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（由申请人提供）：癌细胞运动，趋化性及其通过内皮层进行移民的能力在癌细胞的转移性级联反应中起重要作用。癌症转移是一个动态而复杂的过程，它涉及癌细胞离开原发性肿瘤，进入血液循环，在血管中捕捉，入侵远处的器官并种植新肿瘤。代替原发性肿瘤，转移是导致大多数癌症死亡的原因。尽管它们的临床重要性，但癌症转移量仍然很少了解。当前的基因/蛋白质表达分析工作揭示了许多负责癌症转移的分子因素。动物模型中重要的细胞成像首次将癌细胞转移性行为与体内的分子机制联系起来，并为癌细胞转移性途径提供了见解。尽管我们对癌症转移过程的理解有了所有进步，但这些研究得出的抑制剂仍缺乏特异性和/或在临床上无效。这部分是由于我们缺乏了解癌细胞永远不会单独起作用的原因。他们通过趋化因子，生长因子以及细胞外矩阵（ECM）的重塑来积极与微环境相互作用。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成为最终理解癌症转移酶的关键组成部分。我们建议将微化学，微型机械工程和成像（WU博士），血管血管和癌细胞生物学（Swartz博士）和癌细胞生物学（Dr. YEN）汇总到基本癌细胞生物学及其在癌症转移临床化学中的潜在应用。我们的短期目标是在体外模型上建立生理相关的（3D），并在体外模型上构建一个可调节的模型，并在光线下将癌症转移步骤，迁移和侵入性的两个重要步骤带入。我们的长期目标是在癌细胞转移性行为的基础上找到肿瘤细胞微环境中的关键分子参与者。为此，我们提出了以下特定目标AIM1：开发3D高吞吐量，基于水凝胶的，微流体的体外模型，具有可调的微型和微型力学环境，以模仿癌细胞转移的两个重要步骤 - 通过3D ECM内的ECM肿瘤细胞迁移，并通过3D ECM中的intavisation通过血管迁移。 AIM2：与新开发的4D成像技术一起开发计算算法，以自动评分肿瘤细胞的侵入性（以细胞运动性，趋化性和细胞传播率为特征）。这个目标对于实现真正高吞吐量系统至关重要。 AIM3：在各种趋化因子，生长因子，ECM组成以及免疫细胞和基质细胞的存在/不存在/不存在/不存在的情况下，在体外定量评估肿瘤细胞的侵入性。 公共卫生相关性：转移造成大多数癌症死亡。拟议的工作将与新兴的微流体技术与一种新型的4D Alive细胞跟踪成像技术结合使用，以研究微环境在癌细胞侵入性中的作用。实验结果将推进基本的癌细胞生物学。它还将生成微流体的体外工具，该工具将找到高通量癌抑制剂筛查的直接应用。