An agent-based model of triple-negative breast cancer: the interplay between chemokine receptor CCR5 expression, cancer stem cells, and hypoxia.
An agent-based model of triple-negative breast cancer: the interplay between chemokine receptor CCR5 expression, cancer stem cells, and hypoxia.
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DOI：
10.1186/s12918-017-0445-x
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发表时间：
2017-07-11
影响因子：
--
通讯作者：
Popel AS
中科院分区：
文献类型：
--
作者：
Norton KA;Wallace T;Pandey NB;Popel AS
三阴性乳腺癌缺乏雌激素、孕激素和HER2受体，因此不可能针对这些受体进行靶向治疗。因此，更好地了解三阴性乳腺癌对于治疗这种类型的癌症是必要的。在我们实验室之前的工作中，我们发现在小鼠异种移植模型中，趋化因子配体受体CCL5-CCR5轴对人三阴性乳腺癌细胞MDA-MB-231转移到淋巴结和肺部很重要。我们收集了我们和其他实验室在不同乳腺癌细胞系和不同实验条件下的肿瘤干细胞数量、CCR5+细胞数量和细胞迁移率的相关实验数据。利用这些实验数据，我们建立了一个基于硅试剂的三阴性乳腺癌模型，该模型考虑了表面受体ccr5高和ccr5低细胞和乳腺癌干细胞，以预测肿瘤生长速度和细胞在原发性肿瘤中的时空分布。我们发现高的癌症干细胞百分比极大地促进了肿瘤的生长。我们发现，抗干细胞治疗可以减少肿瘤生长，但可能不会导致休眠，除非所有的干细胞都被清除。我们进一步发现，缺氧会增加肿瘤的总体生长，而使用CCR5抑制剂马拉维洛克治疗会略微降低肿瘤的总体生长。我们还使用几个形状指标来表征实体和侵袭性肿瘤的三维形状。乳腺癌干细胞和CCR5+细胞影响乳腺肿瘤的整体生长和形态。在硅片中，药物治疗对肿瘤干细胞的不完全抑制效果有限，肿瘤生长复发后，CCR5抑制仅引起肿瘤生长的轻微减少。本文的在线版本（doi:10.1186/s12918-017-0445-x）包含补充材料，可供授权用户使用。
Triple-negative breast cancer lacks estrogen, progesterone, and HER2 receptors and is thus not possible to treat with targeted therapies for these receptors. Therefore, a greater understanding of triple-negative breast cancer is necessary for the treatment of this cancer type. In previous work from our laboratory, we found that chemokine ligand-receptor CCL5-CCR5 axis is important for the metastasis of human triple-negative breast cancer cell MDA-MB-231 to the lymph nodes and lungs, in a mouse xenograft model. We collected relevant experimental data from our and other laboratories for numbers of cancer stem cells, numbers of CCR5+ cells, and cell migration rates for different breast cancer cell lines and different experimental conditions. Using these experimental data we developed an in silico agent-based model of triple-negative breast cancer that considers surface receptor CCR5-high and CCR5-low cells and breast cancer stem cells, to predict the tumor growth rate and spatio-temporal distribution of cells in primary tumors. We find that high cancer stem cell percentages greatly increase tumor growth. We find that anti-stem cell treatment decreases tumor growth but may not lead to dormancy unless all stem cells get eliminated. We further find that hypoxia increases overall tumor growth and treatment with a CCR5 inhibitor maraviroc slightly decreases overall tumor growth. We also characterize 3D shapes of solid and invasive tumors using several shape metrics. Breast cancer stem cells and CCR5+ cells affect the overall growth and morphology of breast tumors. In silico drug treatments demonstrate limited efficacy of incomplete inhibition of cancer stem cells after which tumor growth recurs, and CCR5 inhibition causes only a slight reduction in tumor growth. The online version of this article (doi:10.1186/s12918-017-0445-x) contains supplementary material, which is available to authorized users.
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