Cancer cell population growth kinetics at low densities deviate from the exponential growth model and suggest an Allee effect
Cancer cell population growth kinetics at low densities deviate from the exponential growth model and suggest an Allee effect
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DOI：
10.1371/journal.pbio.3000399
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发表时间：
2019-08-01
期刊：
影响因子：
9.8
通讯作者：
Brock, Amy
中科院分区：
文献类型：
--
作者：
Johnson, Kaitlyn E.;Howard, Grant;Brock, Amy
癌细胞群体扩增的大多数模型假设在低细胞密度下的指数生长动力学，其中偏差是由于由于有限的资源如空间和营养物而仅在较高密度下观察到生长速率的减慢。然而，最近的临床前和临床观察肿瘤的起始或复发表明存在肿瘤生长动力学，其中生长速率与细胞数量成正比。这些观察结果类似于生态系统中物种的合作行为，由Allee效应的生态学原理描述。然而，在临床前和临床模型中，肿瘤生长数据受到检测下限（即，可测量的病变）和混杂变量（例如肿瘤微环境）以及免疫应答可能导致并掩盖与指数生长模型的偏差。在这项工作中，我们提出了替代的生长模型，以调查存在的Allee效应的癌细胞接种在低细胞密度在一个受控的体外设置。我们提出了一个随机建模框架，以解开预期偏差，由于小人口规模的随机效应，从合作的增长，并使用随机参数估计的矩方法来校准观察到的增长轨迹。我们验证了模拟数据的框架，并将这种方法应用于BT-474管腔B乳腺癌细胞的纵向细胞增殖数据。我们发现，细胞群体的生长动力学最好的模型结构，考虑Allee效应，在该出生率的肿瘤细胞的细胞数量增加，在该政权的小人口规模。这表明在低细胞密度下肿瘤细胞之间的合作行为具有潜在的关键作用，与新出现和复发肿瘤的早期生长模式相关。
Most models of cancer cell population expansion assume exponential growth kinetics at low cell densities, with deviations to account for observed slowing of growth rate only at higher densities due to limited resources such as space and nutrients. However, recent preclinical and clinical observations of tumor initiation or recurrence indicate the presence of tumor growth kinetics in which growth rates scale positively with cell numbers. These observations are analogous to the cooperative behavior of species in an ecosystem described by the ecological principle of the Allee effect. In preclinical and clinical models, however, tumor growth data are limited by the lower limit of detection (i.e., a measurable lesion) and confounding variables, such as tumor microenvironment, and immune responses may cause and mask deviations from exponential growth models. In this work, we present alternative growth models to investigate the presence of an Allee effect in cancer cells seeded at low cell densities in a controlled in vitro setting. We propose a stochastic modeling framework to disentangle expected deviations due to small population size stochastic effects from cooperative growth and use the moment approach for stochastic parameter estimation to calibrate the observed growth trajectories. We validate the framework on simulated data and apply this approach to longitudinal cell proliferation data of BT-474 luminal B breast cancer cells. We find that cell population growth kinetics are best described by a model structure that considers the Allee effect, in that the birth rate of tumor cells increases with cell number in the regime of small population size. This indicates a potentially critical role of cooperative behavior among tumor cells at low cell densities with relevance to early stage growth patterns of emerging and relapsed tumors.