Engineering a Vascularized Hypoxic Tumor Model for Therapeutic Assessment.
Engineering a Vascularized Hypoxic Tumor Model for Therapeutic Assessment.
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作者：
Ando Y;Oh JM;Zhao W;Tran M;Shen K
晚期癌症中的实体瘤通常通过肿瘤血管生成而出现结构和功能异常的脉管系统，这有助于癌症进展、转移和治疗抵抗。缺氧被认为是肿瘤微环境中血管生成的主要驱动因素。然而，仍然缺乏在同一模型中重现脉管系统和缺氧且与肿瘤微环境生理相似的体外模型，同时允许进行高内涵时空分析以进行机制研究和治疗评估。我们之前构建了一种缺氧微装置，它利用癌细胞的新陈代谢在癌细胞层中产生氧气梯度，如实体瘤切片中所见。在这里，我们设计了一种新的复合微器件-微流体平台，可以概括血管化缺氧肿瘤。将内皮细胞接种到由粘性指法形成的胶原通道中，以产生围绕缺氧肿瘤部分的圆形血管腔，该缺氧肿瘤部分由嵌入 3-D 水凝胶细胞外基质中的癌细胞组成。我们证明，新设备可以与基于显微镜的高内涵分析一起使用，以跟踪血管表型、形态和在 7 天培养中向缺氧肿瘤切片的发芽，以及对不同癌症/基质细胞的反应。我们进一步评估了分子递送中血管腔的完整性/渗漏性，以及该平台研究治疗性免疫细胞的运动/运输的潜力。因此，我们的新平台可以用作了解血管缺氧肿瘤中肿瘤血管生成和治疗递送/功效的模型。
Solid tumors in advanced cancer often feature a structurally and functionally abnormal vasculature through tumor angiogenesis, which contributes to cancer progression, metastasis, and therapeutic resistances. Hypoxia is considered a major driver of angiogenesis in tumor microenvironments. However, there remains a lack of in vitro models that recapitulate both the vasculature and hypoxia in the same model with physiological resemblance to the tumor microenvironment, while allowing for high-content spatiotemporal analyses for mechanistic studies and therapeutic evaluations. We have previously constructed a hypoxia microdevice that utilizes the metabolism of cancer cells to generate an oxygen gradient in the cancer cell layer as seen in solid tumor sections. Here, we have engineered a new composite microdevice-microfluidics platform that recapitulates a vascularized hypoxic tumor. Endothelial cells were seeded in a collagen channel formed by viscous fingering, to generate a rounded vascular lumen surrounding a hypoxic tumor section composed of cancer cells embedded in a 3-D hydrogel extracellular matrix. We demonstrated that the new device can be used with microscopy-based high-content analyses to track the vascular phenotypes, morphology, and sprouting into the hypoxic tumor section over a 7-day culture, as well as the response to different cancer/stromal cells. We further evaluated the integrity/leakiness of the vascular lumen in molecular delivery, and the potential of the platform to study the movement/trafficking of therapeutic immune cells. Therefore, our new platform can be used as a model for understanding tumor angiogenesis and therapeutic delivery/efficacy in vascularized hypoxic tumors.
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DOI：
10.1039/c3ib40170g
发表时间：
2014-06
期刊：
Integrative biology : quantitative biosciences from nano to macro
影响因子：
--
作者：
Ehsan SM;Welch-Reardon KM;Waterman ML;Hughes CC;George SC
通讯作者：
George SC
影响因子：
4.6
作者：
Egawa, Gyohei;Nakamizo, Satoshi;Natsuaki, Yohei;Doi, Hiromi;Miyachi, Yoshiki;Kabashima, Kenji
通讯作者：
Kabashima, Kenji
I型I型与人纤连蛋白的胶原蛋白相互作用的结构分析揭示了一种合作结合模式。
DOI：
10.1074/jbc.m113.469841
发表时间：
2013-06-14
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Erat MC;Sladek B;Campbell ID;Vakonakis I
通讯作者：
Vakonakis I
影响因子：
7.5
作者：
Harris ES;Nelson WJ
通讯作者：
Nelson WJ
影响因子：
16.6
作者：
Gao, Tao;Mirzadeh, Mohammad;Bazant, Martin Z.
通讯作者：
Bazant, Martin Z.