Ludwig Institute for Cancer Research and Nuffield Department of Medicine, University of Oxford, Oxford, UK.
Trends Cancer. 2020 Jun;6(6):454-461. doi: 10.1016/j.trecan.2020.02.016. Epub 2020 Mar 13.
Intratumor heterogeneity is a key hallmark of cancer that contributes to progression and therapeutic resistance. Phenotypic heterogeneity is in part caused by Darwinian selection of subclones that arise by random (epi)genetic aberrations. In addition, cancer cells are endowed with increased cellular plasticity compared with their normal counterparts, further adding to their heterogeneous behavior. However, the molecular mechanisms underpinning cancer cell plasticity are incompletely understood. Here, I outline the hypothesis that cancer-associated perturbations collectively disrupt normal gene regulatory networks (GRNs) by increasing their entropy. Importantly, in this model both somatic driver and passenger alterations contribute to 'perturbation-driven entropy', thereby increasing phenotypic heterogeneity and evolvability. This additional layer of heterogeneity may contribute to our understanding of cancer evolution and therapeutic resistance.
肿瘤内异质性是癌症的一个关键特征，它导致了癌症的进展和治疗耐药性。表型异质性部分是由随机（表观遗传）基因突变亚克隆的达尔文选择引起的。此外，与正常细胞相比，癌细胞具有更高的细胞可塑性，这进一步增加了它们的异质性行为。然而，支持癌细胞可塑性的分子机制尚不完全清楚。在这里，我提出了一个假设，即癌症相关的扰动通过增加它们的熵来共同破坏正常的基因调控网络（GRNs）。重要的是，在这个模型中，体细胞驱动和乘客改变都有助于“扰动驱动的熵”，从而增加表型异质性和可进化性。这种额外的异质性可能有助于我们理解癌症的进化和治疗耐药性。
