Quantitative investigation of MDA-MB-231 breast cancer cell motility: dependence on epidermal growth factor concentration and its gradient,Molecular BioSystems

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Quantitative investigation of MDA-MB-231 breast cancer cell motility: dependence on epidermal growth factor concentration and its gradient
Molecular BioSystems Pub Date : 2017-08-02 00:00:00 , DOI: 10.1039/c7mb00390k
Tanzila Islam _{1,

2,

3,

4} , Haluk Resat _{1,

2,

3,

4}

Affiliation

Enhanced cell motility is one of the primary features of cancer. Accumulated evidence demonstrates that Epidermal Growth Factor Receptor (EGFR) mediated pathways play an important role in breast cancer cell proliferation and migration. We have quantified the MDA-MB-231 breast cancer cell migration in response to the stimulation of EGFR pathways with their ligand EGF to determine how the cell motility of MDA-MB-231 cells depends on the ligand concentration and gradient. Analysis at the single cell level combined with mathematical modeling and the ability to vary the ligand concentration and gradients locally using microfluidic devices allowed us to separate the unique contributions of ligand concentration and ligand gradient to cell motility. We tracked the motility of 6600 cells individually using time lapse imaging under varying EGF stimulation conditions. Trajectory analysis of the tracked cells using non-linear multivariate regression models showed that: (i) cell migration of MDA-MB-231 breast cancer cells depends on the ligand gradient but not on the ligand concentration. This observation was valid for both the total (direction independent) and directed (along gradient direction) cell velocities. Although the dependence of the directed motility on ligand gradient is to be expected, the dependence of the total velocity solely on ligand gradient was an unexpected novel observation. (ii) Enhancement of the motilities of individual cells in a population upon exposure to the ligand was highly heterogeneous, and only a very small percentage of cells responded strongly to the external stimuli. Separating out the non-responding cells using quantitative analysis of individual cell motilities enabled us to establish that enhanced motility of the responding cells indeed increases monotonically with increasing EGF gradient. (iii) A large proportion of cells in a population were unresponsive to ligand stimulation, and their presence introduced considerable random intrinsic variability to the observations. This indicated that studying cell motilities at the individual cell level is necessary to better capture the biological reality and that population averaging methods should be avoided. Studying motilities at the individual cell level is particularly important to understand the biological processes that are possibly driven by the action of a small portion of cells in a population, such as metastasis. We discuss the implications of our results on the total and chemotactic movement of cancer cells in the tumor microenvironment.

中文翻译：

MDA-MB-231乳腺癌细胞运动性的定量研究：对表皮生长因子浓度及其梯度的依赖性

增强的细胞运动性是癌症的主要特征之一。积累的证据表明，表皮生长因子受体（EGFR）介导的途径在乳腺癌细胞的增殖和迁移中起着重要作用。我们已经定量了MDA-MB-231乳腺癌细胞迁移，以响应其配体EGF对EGFR通路的刺激，以确定MDA-MB-231细胞的细胞运动如何取决于配体浓度和梯度。在单细胞水平上进行分析，并结合数学建模以及使用微流体装置局部改变配体浓度和梯度的能力，使我们能够分离出配体浓度和配体梯度对细胞运动的独特贡献。我们在不同的EGF刺激条件下使用延时成像分别跟踪了6600个细胞的运动。使用非线性多元回归模型对跟踪细胞的轨迹分析表明：（i）MDA-MB-231乳腺癌细胞的细胞迁移取决于配体梯度，而不取决于配体浓度。该观察对于总的（独立于方向的）和定向的（沿梯度方向的）细胞速度都是有效的。尽管可以预期定向运动对配体梯度的依赖性，但总速度对配体梯度的依赖性却是出乎意料的新颖观察。（ii）暴露于配体后，种群中单个细胞的功能增强是高度异质的，而且只有极少数的细胞对外部刺激反应强烈。使用对单个细胞运动的定量分析来分离出无反应的细胞，使我们能够确定，随着EGF梯度的增加，反应细胞增强的运动确实单调增加。（iii）群体中的大部分细胞对配体刺激无反应，并且它们的存在为观察结果带来了相当大的随机内在变异性。这表明在单个细胞水平上研究细胞能动性对于更好地捕获生物学现实是必要的，并且应该避免群体平均方法。在单个细胞水平上研究能动性对于理解可能由种群中一小部分细胞的作用（例如转移）驱动的生物学过程尤为重要。我们讨论了我们的结果对肿瘤微环境中癌细胞的总体和趋化运动的影响。

更新日期：2017-08-11

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