3D in vitro bioengineered tumors based on collagen I hydrogels.
3D in vitro bioengineered tumors based on collagen I hydrogels.
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DOI：
10.1016/j.biomaterials.2011.07.001
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发表时间：
2011-11
期刊：
影响因子：
14
通讯作者：
Rylander, Marissa N.
中科院分区：
文献类型：
--
作者：
Szot, Christopher S.;Buchanan, Cara F.;Freeman, Joseph W.;Rylander, Marissa N.
在三维（3D）体外环境中培养的细胞具有获得表型和响应类似于体内生物系统的刺激的能力。这种方法已被用于组织工程，也可以应用于生理相关的体外肿瘤模型的开发。在这项研究中，用MDA-MB-231人乳腺癌细胞培养的I型胶原水凝胶作为体外实体瘤发展的生物工程平台。在3D水凝胶结构中，体内组织进展过程中存在的细胞-细胞和细胞-基质相互作用得到了促进，胶原蛋白的生物相容性支持无限制的细胞增殖。在体外生物工程肿瘤中，坏死深度超过150 ~ 200 μm，缺氧诱导因子(HIF)-1α表达明显。氧和营养物质通过I型胶原基质的扩散限制以及对可用营养物质的竞争导致细胞内缺氧水平的增加，HIF-1α基因表达的上调有统计学意义（p < 0.01）。生物工程肿瘤也显示出良好的血管生成潜力，血管内皮生长因子(VEGF)-A基因表达上调具有统计学意义（p < 0.001）。此外，可比较的基因表达分析表明，与在二维组织培养聚苯乙烯上单层培养的细胞相比，在3D胶原I水凝胶中培养的MDA-MB-231细胞的HIF-1α和VEGF-A的表达有统计学意义（p < 0.05）。本研究的结果表明，I型胶原水凝胶能够促进3D体外生物工程肿瘤的发展，这些肿瘤代表了体内实体肿瘤进展的血管化前阶段。
Cells cultured within a three-dimensional (3D) in vitro environment have the ability to acquire phenotypes and respond to stimuli analogous to in vivo biological systems. This approach has been utilized in tissue engineering and can also be applied to the development of a physiologically relevant in vitro tumor model. In this study, collagen I hydrogels cultured with MDA-MB-231 human breast cancer cells were bioengineered as a platform for in vitro solid tumor development. The cell–cell and cell-matrix interactions present during in vivo tissue progression were encouraged within the 3D hydrogel architecture, and the biocompatibility of collagen I supported unconfined cellular proliferation. The development of necrosis beyond a depth of ~150–200 μm and the expression of hypoxia-inducible factor (HIF)-1α were demonstrated in the in vitro bioengineered tumors. Oxygen and nutrient diffusion limitations through the collagen I matrix as well as competition for available nutrients resulted in growing levels of intra-cellular hypoxia, quantified by a statistically significant (p < 0.01) upregulation of HIF-1α gene expression. The bioengineered tumors also demonstrated promising angiogenic potential with a statistically significant (p < 0.001) upregulation of vascular endothelial growth factor (VEGF)-A gene expression. In addition, comparable gene expression analysis demonstrated a statistically significant increase of HIF-1α (p < 0.05) and VEGF-A (p < 0.001) by MDA-MB-231 cells cultured in the 3D collagen I hydrogels compared to cells cultured in a monolayer on two-dimensional tissue culture polystyrene. The results presented in this study demonstrate the capacity of collagen I hydrogels to facilitate the development of 3D in vitro bioengineered tumors that are representative of the pre-vascularized stages of in vivo solid tumor progression.
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