文章：

肿瘤内异质性：癌症的一面镜子？

Intra-tumour heterogeneity: a looking glass for cancer?

原文发布日期：2012-04-19

DOI: 10.1038/nrc3261

类型: Review Article

开放获取: 否

要点：

1. Primary human tumours consist of cells that differ in clinically important phenotypic features. This phenotypic heterogeneity is a result of the interplay between genetic and non-genetic factors that shape cellular phenotypes.
2. Genomic instability, which is frequently observed in human cancers, in combination with the large numbers of cell divisions required for the formation of macroscopic tumours, leads to inevitable genetic diversity in populations of tumour cells.
3. Somatic evolution that drives tumour progression is characterized by complex dynamics arising from the Darwinian nature of the process. As a result, individual tumours have a unique clonal architecture that is spatially and temporally heterogeneous.
4. The cancer stem cell perspective can explain only some of the non-genetic variability in tumour cell phenotypes. A more comprehensive explanation of non-genetic sources of phenotypic heterogeneity necessitates the consideration of mechanisms that underlie cellular phenotypes.
5. Both deterministic and stochastic determinants of cellular phenotypes can be substantially affected during oncogenic transformation and tumour progression, contributing both to abnormal phenotypes and to an increased degree of phenotypic plasticity.
6. Phenotypic and genetic heterogeneity within tumours impedes clinical diagnostics: owing to topological heterogeneity in the distribution of diagnostically important phenotypes even multiple sampling might not provide adequate information. At the same time, given the link between a high degree of genetic heterogeneity and poor prognosis, a measure of heterogeneity by itself may be useful as a prognostic marker.
7. Phenotypic heterogeneity in tumour cell populations that results from both genetic and non-genetic determinants constitutes a major source of therapeutic resistance. Initial phenotypic heterogeneity and changes in cellular phenotypes resulting from adaptation to response and selection for resistant phenotypes need to be accounted for in order to achieve substantial improvements in therapeutic outcomes.

要点翻译：

1. 原发性人类肿瘤由具有不同临床重要表型特征的细胞组成。这种表型异质性是遗传与非遗传因素相互作用塑造细胞表型的结果。
2. 人类癌症中常见的基因组不稳定性，加上宏观肿瘤形成所需的大量细胞分裂，导致肿瘤细胞群体不可避免地产生遗传多样性。
3. 驱动肿瘤进展的体细胞进化具有达尔文式过程的复杂动力学特征。因此，单个肿瘤具有独特的克隆结构，这种结构在空间和时间上均呈现异质性。
4. 癌症干细胞视角仅能解释肿瘤细胞表型中部分非遗传变异。要更全面地解释表型异质性的非遗传来源，需要考虑细胞表型的内在机制。
5. 在癌变转化和肿瘤进展过程中，细胞表型的决定性和随机性因素均可能受到显著影响，这不仅导致异常表型的产生，还增强了表型可塑性。
6. 肿瘤内部的表型和遗传异质性阻碍临床诊断：由于重要诊断表型存在拓扑异质性分布，即使多次采样也可能无法提供足够信息。同时，鉴于高度遗传异质性与不良预后的关联，对异质性程度的测量本身可作为预后标志物。
7. 由遗传和非遗传因素共同导致的肿瘤细胞群体表型异质性，是治疗耐药性的主要来源。要实现治疗效果的实质性改善，必须综合考虑初始表型异质性，以及细胞为应对治疗压力产生适应性表型转变和耐药表型选择所带来的变化。

英文摘要：

Populations of tumour cells display remarkable variability in almost every discernable phenotypic trait, including clinically important phenotypes such as ability to seed metastases and to survive therapy. This phenotypic diversity results from the integration of both genetic and non-genetic influences. Recent technological advances have improved the molecular understanding of cancers and the identification of targets for therapeutic interventions. However, it has become exceedingly apparent that the utility of profiles based on the analysis of tumours en masse is limited by intra-tumour genetic and epigenetic heterogeneity, as characteristics of the most abundant cell type might not necessarily predict the properties of mixed populations. In this Review, we discuss both genetic and non-genetic causes of phenotypic heterogeneity of tumour cells, with an emphasis on heritable phenotypes that serve as a substrate for clonal selection. We discuss the implications of intra-tumour heterogeneity in diagnostics and the development of therapeutic resistance.

摘要翻译： 

肿瘤细胞群体在几乎所有可辨识的表型特征上均表现出显著差异，包括诸如转移定植能力和治疗耐受性等临床关键表型。这种表型多样性源于遗传与非遗传因素的共同整合。尽管近期技术进步加深了对癌症分子机制的理解并促进了治疗靶点的发现，但日益明显的是，基于整体肿瘤分析的分子谱在应用上受到肿瘤内部遗传与表观遗传异质性的限制，因为最丰富细胞类型的特征未必能预测混合群体的行为。在本综述中，我们探讨肿瘤细胞表型异质的遗传与非遗传成因，重点讨论可作为克隆选择底物的可遗传表型，并阐述肿瘤内异质性在诊断及治疗耐药发展中的意义。

原文链接：

Intra-tumour heterogeneity: a looking glass for cancer?