3D Microtissue Models to Analyze the Effects of Ultralow Dose LPS on Vascular Sprouting Dynamics in the Tumor Microenvironment.
3D Microtissue Models to Analyze the Effects of Ultralow Dose LPS on Vascular Sprouting Dynamics in the Tumor Microenvironment.
复制标题
3D 微组织模型分析超低剂量 LPS 对肿瘤微环境中血管萌芽动力学的影响。
DOI：
10.1021/acsbiomaterials.6b00800
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发表时间：
2018
影响因子：
5.8
通讯作者：
Verbridge,ScottS
中科院分区：
文献类型：
--
作者：
Cox,MeganC;Kuliasha,AndreaS;Li,Liwu;Verbridge,ScottS
脂多糖（LPS）在先天免疫应答中起主要作用，并且已经显示当以高浓度存在时影响血管动力学。然而，在慢性炎症状态期间存在于体内的超低水平的LPS（<100 pg/mL）对血管动力学的影响尚不清楚。在这项研究中，我们将3D胶原蛋白水凝胶组织模拟与先进的成像和细胞表征分析相结合，以评估慢性炎症对血管动力学的潜在影响，并揭示在肿瘤进展的背景下血管对低剂量与高剂量LPS的反应的任何改变。考虑到芽的发芽频率和侵袭性，用血管内皮生长因子（VEGF）（一种有效的血管生成促进剂，在肿瘤微环境中过量存在）处理超低剂量LPS，可增强人脑微血管内皮细胞的血管发育（HBMEC）在我们的体外模型中。在不同的VEGF治疗组中没有证据表明增殖或凋亡发生改变，表明暴露于超低剂量LPS和VEGF导致迁移性内皮细胞表型增强。在VEGF存在的情况下，高剂量LPS处理后缺乏增强的血管发育可能部分归因于NF-κB活化的LPS剂量依赖性增加。这项研究提供了通过不同水平的LPS对血管发育的动态调节以及慢性炎症在引发促血管生成微环境和促进肿瘤进展中的潜在作用的见解。
Lipopolysaccharide (LPS) plays a major role in innate immune responses and has been shown to impact vascular dynamics when present at high concentrations. However, the impact of ultralow levels of LPS (<100 pg/mL), present in the body during states of chronic inflammation, on vascular dynamics is unclear. In this study, we have integrated a 3D collagen hydrogel tissue mimic with advanced imaging and cell characterization assays to assess the potential impact of chronic inflammation on vascular dynamics, and uncover any alterations in the vascular response to low vs high dose LPS in the context of tumor progression. Accounting for both frequency of sprouting and invasiveness of the sprouts, the treatments of ultralow dose LPS with vascular endothelial growth factor (VEGF), a potent angiogenic promoter and present in excess in the tumor microenvironment, produced enhanced vascular development of human brain microvascular endothelial cells (HBMECs) in our in vitro model. There was no evidence of altered proliferation or apoptosis among the various VEGF treatment groups, indicating an enhanced migratory endothelial cell phenotype results from exposure to ultralow dose LPS with VEGF. The lack of enhanced vascular development upon treatments of high doses of LPS in the presence of VEGF could be partially attributed to an LPS dose-dependent increase in the activation of NF-κB. This study provides insight into the dynamic regulation of vascular development by varying levels of LPS and the potential role of chronic inflammation to prime a pro-angiogenic microenvironment and contribute to tumor progression.