Engineered Breast Cancer Cell Spheroids Reproduce Biologic Properties of Solid Tumors.
Engineered Breast Cancer Cell Spheroids Reproduce Biologic Properties of Solid Tumors.
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DOI：
10.1002/adhm.201600644
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发表时间：
2016-11
影响因子：
10
通讯作者：
Tavana, Hossein
中科院分区：
文献类型：
--
作者：
Ham, Stephanie L.;Joshi, Ramila;Luker, Gary D.;Tavana, Hossein
实体瘤发展为三维组织结构。随着肿瘤变大，营养物和氧气的空间梯度以及远离脉管系统的细胞的扩散供应不足会出现。缺氧会启动信号传导和转录改变，以促进癌细胞的存活和具有自我更新和肿瘤启动能力的癌症干细胞（CSC）的生成。缺氧和 CSC 都与治疗抵抗和肿瘤复发有关。在这里，我们进行了一项系统研究，以证明通过聚合物水性两相系统 (ATPS) 技术生成的 3D 癌细胞模型（称为肿瘤球体）能够捕获这些重要的生物过程。与实体瘤类似，三阴性乳腺癌 (TNBC) 细胞的球体沉积主要的细胞外基质蛋白。我们的分子分析确定了核心区域存在缺氧细胞，并且 CSC 基因和蛋白质标记物（包括 CD24、CD133 和 Nanog）表达。重要的是，这些球体对化疗药物有抵抗力。我们通过使用缺氧激活的前药 TH-302 和化疗药物阿霉素的联合治疗方法，成功地靶向耐药球体。这项研究表明，ATPS 球体概括了实体瘤的重要生物学和功能特性，并为癌症研究提供了独特的模型。采用水性两相系统技术（上左）以较大密度形成的三维癌症球体再现了关键的生物学特性，例如胶原蛋白 I 表达（上右）、仅外部细胞的密度依赖性增殖（下左）以及与耐药性和癌症干细胞特性相关的内核缺氧（下右）。
Solid tumors develop as three-dimensional tissue constructs. As tumors grow larger, spatial gradients of nutrients and oxygen and inadequate diffusive supply to cells distant from vasculature develops. Hypoxia initiates signaling and transcriptional alterations to promote survival of cancer cells and generation of cancer stem cells (CSCs) that have self-renewal and tumor-initiation capabilities. Both hypoxia and CSCs are associated with resistance to therapies and tumor relapse. Here, we conduct a systematic study to demonstrate that 3D cancer cell models, known as tumor spheroids, generated with a polymeric aqueous two-phase system (ATPS) technology capture these important biological processes. Similar to solid tumors, spheroids of triple negative breast cancer (TNBC) cells deposit major extracellular matrix proteins. Our molecular analysis establishes presence of hypoxic cells in the core region and expression of CSC gene and protein markers including CD24, CD133, and Nanog. Importantly, these spheroids resist treatment with chemotherapy drugs. We successfully target drug resistant spheroids through a combination treatment approach using a hypoxia-activated prodrug, TH-302, and a chemotherapy drug, doxorubicin. This study demonstrates that ATPS spheroids recapitulate important biological and functional properties of solid tumors and provide a unique model for studies in cancer research. Three dimensional cancer spheroids formed with the aqueous two phase system technology (top, left) at a larger density reproduce key biological properties such as collagen I expression (top, right), density dependent proliferation of only outer cells (bottom, left), and inner core hypoxia (bottom, right) that correlate with drug resistance and cancer stem cell properties.
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影响因子：
3.7
作者：
El Guerrab A;Zegrour R;Nemlin CC;Vigier F;Cayre A;Penault-Llorca F;Rossignol F;Bignon YJ
通讯作者：
Bignon YJ
影响因子：
2.6
作者：
Huebschman, Michael L.;Lane, Nancy L.;Frenkel, Eugene P.
通讯作者：
Frenkel, Eugene P.
影响因子：
1.2
作者：
Ham, Stephanie Lemmo;Atefi, Ehsan;Tavana, Hossein
通讯作者：
Tavana, Hossein
影响因子：
5.5
作者：
Boisserie-Lacroix, M;Mac Grogan, G;Hurtevent-Labrot, G
通讯作者：
Hurtevent-Labrot, G
影响因子：
5.3
作者：
Goda, N;Ryan, HE;Johnson, RS
通讯作者：
Johnson, RS