Three-Dimensional Breast Cancer Models Mimic Hallmarks of Size-Induced Tumor Progression.
Three-Dimensional Breast Cancer Models Mimic Hallmarks of Size-Induced Tumor Progression.
复制标题
DOI：
10.1158/0008-5472.can-15-2304
复制
发表时间：
2016-07-01
期刊：
影响因子：
11.2
通讯作者：
Sant S
中科院分区：
文献类型：
--
作者：
Singh M;Mukundan S;Jaramillo M;Oesterreich S;Sant S
肿瘤大小与乳腺癌转移和患者生存密切相关。肿瘤大小的增加导致实体瘤中的缺氧和代谢梯度以及侵袭性肿瘤表型。因此，开发三维（3D）乳腺肿瘤模型非常重要，该模型可以在不使用人工培养条件或基因操作的情况下实时重现大小引起的微环境变化，从而实现肿瘤的自然进展。在这里，我们通过使用规定尺寸（150-600 μm）的非粘附性聚乙二醇二甲基丙烯酸酯水凝胶微孔，开发了亚型特异性乳腺癌细胞的尺寸控制的多细胞聚集体（“微肿瘤”）。这些 3D 微肿瘤模型忠实地代表了尺寸引起的微环境变化，例如缺氧梯度、细胞异质性和坏死/增殖细胞的空间分布。这些微肿瘤在 6 天内在相同的细胞系中获得肿瘤进展的标志。值得注意的是，激素受体阳性细胞的大微肿瘤表现出侵袭性表型，其特征是集体细胞迁移和 mRNA 和蛋白质水平的间充质标记物上调，而在小微肿瘤中没有观察到这种情况。有趣的是，三阴性乳腺癌（TNBC）细胞系没有表现出间充质标志物大小依赖性的上调。总之，大小控制的微肿瘤模型成功地重现了临床观察到的激素受体阳性乳腺癌中肿瘤大小与侵袭性表型之间的正相关性，同时保持了临床证明的 TNBC 中肿瘤大小与侵袭性表型之间的不良相关性。这种在受控实验条件下生成的临床相关 3D 模型可以作为精确的临床前模型来研究乳腺肿瘤进展的机制以及作为肿瘤进展函数的抗肿瘤药物作用。
Tumor size is strongly correlated with breast cancer metastasis and patient survival. Increased tumor size contributes to hypoxic and metabolic gradients in the solid tumor and to an aggressive tumor phenotype. Thus, it is important to develop three-dimensional (3D) breast tumor models that recapitulate size-induced microenvironmental changes and consequently, natural tumor progression in real time without the use of artificial culture conditions or gene manipulations. Here, we developed size-controlled multicellular aggregates (“microtumors”) of subtype-specific breast cancer cells by using non-adhesive polyethylene glycol dimethacrylate hydrogel microwells of defined sizes (150–600 μm). These 3D microtumor models faithfully represent size-induced microenvironmental changes such as hypoxic gradients, cellular heterogeneity and spatial distribution of necrotic/proliferating cells. These microtumors acquire hallmarks of tumor progression in the same cell lines within 6 days. Of note, large microtumors of hormone receptor positive cells exhibited an aggressive phenotype characterized by collective cell migration and upregulation of mesenchymal markers at mRNA and protein level, which was not observed in small microtumors. Interestingly, triple negative breast cancer (TNBC) cell lines did not show size-dependent upregulation of mesenchymal markers. In conclusion, size-controlled microtumor models successfully recapitulated clinically observed positive association between tumor size and aggressive phenotype in hormone receptor positive breast cancer while maintaining clinically proven poor correlation of tumor size with aggressive phenotype in TNBC. Such clinically relevant 3D models generated under controlled experimental conditions can serve as precise preclinical models to study mechanisms involved in breast tumor progression as well as antitumor drug effects as a function of tumor progression.