Optimum 3D Matrix Stiffness for Maintenance of Cancer Stem Cells Is Dependent on Tissue Origin of Cancer Cells.
Optimum 3D Matrix Stiffness for Maintenance of Cancer Stem Cells Is Dependent on Tissue Origin of Cancer Cells.
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DOI：
10.1371/journal.pone.0132377
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Moeinzadeh S
中科院分区：
文献类型：
--
作者：
Jabbari E;Sarvestani SK;Daneshian L;Moeinzadeh S
肿瘤干细胞的生长和表达依赖于肿瘤微环境中的许多因素。这项工作的目的是研究癌细胞的组织来源对CSC生长的最佳基质刚度和在模型聚乙二醇二丙烯酸酯（PEGDA）水凝胶中的标记物表达的影响，而不受微环境中其他因素的干扰。使用人MCF 7和MDA-MB-231乳腺癌、HCT 116结肠直肠癌和AGS胃癌以及U2 OS骨肉瘤细胞。将细胞包封在PEGDA凝胶中，其压缩模量在2-70 kPa范围内，优化的细胞接种密度为0.6 × 106个细胞/mL。微图案化用于优化相对于平均肿瘤球大小的包封细胞的生长。通过细胞数量、肿瘤球大小和数量密度以及CSC标志物的mRNA表达来表征包封细胞的CSC亚群。对于癌细胞的CSC亚群的生长和标志物表达，乳腺MCF 7和MDA 231的最佳基质刚度为5 kPa，结肠直肠HCT 116和胃AGS的最佳基质刚度为25 kPa，骨U2 OS细胞的最佳基质刚度为50 kPa。将CD 44结合肽偶联到凝胶上可以阻止来自不同组织来源的癌细胞形成肿瘤球。在最佳硬度下，包封的癌细胞的雅普/TAZ转录因子的表达最高，表明Hippo转换器和CSC生长之间的联系。CSC生长和标记物表达的最佳平均肿瘤球大小为50 μm。标志物表达结果表明，癌细胞的CSC亚群位于具有最佳硬度的小生境内，这取决于癌细胞的组织来源。
The growth and expression of cancer stem cells (CSCs) depend on many factors in the tumor microenvironment. The objective of this work was to investigate the effect of cancer cells’ tissue origin on the optimum matrix stiffness for CSC growth and marker expression in a model polyethylene glycol diacrylate (PEGDA) hydrogel without the interference of other factors in the microenvironment. Human MCF7 and MDA-MB-231 breast carcinoma, HCT116 colorectal and AGS gastric carcinoma, and U2OS osteosarcoma cells were used. The cells were encapsulated in PEGDA gels with compressive moduli in the 2-70 kPa range and optimized cell seeding density of 0.6x106 cells/mL. Micropatterning was used to optimize the growth of encapsulated cells with respect to average tumorsphere size. The CSC sub-population of the encapsulated cells was characterized by cell number, tumorsphere size and number density, and mRNA expression of CSC markers. The optimum matrix stiffness for growth and marker expression of CSC sub-population of cancer cells was 5 kPa for breast MCF7 and MDA231, 25 kPa for colorectal HCT116 and gastric AGS, and 50 kPa for bone U2OS cells. Conjugation of a CD44 binding peptide to the gel stopped tumorsphere formation by cancer cells from different tissue origin. The expression of YAP/TAZ transcription factors by the encapsulated cancer cells was highest at the optimum stiffness indicating a link between the Hippo transducers and CSC growth. The optimum average tumorsphere size for CSC growth and marker expression was 50 μm. The marker expression results suggest that the CSC sub-population of cancer cells resides within a niche with optimum stiffness which depends on the cancer cells’ tissue origin.