3D culture broadly regulates tumor cell hypoxia response and angiogenesis via pro-inflammatory pathways.
3D culture broadly regulates tumor cell hypoxia response and angiogenesis via pro-inflammatory pathways.
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DOI：
10.1016/j.biomaterials.2015.03.035
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发表时间：
2015-07
期刊：
影响因子：
14
通讯作者：
Fischbach C
中科院分区：
文献类型：
--
作者：
DelNero P;Lane M;Verbridge SS;Kwee B;Kermani P;Hempstead B;Stroock A;Fischbach C
氧状态和组织维度是肿瘤血管生成的关键决定因素，是癌症的标志和治疗干预的持久目标。然而，目前还不清楚这些微环境条件如何相互作用，以促进新血管形成，部分原因是缺乏全面的，公正的数据集，描述肿瘤细胞基因表达作为三维（3D）培养中氧水平的函数。在这里，我们利用基于藻酸盐的氧气控制的3D肿瘤模型来研究培养环境和缺氧反应的相互依赖性。微阵列基因表达分析的肿瘤细胞培养在2D与3D环境或缺氧条件下揭示了显着的相互依赖性之间的文化维度和缺氧反应，这是介导的促炎信号通路的一部分。特别是，白细胞介素-8（IL-8）成为低氧程序微环境调节的主要参与者。值得注意的是，在3D内皮侵袭测定中，维度和氧状态之间经由IL-8的这种相互作用增加了血管生成发芽。总之，我们的数据表明，促炎途径是3D环境中肿瘤缺氧反应的关键调节因子，最终影响肿瘤血管生成，可能提供重要的治疗靶点。此外，这些结果强调了病理相关的组织培养模型的重要性，以研究癌症微环境介导新血管形成的复杂物理和化学过程。
Oxygen status and tissue dimensionality are critical determinants of tumor angiogenesis, a hallmark of cancer and an enduring target for therapeutic intervention. However, it is unclear how these microenvironmental conditions interact to promote neovascularization, due in part to a lack of comprehensive, unbiased data sets describing tumor cell gene expression as a function of oxygen levels within three-dimensional (3D) culture. Here, we utilized alginate-based, oxygen-controlled 3D tumor models to study the interdependence of culture context and the hypoxia response. Microarray gene expression analysis of tumor cells cultured in 2D versus 3D under ambient or hypoxic conditions revealed striking interdependence between culture dimensionality and hypoxia response, which was mediated in part by pro-inflammatory signaling pathways. In particular, interleukin-8 (IL-8) emerged as a major player in the microenvironmental regulation of the hypoxia program. Notably, this interaction between dimensionality and oxygen status via IL-8 increased angiogenic sprouting in a 3D endothelial invasion assay. Taken together, our data suggest that pro-inflammatory pathways are critical regulators of tumor hypoxia response within 3D environments that ultimately impact tumor angiogenesis, potentially providing important therapeutic targets. Furthermore, these results highlight the importance of pathologically relevant tissue culture models to study the complex physical and chemical processes by which the cancer microenvironment mediates new vessel formation.
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