蛋白质被认为是基因型的表型表现，因为蛋白质编码基因携带构成蛋白质的氨基酸串的信息。人们普遍认为蛋白质功能取决于细胞内相应的“天然”结构或折叠，并且天然蛋白质折叠对应于给定蛋白质的最低自由能最小值。然而，细胞内的蛋白质折叠是一个非确定性耗散过程，相同的输入可能会产生不同的结果，因此折叠蛋白质的构象异质性是规则而不是例外。细胞内环境的局部变化促进蛋白质折叠的变化。因此，蛋白质折叠需要大量伴侣和辅助伴侣的“监督”，帮助其客户蛋白质根据局部环境实现最稳定的折叠。这种环境对蛋白质折叠的影响在细胞应激反应（CSR）的帮助下不断转导，这可能会导致蛋白质之间的相互作用规则发生变化，从而使相应的蛋白质相互作用组可以被环境修改，从而产生替代的蛋白质折叠。细胞表型。这允许表型可塑性用于适应细胞水平上的突然和/或短暂的环境变化。从这个角度出发，我们在下文提出这样的论点：持续的细胞应激与有效的 CSR 相结合可能导致选择异常表型，作为细胞蛋白质组（和相应的相互作用组）对这种应激条件的适应，并且这可能是癌症的常见表观遗传途径。版权所有 © 2024。由 Elsevier Ltd 出版。

Proteins are acknowledged as the phenotypical manifestation of the genotype, because protein-coding genes carry the information for the strings of amino acids that constitute the proteins. It is widely accepted that protein function depends on the corresponding "native" structure or folding achieved within the cell, and that native protein folding corresponds to the lowest free energy minimum for a given protein. However, protein folding within the cell is a non-deterministic dissipative process that from the same input may produce different outcomes, thus conformational heterogeneity of folded proteins is the rule and not the exception. Local changes in the intracellular environment promote variation in protein folding. Hence protein folding requires "supervision" by a host of chaperones and co-chaperones that help their client proteins to achieve the folding that is most stable according to the local environment. Such environmental influence on protein folding is continuously transduced with the help of the cellular stress responses (CSRs) and this may lead to changes in the rules of engagement between proteins, so that the corresponding protein interactome could be modified by the environment leading to an alternative cellular phenotype. This allows for a phenotypic plasticity useful for adapting to sudden and/or transient environmental changes at the cellular level. Starting from this perspective, hereunder we develop the argument that the presence of sustained cellular stress coupled to efficient CSRs may lead to the selection of an aberrant phenotype as the resulting adaptation of the cellular proteome (and the corresponding interactome) to such stressful conditions, and this can be a common epigenetic pathway to cancer.Copyright © 2024. Published by Elsevier Ltd.