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

描述（由申请人提供）：肿瘤微环境的研究有望为癌症治疗带来突破性的策略。不幸的是，由于缺乏能够概括肿瘤细胞、基质和血管系统在三维体外环境中相互作用的关键特征的可用模型，这项研究的进展受到了损害。美国国家癌症研究所（National Cancer Institute）已将这类模型的开发列为重中之重。该项目的长期目标是建立一个血管化的体外肿瘤微环境模型。该模型的基本组成部分是一个一次性的、灌注的微流体装置，带有一个充满细胞外基质凝胶的观察室。在凝胶内形成管状通道，内皮细胞被引入其中形成母血管。母血管能够新生发芽并形成毛细血管样网络。流体装置的设计允许对工程血管和芽进行直接腔内灌注。癌细胞可以通过各种方式整合到这个模型中，用于研究包括转移、肿瘤血管生成和癌症治疗方法的筛选。在其商业版本中，该系统将是独立的，包括流体泵，生长介质储存器，传感器和一系列微流体装置。目标1将侧重于商业上可行的体外肿瘤微环境模型设备的微制造和质量控制测试。所有设备的特点是能够产生可灌注的母血管和相关的血管新生芽。目的2将建立该装置在外渗研究中的实用性，外渗是癌细胞突破血管内皮形成转移的过程。外渗是指癌细胞冲破血管芽进入细胞外基质的数量。将两种具有不同转移潜能的前列腺癌细胞系与正常前列腺细胞系进行比较。这些研究的成功完成向新一代肿瘤微环境模型的发展迈出了重要的一步，这些模型可以标准化，并为学术界和工业界的广泛研究人员提供商业服务。

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.