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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

基本信息

批准号：
8548109
负责人：
Luis Fernando Alonzo
金额：
$ 3.63万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
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/8548109
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 microenvironment tumor progression

项目摘要

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）：人们普遍认为炎症在肿瘤恶性肿瘤的发生和进展中发挥着核心作用。肿瘤细胞通过分泌可溶性因子（例如集落刺激因子-1 (CSF-1) 和 C-C 趋化因子配体 2 (CCL-2)）来招募循环巨噬细胞。通过这些机制，巨噬细胞被迫获得营养表型，同时释放可促进血管生成、肿瘤细胞侵袭和内渗的可溶性因子。特别令人感兴趣的是 TAM 衍生的肿瘤坏死因子-α (TNF-)，它被认为会导致肿瘤细胞中细胞粘附分子（例如 E-钙粘蛋白）的下调，从而增加细胞运动性并进入循环。了解这种关系是设计抗转移疗法的关键。然而，该领域报告的大部分数据都是在异种移植模型和/或 2D 培养物中进行的；它们受到可控变量数量的限制，外推到人类肿瘤生理学，并且不适合高通量设计。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更好地了解肿瘤细胞、内皮细胞和 TAM 在 2D 环境中的行为。该目标的结果将生成相关的设计参数，这些参数将在该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，创建具有灌注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结果。最重要的是，创建具有灌注人体毛细血管床的体外 3D 转移模型可以显着增强高通量抗转移药物筛选。