Cell Reversal From a Differentiated to a Stem-Like State at Cancer Initiation
Cell Reversal From a Differentiated to a Stem-Like State at Cancer Initiation
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DOI：
10.3389/fonc.2020.00541
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发表时间：
2020-04-15
影响因子：
4.7
通讯作者：
Carvalho, Joao
中科院分区：
文献类型：
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作者：
Carvalho, Joao
即使癌发生的体细胞突变理论解释了肿瘤起源和发展的许多相关实验结果，也经常有不合理的事件，甚至与这个广泛接受的理论相矛盾。提出了一种细胞逆转理论，提出了这样的假设，即癌症是由分化的细胞逆转成未分化的干细胞样状态，通过改变其内在的表观遗传状态，然后对细胞和/或其微环境进行扰动而起源的。在目前的提议中，可以建立一群癌症干细胞，而不需要正常干细胞小生境的严格控制机制，并引发肿瘤。有人提出，多能状态的逆转是在肿瘤起源，而不是肿瘤进展，促使细胞去分化。癌症干细胞的不受控制的增殖导致微环境破坏，导致应激条件，如缺氧和营养缺乏，这会诱导肿瘤的遗传不稳定性;因此，在大多数情况下，突变是肿瘤的结果，而不是肿瘤的直接原因。也有人提出，转移是由去分化信号分散而不是细胞迁移引起的。然而，可以想象，一旦微环境正常化，干细胞样状态可以分化回成熟细胞状态并失去其致癌能力。因此，这可能是一个可逆的条件，这表明重要的治疗机会。
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.