A spatial model predicts that dispersal and cell turnover limit intratumour heterogeneity.
A spatial model predicts that dispersal and cell turnover limit intratumour heterogeneity.
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DOI：
10.1038/nature14971
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发表时间：
2015-09-10
期刊：
影响因子：
64.8
通讯作者：
Nowak MA
中科院分区：
文献类型：
--
作者：
Waclaw B;Bozic I;Pittman ME;Hruban RH;Vogelstein B;Nowak MA
大多数人类癌症都很大，直径为厘米，由数十亿个细胞组成。由于每次细胞分裂期间发生的突变，同等质量的正常细胞将具有高度异质性。癌症的显着之处在于，大肿瘤内的几乎每个肿瘤细胞通常都包含相同的核心基因改变，异质性仅限于肿瘤生长后期出现的突变。这种改变如何在肿瘤的空间受限的三维结构中扩展，并主导一个大的、预先存在的病变，目前尚不清楚。在这里，我们描述了一个肿瘤进化模型，该模型展示了短程扩散和细胞更新如何解释肿瘤内细胞的快速混合。我们表明，即使大肿瘤内单个细胞的选择性优势很小，也可以使该细胞的后代在临床相关的时间范围内取代前体物质。我们还证明，相同的机制可能导致化疗耐药性的快速发生。我们的模型不仅提供了对肿瘤生长的空间和时间方面的见解，而且还表明针对短程细胞迁移活动可能对肿瘤生长速率产生显着影响。
Most cancers in humans are large, measuring centimetres in diameter, and composed of many billions of cells. An equivalent mass of normal cells would be highly heterogeneous as a result of the mutations that occur during each cell division. What is remarkable about cancers is that virtually every neoplastic cell within a large tumour often contains the same core set of genetic alterations, with heterogeneity confined to mutations that emerge late during tumour growth. How such alterations expand within the spatially constrained three-dimensional architecture of a tumour, and come to dominate a large, pre-existing lesion, has been unclear. Here we describe a model for tumour evolution that shows how short-range dispersal and cell turnover can account for rapid cell mixing inside the tumour. We show that even a small selective advantage of a single cell within a large tumour allows the descendants of that cell to replace the precursor mass in a clinically relevant time frame. We also demonstrate that the same mechanisms can be responsible for the rapid onset of resistance to chemotherapy. Our model not only provides insights into spatial and temporal aspects of tumour growth, but also suggests that targeting short-range cellular migratory activity could have marked effects on tumour growth rates.