Institute for Systems Biology, 401 Terry Avenue North, Seattle, WA 98109, USA.
Prog Biophys Mol Biol. 2012 Sep;110(1):69-86. doi: 10.1016/j.pbiomolbio.2012.05.001. Epub 2012 May 11.
Current investigation of cancer progression towards increasing malignancy focuses on the molecular pathways that produce the various cancerous traits of cells. Their acquisition is explained by the somatic mutation theory: tumor progression is the result of a neo-Darwinian evolution in the tissue. Herein cells are the units of selection. Random genetic mutations permanently affecting these pathways create malignant cell phenotypes that are selected for in the disturbed tissue. However, could it be that the capacity of the genome and its gene regulatory network to generate the vast diversity of cell types during development, i.e., to produce inheritable phenotypic changes without mutations, is harnessed by tumorigenesis to propel a directional change towards malignancy? Here we take an encompassing perspective, transcending the orthodoxy of molecular carcinogenesis and review mechanisms of somatic evolution beyond the Neo-Darwinian scheme. We discuss the central concept of "cancer attractors" - the hidden stable states of gene regulatory networks normally not occupied by cells. Noise-induced transitions into such attractors provide a source for randomness (chance) and regulatory constraints (necessity) in the acquisition of novel expression profiles that can be inherited across cell divisions, and hence, can be selected for. But attractors can also be reached in response to environmental signals - thus offering the possibility for inheriting acquired traits that can also be selected for. Therefore, we face the possibility of non-genetic (mutation-independent) equivalents to both Darwinian and Lamarckian evolution which may jointly explain the arrow of change pointing toward increasing malignancy.
目前对癌症向恶性程度增加的进展的研究集中在产生细胞各种癌变特征的分子途径上。这些途径的获得可以用体细胞突变理论来解释：肿瘤的进展是组织中新达尔文进化的结果。在这里，细胞是选择的单位。随机的遗传突变会永久性地影响这些途径，从而产生恶性细胞表型，在紊乱的组织中被选择。然而，基因组及其基因调控网络在发育过程中产生细胞类型多样性的能力——即在没有突变的情况下产生可遗传的表型变化——是否被肿瘤发生所利用，以推动向恶性程度的定向变化呢？在这里，我们采取了一种全面的观点，超越了分子致癌作用的正统观念，回顾了超越新达尔文主义方案的体细胞进化机制。我们讨论了“癌症吸引子”的核心概念——基因调控网络的隐藏稳定状态，通常细胞不会占据这些状态。噪声诱导的向这些吸引子的转变为获得新的表达谱提供了随机性（机会）和调控约束（必要性）的来源，这些表达谱可以在细胞分裂中遗传，因此可以被选择。但是吸引子也可以响应环境信号而达到——从而提供了继承获得的特征的可能性，这些特征也可以被选择。因此，我们面临着非遗传（独立于突变）的达尔文式和拉马克式进化的可能性，这些进化可能共同解释了指向恶性程度增加的变化方向。
