A three-dimensional (3D) organotypic microfluidic model for glioma stem cells - Vascular interactions.
A three-dimensional (3D) organotypic microfluidic model for glioma stem cells - Vascular interactions.
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DOI：
10.1016/j.biomaterials.2018.07.048
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发表时间：
2019-04
期刊：
影响因子：
14
通讯作者：
Nikkhah M
中科院分区：
文献类型：
--
作者：
Truong D;Fiorelli R;Barrientos ES;Melendez EL;Sanai N;Mehta S;Nikkhah M
胶质母细胞瘤(GBM)是最致命的癌症之一。尽管有许多治疗方法，但GBM的预后仍然很差，5年生存率为4.7%。即便如此，肿瘤在治疗后往往会复发。肿瘤复发被认为是由胶质瘤干细胞(GSC)群体驱动的，GSC群体具有高度的致瘤性、侵袭性和对多种形式的治疗耐药。GSC通常集中在肿瘤血管周围，称为血管壁龛，已知为维持GSC干性、促进侵袭和抵抗治疗提供微环境线索。在这项工作中，我们开发了一个3D器官型微流控平台，与基于水凝胶的生物材料相结合，模拟GSC血管生态位，研究内皮细胞对患者来源GSC行为的影响，并识别介导其侵袭和表型的信号线索。建立的微血管网络促进了GSC在3D水凝胶中的迁移，促进了侵袭形态，并保持了GSC的增殖率和表型(Nestin，SOX2，CD44)。值得注意的是，我们将迁移行为与体内小鼠模型进行了比较，发现了类似的侵袭形态，这表明我们的微流体系统可能代表了体内生理上相关的微环境。此外，我们利用CXCR4拮抗剂(AMD3100)证实了CXCL12-CXCR4信号参与了3D血管微环境中促进GSC侵袭的过程，同时也证明了微流体作为药物筛选实验的有效性。我们的模型提供了一个潜在的体外平台，用于研究GSC与其周围微环境的相互作用，以及开发未来的治疗策略，以破坏GSC调控机制中涉及的关键分子途径。
Glioblastoma (GBM) is one of the deadliest forms of cancer. Despite many treatment options, prognosis of GBM remains dismal with a 5-year survival rate of 4.7%. Even then, tumors often recur after treatment. Tumor recurrence is hypothesized to be driven by glioma stem cell (GSC) populations which are highly tumorigenic, invasive, and resistant to several forms of therapy. GSCs are often concentrated around the tumor vasculature, referred to as the vascular niche, which are known to provide microenvironmental cues to maintain GSC stemness, promote invasion, and resistance to therapies. In this work, we developed a 3D organotypic microfluidic platform, integrated with hydrogel-based biomaterials, to mimic the GSC vascular niche and study the influence of endothelial cells (ECs) on patient-derived GSC behavior and identify signaling cues that mediate their invasion and phenotype. The established microvascular network enhanced GSC migration within a 3D hydrogel, promoted invasive morphology as well as maintained GSC proliferation rates and phenotype (Nestin, SOX2, CD44). Notably, we compared migration behavior to in vivo mice model and found similar invasive morphology suggesting that our microfluidic system could represent a physiologically relevant in vivo microenvironment. Moreover, we confirmed that CXCL12-CXCR4 signaling is involved in promoting GSC invasion in a 3D vascular microenvironment by utilizing a CXCR4 antagonist (AMD3100), while also demonstrating the effectiveness of the microfluidic as a drug screening assay. Our model presents a potential ex vivo platform for studying the interplay of GSCs with its surrounding microenvironment as well as development of future therapeutic strategies tailored toward disrupting key molecular pathways involved in GSC regulatory mechanisms.
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