Darwinian Dynamics of Intratumoral Heterogeneity: Not Solely Random Mutations but Also Variable Environmental Selection Forces.
Darwinian Dynamics of Intratumoral Heterogeneity: Not Solely Random Mutations but Also Variable Environmental Selection Forces.
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DOI：
10.1158/0008-5472.can-15-2962
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发表时间：
2016-06-01
期刊：
影响因子：
11.2
通讯作者：
Gatenby RA
中科院分区：
文献类型：
--
作者：
Lloyd MC;Cunningham JJ;Bui MM;Gillies RJ;Brown JS;Gatenby RA
肿瘤的空间异质性通常被认为是由肿瘤发展过程中积累的随机突变驱动的分支克隆进化造成的。然而，这个概念建立在一个隐含的假设之上，即癌细胞永远不会进化到适应度最大值，因为它们总是可以获得增加增殖能力的突变。在本研究中，我们调查了这一假设的有效性。利用进化博弈论，我们证明了在稳定的环境下，局部癌细胞群将迅速收敛到最适合的表型。在这种情况下，肿瘤细胞的空间异质性在很大程度上取决于环境条件的区域差异，例如血流量的改变。模型模拟特别预测了一种常见的空间模式，即肿瘤-宿主界面的癌细胞表现出促进侵袭、快速增殖的表型特性，而肿瘤核心的细胞通过促进支持性组织基础设施（例如促进血管生成）来最大化其种群密度。我们通过对10例2期浸润性乳腺癌患者组织学切片中表型空间分布的详细定量图像分析来检验模型预测。CAIX、GLUT1和Ki67在肿瘤边缘表达上调，与产酸侵袭性增殖性表型一致。肿瘤核心的细胞密度比边缘高20%，CAXII、HIF-1α和cleaved caspase-3表达上调，符合更静态、更低增殖的表型。同样，肿瘤中心的血管密度也比肿瘤边缘低。淋巴细胞对肿瘤抗原的免疫应答在肿瘤边缘也有升高的趋势，尽管这种影响没有达到统计学意义。就像自然界的入侵物种一样，肿瘤前沿的癌细胞与肿瘤核心的细胞具有不同的表型。我们的研究结果表明，肿瘤中癌细胞的分子异质性至少有一部分是由环境选择力量中可预测的区域差异所控制的，这反驳了癌细胞可以通过突变的随机积累向局部适应度最大化进化的假设。就像自然界的入侵物种一样，肿瘤前沿的癌细胞与肿瘤核心的细胞具有不同的表型。我们的结论是，至少癌细胞分子特性的一些肿瘤内异质性是由环境选择力量中可预测的区域差异控制的。
Spatial heterogeneity in tumors is generally thought to result from branching clonal evolution driven by random mutations that accumulate during tumor development. However, this concept rests on the implicit assumption that cancer cells never evolve to a fitness maximum because they can always acquire mutations that increase proliferative capacity. In this study, we investigated the validity of this assumption. Using evolutionary game theory, we demonstrate that local cancer cell populations will rapidly converge to the fittest phenotype given a stable environment. In such settings, cellular spatial heterogeneity in a tumor will be largely governed by regional variations in environmental conditions, e.g. alterations in blood flow. Model simulations specifically predict a common spatial pattern in which cancer cells at the tumor-host interface exhibit invasion-promoting, rapidly-proliferating phenotypic properties, while cells in the tumor core maximize their population density by promoting supportive tissue infrastructures e.g. to promote angiogenesis. We tested model predictions through detailed quantitative image analysis of phenotypic spatial distribution in histological sections of 10 patients with stage 2 invasive breast cancers. CAIX, GLUT1 and Ki67 were upregulated in the tumor edge consistent with an acid-producing invasive, proliferative phenotype. Cells in the tumor core were 20% denser than the edge, exhibiting upregulation of CAXII, HIF-1α and cleaved caspase-3, consistent with a more static and less proliferative phenotype. Similarly, vascularity was consistently lower in the tumor center compared to the tumor edges. Lymphocytic immune responses to tumor antigens also trended to higher level in the tumor edge, although this effect did not reach statistical significance. Like invasive species in nature, cancer cells at the leading edge of the tumor possess a different phenotype from cells in the tumor core. Our results suggest that at least some of the molecular heterogeneity in cancer cells in tumors is governed by predictable regional variations in environmental selection forces, arguing against the assumption that cancer cells can evolve toward a local fitness maximum by random accumulation of mutations. Like invasive species in nature, cancer cells at the leading edge of the tumor possess a different phenotype from cells in the tumor core. We conclude that at least some intratumoral heterogeneity in the molecular properties of cancer cells is governed by predictable regional variations in environmental selection forces.