Intra-tumour heterogeneity - going beyond genetics
Intra-tumour heterogeneity - going beyond genetics
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DOI：
10.1111/febs.13705
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发表时间：
2016-06-01
期刊：
影响因子：
5.4
通讯作者：
Norell, Hakan
中科院分区：
文献类型：
--
作者：
Caiado, Francisco;Silva-Santos, Bruno;Norell, Hakan
癌症患者的死亡主要是由于短暂治疗后疾病复发。耐药逃逸变异的出现是由肿瘤内部异质性推动的，这是由突变肿瘤中不断发展的亚克隆之间的干扰和达尔文进化所支撑的。新的癌细胞变异建立在先前存在的遗传景观和肿瘤异质性通常主要归因于遗传变异。虽然突变是癌症发展所必需的，肿瘤遗传进化的研究提高了我们对癌症生物学的理解，但遗传学只代表了每个癌细胞适应性的一个方面。除了突变，一些非遗传因素也增加了显著的可变性，导致一个复杂和高度动态的肿瘤细胞群，几乎可以在任何条件下驱动疾病。这篇观点文章总结了肿瘤内异质性的遗传基础，然后剖析了四个主要的相互依赖的非遗传因素，我们认为这些因素对所有类型癌症中肿瘤细胞的整体变异性至关重要：表观遗传调控、细胞分化层次、基因表达随机性和肿瘤微环境。我们最后提出了相关的技术方法，以解决遗传和非遗传因素对肿瘤内异质性的综合贡献，重点是基因组分析，细胞谱系追踪和单细胞RNA测序技术。这一策略最终将允许解剖肿瘤内异质性的全范围和深度。因此，我们相信，了解癌症遗传学如何与新兴的非遗传因素协同作用，将是开发能够解决肿瘤逃逸的治疗方法的关键，从而提高癌症患者的生存率。
Cancer patients die primarily due to disease recurrence after transient treatment responses. The emergence of therapy-resistant escape variants is fuelled by intra-tumour heterogeneity, underpinned by interference and Darwinian evolution among continuously developing sub-clones in the mutating tumour. Novel cancer cell variants build upon the pre-existing genetic landscape and tumour heterogeneity is often ascribed largely to genetic variability. While mutations are required for cancer development and studies of genetic evolution of tumours have improved our understanding of cancer biology, genetics only represents one dimension of the fitness of each cancer cell. Beyond the mutations, several non-genetic factors also add significant variability, resulting in a complex and highly dynamic tumour cell population that can drive disease under almost any condition. This viewpoint article summarizes the genetic basis of intra-tumour heterogeneity, before dissecting four major interdependent non-genetic factors we think critically contribute to the overall variability of tumour cells in all types of cancer: epigenetic regulation, cellular differentiation hierarchies, gene expression stochasticity and tumour microenvironment. We finally present the relevant technological approaches to address the combined contribution of both genetic and non-genetic factors to intra-tumour heterogeneity, focusing on genomic profiling, cellular lineage tracing and single-cell RNA sequencing technologies. This strategy will ultimately allow dissection of the full range and depth of intra-tumour heterogeneity. We thus believe that understanding how cancer genetics synergize with the emerging non-genetic factors will be key for development of therapies able to tackle tumour escape and thereby improve cancer patient survival.