Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia.
Br J Cancer. 2020 Feb;122(4):465-472. doi: 10.1038/s41416-019-0648-6. Epub 2019 Dec 13.
As well as undergoing genetic evolution, cancer cells can alter their epigenetic state to adapt and resist treatment. This non-genetic evolution is emerging as a major component of cancer resistance. Only now are we beginning to acquire the necessary data and tools to establish some of the underlying principles and mechanisms that define when, why and how non-genetic resistance occurs. Preliminary studies suggest that it can exist in a number of forms, including drug persistence, unstable non-genetic resistance and, most intriguingly, stable non-genetic resistance. Exactly how they each arise remains unclear; however, epigenetic heterogeneity and plasticity appear to be important variables. In this review, we provide an overview of these different forms of non-genetic resistance, before exploring how epigenetic heterogeneity and plasticity influence their emergence. We highlight the distinction between non-genetic Darwinian selection and Lamarckian induction and discuss how each is capable of generating resistance. Finally, we discuss the potential interaction between genetic and non-genetic adaptation and propose the idea of 'the path of most resistance', which outlines the variables that dictate whether cancers adapt through genetic and/or epigenetic means. Through these discussions, we hope to provide a conceptual framework that focuses future studies, whose insights might help prevent or overcome non-genetic resistance.
除了经历遗传进化，癌细胞还可以改变其表观遗传状态以适应和抵抗治疗。这种非遗传进化正在成为癌症耐药性的一个主要组成部分。我们现在才开始获得必要的数据和工具来建立一些定义何时、为何以及如何发生非遗传耐药性的基本原则和机制。初步研究表明，它可能以多种形式存在，包括药物持续存在、不稳定的非遗传耐药性，以及最有趣的稳定的非遗传耐药性。它们各自如何出现仍然不清楚；然而，表观遗传异质性和可塑性似乎是重要的变量。在这篇综述中，我们首先概述了这些不同形式的非遗传耐药性，然后探讨了表观遗传异质性和可塑性如何影响它们的出现。我们强调了非遗传达尔文选择和拉马克诱导之间的区别，并讨论了它们各自如何产生耐药性。最后，我们讨论了遗传和非遗传适应之间的潜在相互作用，并提出了“最抵抗路径”的概念，该概念概述了决定癌症是通过遗传和/或表观遗传方式适应的变量。通过这些讨论，我们希望提供一个概念框架，以指导未来的研究，这些研究的见解可能有助于预防或克服非遗传耐药性。
