A 3D microfluidic platform for quantitative assessments of tumor cell migration

用于定量评估肿瘤细胞迁移的 3D 微流控平台

• 批准号: 8129653
• 负责人: Mingming Wu
• 金额: $ 15.68万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8129653
• 关键词: Algorithms; Animal Model; Behavior; Biology; Blood Circulation; Blood Vessels; Cells; Cellular biology; Cessation of life; Chemicals; Chemotaxis; Clinical; Complex; Development; Distant; Endothelium; Engineering; Environment; Extracellular Matrix; Foundations; Gene Proteins; Goals; Growth Factor; Hydrogels; Image; Imaging Techniques; Immune; In Vitro; Invaded; Left; Life; Light; Malignant Neoplasms; Mechanics; Microfluidics; Molecular; Molecular Profiling; Neoplasm Metastasis; Organ; Pathway interactions; Play; Primary Neoplasm; Process; Role; Screening procedure; Specificity; Stromal Cells; System; Technology; Time; Work; base; cancer cell; cell motility; cell type; cellular imaging; chemokine; chemotherapy; direct application; in vitro Model; in vivo; inhibitor/antagonist; insight; migration; neoplastic cell; novel; protein expression; public health relevance; tool; tumor

DESCRIPTION (provided by applicant): Cancer cell motility, chemotaxis as well as its ability to transmigrate through an endothelium layer play important roles in cancer cells' metastatic cascade. Cancer metastasis is a dynamic and complex process, it involves cancer cells leaving the primary tumor, entering blood circulation, arresting in blood vessel, invading a distant organ, and growing a new tumor. Rather than primary tumors, metastases are responsible for most cancer deaths. Despite their clinical importance, cancer metastases remain poorly understood. Current gene/protein expression profiling work has revealed many molecular factors that are responsible for cancer metastases. Intra-vital cell imaging in animal models has, for the first time, connected the cancer cell metastatic behavior directly with the molecular mechanism in vivo and provided insights into the cancer cell metastatic pathways. Despite of all the advances in our understanding of the cancer metastasis processes, inhibitors derived from these studies have either lacked specificity and/or been ineffective clinically. This is, in part, due to our lack of understanding that cancer cells never act alone. They are actively interacting with the microenvironment via the secretion of chemokines, growth factors, as well as the remodeling of the extracellular matrices (ECM). The understanding of the intricate interactions among different cell types and the extracellular matrices has becoming a critical component towards the eventual understanding of cancer metastases. We propose to bring together expertise on micro-chemical, micro-mechanical engineering and imaging (Dr. Wu), vascular vessel and cancer cell biology (Dr. Swartz) and cancer cell biology (Dr. Yen) to the challenges in both fundamental cancer cell biology and its potential applications in clinical chemotherapy for cancer metastases. Our short term goal is to build a physiologically relevant (3D), mechanically and chemically tunable in vitro model, and to bring the two important steps in cancer metastasis steps, migration and intravasation, under the light. Our long term goal is to find the key molecular players in the tumor cell microenvironment that underlie the cancer cell's metastatic behavior. To achieve this, we propose the following Specific Aims Aim1: To develop a 3D high throughput, hydrogel based, microfluidic in vitro model, with tunable micro- chemical and micro-mechanical environments, for mimicking two important steps in cancer cell metastasis - tumor cell migration within a ECM and intravasation from a 3D ECM through a vascular vessel. Aim2: To develop a computation algorithm, in conjunction with a newly developed 4D imaging technique, to automatically score the tumor cell invasiveness (characterized by cell motility, chemotaxis and cell transmigration rate). This Aim is critical in the realization of a truly high throughput system. Aim3: To assess quantitatively the tumor cell invasiveness in vitro under the influences of various chemokines, growth factors, ECM compositions, as well as the presence/absence of immune cells and stromal cells. PUBLIC HEALTH RELEVANCE: Metastases are responsible for most cancer deaths. The proposed work will use the emerging microfluidic technology in conjunction with a novel 4D alive cell tracking imaging technique to investigate roles of microenvironments in cancer cell invasiveness. Experimental results will advance the basic cancer cell biology; and it will also generate microfluidic in vitro tools that will find direct applications for high throughput cancer inhibitor screening.

描述（由申请人提供）：癌细胞运动性、趋化性及其通过内皮层迁移的能力在癌细胞的转移级联中起重要作用。肿瘤转移是一个动态的、复杂的过程，它涉及到癌细胞离开原发肿瘤，进入血液循环，在血管中停滞，侵入远处器官，生长新的肿瘤。与原发性肿瘤不同，转移瘤是导致大多数癌症死亡的原因。尽管其临床重要性，癌症转移仍然知之甚少。目前的基因/蛋白质表达谱分析工作揭示了许多负责癌症转移的分子因素。动物模型活体细胞成像首次将癌细胞转移行为与体内分子机制直接联系起来，并提供了对癌细胞转移途径的见解。尽管我们对癌症转移过程的理解取得了所有进展，但从这些研究中获得的抑制剂要么缺乏特异性和/或在临床上无效。这在一定程度上是由于我们缺乏对癌细胞从不单独行动的理解。它们通过分泌趋化因子、生长因子以及细胞外基质（ECM）的重塑与微环境积极相互作用。对不同细胞类型和细胞外基质之间复杂相互作用的理解已经成为最终理解癌症转移的关键组成部分。我们建议将微化学，微机械工程和成像（吴博士），血管和癌细胞生物学（Swartz博士）和癌细胞生物学（Yen博士）的专业知识结合起来，以应对基础癌细胞生物学及其在癌症转移临床化疗中的潜在应用的挑战。我们的短期目标是建立一个生理相关的（3D），机械和化学可调的体外模型，并将癌症转移步骤中的两个重要步骤，迁移和内渗，置于光下。我们的长期目标是找到肿瘤细胞微环境中的关键分子参与者，这些分子是癌细胞转移行为的基础。为了实现这一点，我们提出了以下具体目标目标1：开发具有可调微化学和微机械环境的3D高通量、基于水凝胶的微流体体外模型，用于模拟癌细胞转移中的两个重要步骤-肿瘤细胞在ECM内的迁移和从3D ECM通过血管的内渗。目标2：开发一种计算算法，结合新开发的4D成像技术，自动对肿瘤细胞侵袭性（以细胞运动性、趋化性和细胞迁移率为特征）进行评分。这一目标对于实现真正的高通量系统至关重要。目标3：定量评估在各种趋化因子、生长因子、ECM成分以及存在/不存在免疫细胞和基质细胞的影响下肿瘤细胞的体外侵袭力。 公共卫生相关性：转移是大多数癌症死亡的原因。拟议的工作将使用新兴的微流体技术与一种新的4D活细胞跟踪成像技术相结合，以研究微环境在癌细胞侵袭中的作用。实验结果将推进基本的癌细胞生物学;它还将产生微流体体外工具，这些工具将直接应用于高通量癌症抑制剂筛选。