Department of Mathematics, Duke University, Durham, North Carolina 27708, USA.
Genetics. 2011 Jun;188(2):461-77. doi: 10.1534/genetics.110.125724. Epub 2011 Mar 15.
With rare exceptions, human tumors arise from single cells that have accumulated the necessary number and types of heritable alterations. Each such cell leads to dysregulated growth and eventually the formation of a tumor. Despite their monoclonal origin, at the time of diagnosis most tumors show a striking amount of intratumor heterogeneity in all measurable phenotypes; such heterogeneity has implications for diagnosis, treatment efficacy, and the identification of drug targets. An understanding of the extent and evolution of intratumor heterogeneity is therefore of direct clinical importance. In this article, we investigate the evolutionary dynamics of heterogeneity arising during exponential expansion of a tumor cell population, in which heritable alterations confer random fitness changes to cells. We obtain analytical estimates for the extent of heterogeneity and quantify the effects of system parameters on this tumor trait. Our work contributes to a mathematical understanding of intratumor heterogeneity and is also applicable to organisms like bacteria, agricultural pests, and other microbes.
除了极少数例外，人类肿瘤起源于单个细胞，这些细胞积累了必要数量和类型的可遗传改变。每个这样的细胞都会导致失调的生长，最终形成肿瘤。尽管它们具有克隆起源，但在诊断时，大多数肿瘤在所有可测量的表型中都显示出明显的肿瘤内异质性；这种异质性对诊断、治疗效果和药物靶点的识别都有影响。因此，了解肿瘤内异质性的程度和演变具有直接的临床意义。在本文中，我们研究了在肿瘤细胞群体指数增长过程中出现的异质性的进化动态，其中可遗传的改变赋予细胞随机的适应性变化。我们获得了对异质性程度的分析估计，并量化了系统参数对这一肿瘤特征的影响。我们的工作有助于对肿瘤内异质性的数学理解，也适用于细菌、农业害虫和其他微生物等生物体。
