Abstract：
Tetraploidy, a condition in which a cell has four homologous sets of chromosomes, may be a natural physiological condition or pathophysiological such as in cancer cells or stress induced tetraploidisation. Its contribution to cancer development is well known. However, among the many models proposed to explain the causes, mechanisms and steps of malignant cell transformation, only few integrate tetraploidization into a systemic multistep approach of carcinogenesis. Therefore, we will i) describe the molecular and cellular characteristics of tetraploidy; ii) assess the contribution of stress-induced tetraploidy in cancer development; iii) situate tetraploidy as a metastable state leading to cancer development in a systemic cell-centered approach; iiii) consider knowledge gaps and future perspectives. The available data shows that stress-induced tetraploidisation/polyploidisation leads to p53 stabilisation, cell cycle arrest, followed by cellular senescence or apoptosis, suppressing the proliferation of tetraploid cells. However, if tetraploid cells escape the G1-tetraploidy checkpoint, it may lead to uncontrolled proliferation of tetraploid cells, micronuclei induction, aneuploidy and deploidisation. In addition, tetraploidization favors 3D-chromatin changes and epigenetic effects. The combined effects of genetic and epigenetic changes allow the expression of oncogenic gene expression and cancer progression. Moreover, since micronuclei are inducing inflammation, which in turn may induce additional tetraploidization, tetraploidy-derived genetic instability leads to a carcinogenic vicious cycle. The concept that polyploid cells are metastable intermediates between diploidy and aneuploidy is not new. Metastability denotes an intermediate energetic state within a dynamic system other than the system\'s state at least energy. Considering in parallel the genetic/epigenetic changes and the probable entropy levels induced by stress-induced tetraploidisation provides a new systemic approach to describe cancer development.
摘要：
四倍体,细胞具有四组同源染色体的情况，可以是天然的生理状况或病理生理状况,例如癌细胞或应激诱导的四倍体化。它对癌症发展的贡献是众所周知的。然而,在提出的解释原因的许多模型中，恶性细胞转化的机制和步骤，只有少数人将四倍体化整合到系统的多步骤致癌方法中。因此,我们将i）描述四倍体的分子和细胞特征;ii）评估应激诱导的四倍体在癌症发展中的贡献;iii）以系统性细胞为中心的方法将四倍体定位为导致癌症发展的亚稳态;iiii）考虑知识差距和未来观点。现有数据表明，应激诱导的四倍体化/多倍体化导致p53稳定，细胞周期停滞,随后是细胞衰老或凋亡，抑制四倍体细胞的增殖。然而,如果四倍体细胞逃脱了G1-四倍体检查点，它可能导致四倍体细胞不受控制的增殖，微核诱导，非整倍体和去分裂。此外,四倍体化有利于3D染色质变化和表观遗传效应。遗传和表观遗传变化的组合效应允许致癌基因表达和癌症进展的表达。此外，由于微核诱导炎症，这反过来可能会诱导额外的四倍体化，四倍体遗传不稳定性导致致癌恶性循环。多倍体细胞是二倍体和非整倍体之间的亚稳态中间体的概念并不是新的。亚稳态表示动态系统内的中间能量状态，而不是系统的至少能量状态。同时考虑遗传/表观遗传变化和应激诱导的四倍体化可能引起的熵水平，为描述癌症发展提供了一种新的系统方法。
