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: 7944461
• 负责人: Mingming Wu
• 金额: $ 19.06万
• 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/7944461
• 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; Figs - dietary; 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（申请人提供）：癌细胞的运动性、趋化性及其通过内皮层的迁移能力在癌细胞的转移级联中起着重要作用。肿瘤转移是一个动态而复杂的过程，它涉及癌细胞离开原发肿瘤，进入血液循环，在血管中停滞，向远处器官侵袭，生长出新的肿瘤。与原发肿瘤相比，大多数癌症死亡是由转移引起的。尽管癌症转移具有重要的临床意义，但人们对其了解甚少。目前的基因/蛋白表达谱工作已经揭示了许多与癌症转移有关的分子因素。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，为癌细胞转移途径的研究提供了新的思路。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，要么在临床上无效。这在一定程度上是由于我们不了解癌细胞从来不单独行动。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，积极地与微环境相互作用。了解不同细胞类型和细胞外基质之间复杂的相互作用已成为最终理解癌症转移的关键组成部分。我们建议汇集微化学、微机械工程和成像（Wu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，以应对基础癌细胞生物学及其在癌症转移的临床化疗中的潜在应用。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，置于光线下。我们的长期目标是找到肿瘤细胞微环境中影响癌细胞转移行为的关键分子。为了实现这一目标，我们提出了以下具体目标：开发一种3D高通量，基于水凝胶的微流体体外模型，具有可调的微化学和微机械环境，用于模拟癌细胞转移的两个重要步骤-肿瘤细胞在ECM内的迁移和从3D ECM通过血管的内渗。目的2：开发一种计算算法，结合新开发的4D成像技术，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）进行自动评分。这一目标对于实现真正的高吞吐量系统至关重要。目的3：定量评价肿瘤细胞在各种趋化因子、生长因子、ECM成分以及免疫细胞和基质细胞存在/不存在的影响下的体外侵袭性。