Creating a 3D dynamic in vitro model of the tumor microenvironment to characteriz

创建肿瘤微环境的 3D 动态体外模型来表征

• 批准号: 8514928
• 负责人: Luis Fernando Alonzo
• 金额: $ 3.57万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8514928
• 关键词: Address; Angiogenic Factor; Behavior; Blood; Blood Circulation; Blood Vessels; Blood capillaries; Cell Adhesion Molecules; Cell Line; Cells; Clinical; Coculture Techniques; Colon Adenocarcinoma; Data Reporting; Development; Devices; Diffusion; Disease; Disease Management; Down-Regulation; E-Cadherin; Endothelial Cells; Environment; Epithelial; Equilibrium; Fellowship; Fibroblasts; Genome; Goals; Growth; Growth Factor; Human; In Vitro; Inflammation; Lead; Leukocytes; Ligands; Macrophage Colony-Stimulating Factor; Malignant Neoplasms; Mesenchymal; Microfluidics; Modeling; Neoplasm Metastasis; Normal Cell; Nutrient; Outcome; Oxygen; Phenotype; Physiologic Neovascularization; Physiological; Physiology; Play; Preclinical Drug Evaluation; Process; Recruitment Activity; Relative (related person); Reporting; Reproduction; Research Training; Role; Site; System; Technology; Therapeutic; Tissue Engineering; Tissue Model; Tumor Cell Invasion; Tumor Necrosis Factor-alpha; Tumor-Associated Process; Work; Wound Healing; Xenograft Model; Xenograft procedure; angiogenesis; beta-Chemokines; cancer cell; cancer therapy; capillary; capillary bed; cell motility; chemokine; density; design; human TNF protein; in vitro Model; in vivo; interest; macrophage; monocyte; neoplastic cell; research study; three-dimensional modeling; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): Inflammation is widely recognized to play a central role in the initiation and progression of tumor malignancy. Circulating macrophages are recruited by tumor cells through the secretion of soluble factors such as colony stimulating factor-1 (CSF-1) and C-C chemokine ligand 2 (CCL- 2). Through these mechanisms the macrophages are coerced to acquire a trophic phenotype accompanied by the release of soluble factors which promote angiogenesis, tumor cell invasion, and intravasation. Of particular interest is TAM-derived tumor necrosis factor-alpha (TNF-), which is believed to cause the downregulation of cell adhesion molecules (e.g. E-cadherin) in tumor cells, increasing cell motility and entry into the circulation. Understanding of such relationship is key for the design of anti-metastatic therapeutics. However, much of the data reported in this field has been performed in xenograft models and/or 2D cultures; which are limited by the number of controllable variables, extrapolation to human tumor physiology, and not amenable for a high-throughput design. In this proposed research training fellowship, the goal is to create an optimal in vitro model to study the tumor microenvironment. The first aim seeks to gain a better understanding of the behavior of tumor cells, endothelial cells, and TAMs in a 2D environment through an array of classical co-culture experiments. Results of this aim will generate relevant design parameters which will be implemented in the second aim of this project, which combines principles of microfluidics with tissue engineering to create a 3D tissue model of the tumor microenvironment with perfused human capillaries. This model will be able to replicate the physiology of the in vivo tumor microenvironment; thus providing relevant physiological results. Most importantly, the impact of creating an in vitro 3D metastasis model with perfused human capillary bed could significantly enhance high-throughput anti-metastatic drug screening.

描述(由申请人提供)：炎症被广泛认为在肿瘤恶性肿瘤的发生和发展中起着中心作用。肿瘤细胞通过分泌集落刺激因子-1(CSF-1)和C-C趋化因子配体2(CCL-2)等可溶性因子来募集循环中的巨噬细胞。通过这些机制，巨噬细胞被迫获得一种营养表型，同时伴随着促进血管生成、肿瘤细胞侵袭和血管内皮细胞生长的可溶性因子的释放。尤其令人感兴趣的是衍生的肿瘤坏死因子-α，它被认为能导致肿瘤细胞中细胞黏附分子(如E-钙粘附素)的下调，增加细胞的运动性和进入循环。了解这种关系是设计抗转移治疗药物的关键。然而，该领域报道的许多数据都是在异种移植模型和/或2D培养中进行的；这些数据受到可控变量数量的限制，外推到人类肿瘤生理学，不适合高通量设计。在这项拟议的研究培训奖学金中，目标是创建一个最佳的体外模型来研究肿瘤微环境。第一个目标是通过一系列经典的共培养实验，寻求更好地了解肿瘤细胞、内皮细胞和TAM在2D环境中的行为。这一目标的结果将产生相关的设计参数，这些参数将在本项目的第二个目标中实施，该目标将微流体原理与组织工程相结合，创建具有灌流的人体毛细血管的肿瘤微环境的3D组织模型。该模型将能够复制体内肿瘤微环境的生理学，从而提供相关的生理学结果。最重要的是，使用灌流的人体毛细血管床建立体外三维转移模型的影响可以显著提高高通量抗转移药物的筛选。