空间模型预测扩散和细胞更新导致肿瘤内异质性降低
Spatial model predicts dispersal and cell turnover cause reduced intra-tumor heterogeneity
摘要：
人类的大多数癌症都很大，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是高度异质的。癌症的显著之处在于它们的同质性--几乎一个大型癌症中的每一个肿瘤细胞都包含相同的核心遗传改变集，异质性仅限于最后一次克隆扩增后出现的突变。这种克隆如何在肿瘤的空间受限的三维结构内扩展，并开始支配大的预先存在的病变，从未被解释过。我们在这里描述了一个肿瘤演变的模型，该模型显示了短程迁移和细胞更新如何解释肿瘤内的快速细胞混合。有了它，我们表明，即使是一个小的选择性优势，一个大的肿瘤内的单个细胞允许该细胞的后代，以取代在临床相关的时间范围内的前体质量。我们还证明，同样的机制可以负责化疗耐药性的快速发作。我们的模型不仅为肿瘤生长的空间和时间方面提供了新的见解，而且还表明靶向短程细胞迁移活动可能对肿瘤生长速率产生巨大影响。
英文摘要：
Most cancers in humans are large, measuring centimeters in diameter, 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 their homogeneity - virtually every neoplastic cell within a large cancer contains the same core set of genetic alterations, with heterogeneity confined to mutations that have emerged after the last clonal expansions. How such clones expand within the spatially-constrained three dimensional architecture of a tumor, and come to dominate a large, pre-existing lesion, has never been explained. We here describe a model for tumor evolution that shows how short-range migration and cell turnover can account for rapid cell mixing inside the tumor. With it, we show that even a small selective advantage of a single cell within a large tumor 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 novel insights into spatial and temporal aspects of tumor growth but also suggests that targeting short range cellular migratory activity could have dramatic effects on tumor growth rates.
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