbra, Portugal.
Front Oncol. 2020 Apr 15;10:541. doi: 10.3389/fonc.2020.00541. eCollection 2020.
Even if the Somatic Mutation Theory of carcinogenesis explains many of the relevant experimental results in tumor origin and development, there are frequent events that are not justified, or are even contradictory to this widely accepted theory. A Cell Reversal Theory is presented, putting forward the hypothesis that cancer is originated by reversal of a differentiated cell into a non-differentiated stem-like state, by a change of its intrinsic epigenetic state, following a perturbation on the cell and/or its microenvironment. In the current proposal a cluster of cancer stem cells can be established, without the strict control mechanisms of a normal stem cell niche, and initiate a tumor. It is proposed that a reversal to a pluripotent state is at tumor origin and not tumor progress that prompts cell dedifferentiation. The uncontrolled proliferation of cancer stem cells causes a microenvironment disorganization, resulting in stressful conditions, like hypoxia and nutrient deprivation, which induces the genetic instability characteristic of a tumor; thus, in most cases, mutations are a consequence and not the direct cause of a tumor. It is also proposed that metastases result from dedifferentiation signaling dispersion instead of cell migration. However, conceivably, once the microenvironment is normalized, the stem cell-like state can differentiate back to a mature cell state and loose its oncogenic capacity. Therefore, this can be a reversible condition, suggesting important therapeutic opportunities.
即使致癌作用的体细胞突变理论解释了肿瘤发生和发展中的许多相关实验结果，但仍存在一些频繁出现的事件无法用该理论解释，甚至与之相矛盾。本文提出了细胞逆转理论，该理论假设癌症是由分化细胞通过改变其内在表观遗传状态，在细胞和/或其微环境受到扰动后逆转为未分化的干细胞样状态而引发的。在当前的设想中，一群癌症干细胞可以在没有正常干细胞微环境严格控制机制的情况下形成，并引发肿瘤。本文提出，肿瘤起源于向多能状态的逆转，而不是促使细胞去分化的肿瘤进展。癌症干细胞的不受控制的增殖会导致微环境紊乱，从而产生诸如缺氧和营养剥夺等应激条件，进而诱导肿瘤的遗传不稳定性特征；因此，在大多数情况下，突变是肿瘤的结果而非直接原因。本文还提出，转移是由去分化信号扩散而非细胞迁移导致的。然而，可以想象，一旦微环境恢复正常，干细胞样状态可以重新分化回成熟细胞状态并失去其致癌能力。因此，这可能是一种可逆的情况，提示了重要的治疗机会。
