Development of a Vascularized In-Vitro Model of the Tumor Microenvironment

描述(由申请人提供)：对肿瘤微环境的研究有望为癌症的治疗带来开创性的策略。不幸的是，由于缺乏现有的模型来概括3D体外环境中肿瘤细胞、间质和血管系统之间的相互作用的关键特征，这项研究的进展受到了阻碍。国家癌症研究所已将这类模型的开发确定为高度优先事项。该项目的长期目标是开发一种肿瘤微环境的血管化体外模型。该模型的基本组件是一个一次性的、灌流的微流体设备，该设备的观察室中充满了细胞外基质凝胶。管状通道是在凝胶中创建的，内皮细胞被引入其中以形成亲本血管。亲本血管具有新生血管萌发和形成毛细血管样网络的能力。流体装置的设计允许工程血管和芽的直接管腔灌流。癌细胞可以以不同的方式整合到这个模型中，用于研究转移、肿瘤血管生成和癌症治疗药物的筛选。在其商业版本中，该系统将是独立的，包括流体泵、生长介质储存库、传感器和一系列微流控设备。目标1将专注于用于体外肿瘤微环境模型的商业可行装置的微制造和质量控制测试。所有设备的特点将是它们创造可灌流的母体血管和相关的血管新生芽的能力。目的2将建立该设备用于研究外渗，外渗是癌细胞突破血管内皮细胞衬里形成转移的过程。外渗量将被测量为突破血管萌芽进入细胞外基质的癌细胞数量。两种不同转移潜能的前列腺癌细胞系将与正常的前列腺癌细胞系进行比较。这些研究的成功完成代表着朝着开发新一代肿瘤微环境模型迈出的重要一步，该模型可以标准化，并可供学术界和工业界的广大研究人员商业化使用。 公共卫生相关性：对肿瘤生长和扩散的特定器官环境的研究对于开发新的癌症疗法至关重要。不幸的是，由于缺乏可用的研究工具，进展受到了阻碍。我们建议开发一种模拟自然肿瘤环境的模型，包括灌流的血管和毛细血管。我们希望我们的模型成为癌症研究中的一个有价值的系统，供学术界和工业界的科学家商业化使用。

DESCRIPTION (provided by applicant): The study of the tumor microenvironment promises to lead to groundbreaking strategies for the therapy of cancer. Unfortunately, progress of this research is impaired by the lack of available models that recapitulate key features of the interaction between tumor cells, stroma, and vasculature in a 3D in-vitro environment. The National Cancer Institute has identified the development of such models as a high priority. The long-term objective of this project is the development of a vascularized in-vitro model of the tumor microenvironment. The basic components of this model are a disposable, perfused microfluidic device with a viewing chamber filled with an extracellular-matrix gel. Tubular channels are created within the gel into which endothelial cells are introduced to form parent vessels. The parent vessels are capable of angiogenic sprouting and the formation of capillary-like networks. The design of the fluidic device allows for direct luminal perfusion of the engineered vessels and sprouts. Cancer cells can be integrated into this model in various ways for studies including metastasis, tumor-angiogenesis, and the screening of cancer therapeutics. In its commercial version, the system will be self-contained, comprising fluidic pumps, reservoirs for growth medium, sensors, and an array of microfluidic devices. Aim 1 will focus on the microfabrication and quality-control testing of a commercially-viable device for an in-vitro tumor microenvironment model. All devices will be characterized for their ability to create perfusable parent vessels and the associated angiogenic sprouts. Aim 2 will establish the utility of the device for the study of extravasation, which is the process of cancer cells breaking through the endothelial lining of the vasculature to form metastases. Extravasation will be measured as the number of cancer cells which break through the vascular sprouts into the extracellular matrix. Two prostate-cancer cell lines of different metastatic potential will be compared to a normal prostate cell line. The successful completion of these studies presents an important step toward the development of a new generation of tumor- microenvironment models that can be standardized and made commercially available to a broad community of researcher in academia and industry. PUBLIC HEALTH RELEVANCE: The study of the organ-specific environment in which tumors grow and spread is crucial for developing new cancer therapeutics. Unfortunately, progress is impaired by the lack of available research tools. We propose the development of a model that mimics the natural tumor environment, including perfused blood vessels and capillaries. We expect our model to become a valuable system in cancer research, commercially available to scientists in academia and industry.