Matrix Stiffness-Regulated Growth of Breast Tumo Spheroids and Their Response to Chemotherapy
Matrix Stiffness-Regulated Growth of Breast Tumo Spheroids and Their Response to Chemotherapy
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DOI：
10.1021/acs.biomac.0c01287
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发表时间：
2021-02-01
影响因子：
6.2
通讯作者：
Kumacheva, Eugenia
中科院分区：
文献类型：
--
作者：
Li, Yunfeng;Khuu, Nancy;Kumacheva, Eugenia
肿瘤细胞与细胞外基质（ECM）之间的相互作用是导致肿瘤患者治疗失败的重要因素。目前的体外乳腺癌球体模型考察了力学特性对化疗球体反应的作用，但由于使用二维细胞培养，以及水凝胶基质刚度和其他特性（如水凝胶组成、孔径和细胞粘附配体密度）的同时变化，这些模型受到了限制。此外，目前使用的水凝胶基质不能在乳腺肿瘤微环境中复制丝状ECM结构。在这里，我们报道了一种胶原-海藻酸盐水凝胶，具有丝状结构和20倍的硬度变化，独立于其他特性，用于评估雌激素受体阳性乳腺癌对阿霉素的球形反应。水凝胶力学性能的变化是通过改变海藻酸盐分子的交联程度来实现的。我们发现，软水凝胶促进了更大的MCF-7肿瘤球体的生长，增殖细胞的比例更低，并增强了球体对阿霉素的耐药性。值得注意的是，椭球体的硬度依赖性化疗反应是暂时介导的：在足够长的细胞培养时间内，当基质硬度影响椭球体生长时，它变得明显。这些发现突出了将基质刚度与其他特征解耦在肿瘤球体化疗耐药研究和药物筛选平台开发中的重要性。
Interactions between tumor cells and the extracellular matrix (ECM) are an important factor contributing to therapy failure in cancer patients. Current in vitro breast cancer spheroid models examining the role of mechanical properties on spheroid response to chemotherapy are limited by the use of two-dimensional cell culture, as well as simultaneous variation in hydrogel matrix stiffness and other properties, e.g., hydrogel composition, pore size, and cell adhesion ligand density. In addition, currently used hydrogel matrices do not replicate the filamentous ECM architecture in a breast tumor microenvironment. Here, we report a collagen-alginate hydrogel with a filamentous architecture and a 20-fold variation in stiffness, achieved independently of other properties, used for the evaluation of estrogen receptor-positive breast cancer spheroid response to doxorubicin. The variation in hydrogel mechanical properties was achieved by altering the degree of cross-linking of alginate molecules. We show that soft hydrogels promote the growth of larger MCF-7 tumor spheroids with a lower fraction of proliferating cells and enhance spheroid resistance to doxorubicin. Notably, the stiffness-dependent chemotherapeutic response of the spheroids was temporally mediated: it became apparent at sufficiently long cell culture times, when the matrix stiffness has influenced the spheroid growth. These findings highlight the significance of decoupling matrix stiffness from other characteristics in studies of chemotherapeutic resistance of tumor spheroids and in development of drug screening platforms.