Multiscale modeling of leukocyte-tumor cell adhesion to endothelium in shear flow

剪切流中白细胞-肿瘤细胞与内皮粘附的多尺度建模

• 批准号: 7613354
• 负责人: CHENG DONG
• 金额: $ 23.56万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7613354
• 关键词: 3-Dimensional; Accounting; Adhesions; Affect; Binding; Biomedical Research; Blood Circulation; Cell Adhesion; Cell Adhesion Molecules; Cell Aggregation; Cell Communication; Cells; Coagulation Process; Code; Complex; Computational Science; Disseminated Malignant Neoplasm; Embolism; Emerging Technologies; Endothelium; Environment; Equilibrium; Experimental Neoplasms; Extravasation; Fostering; In Vitro; Integrin Binding; Integrins; Intercellular adhesion molecule 1; Kinetics; Knowledge; Leukocytes; Ligands; Liquid substance; Mathematics; Mechanics; Mediating; Melanoma Cell; Methods; Microcirculation; Modeling; Molecular; Neoplasm Metastasis; Phase; Population; Population Dynamics; Population Statistics; Process; Relative (related person); Research; Role; Side; Simulate; Stream; Surface; Techniques; Technology; Time; Vascular Endothelium; Work; cancer cell; cancer therapy; chemokine; computerized tools; hemodynamics; innovation; innovative technologies; interest; melanoma; multi-scale modeling; neoplastic cell; novel; receptor; research study; shear stress; simulation

DESCRIPTION (provided by applicant): Computational tools have become increasingly important in enabling progress in biomedical research. The objective of this proposal is to apply emerging technologies in developing multi-scale computational approaches for studying heterotypic cell-cell collision and adhesion in the near wall region under dynamic shear forces. In particular, we focus on leukocyte (PMN)-melanoma cell emboli formation in a non-linear shear flow and subsequent tethering to the vascular endothelium (EC) as a result of cell-cell aggregation. The extent of tumor cell adhesion to a vessel wall is governed by the kinetic formation/disruption of receptor- ligand bonds, the hydrodynamic shear environment and the heterotypic cell populations within the circulation. Preliminary studies found PMNs increased melanoma cell extravasation, which involves PMNs initially tethering on the EC and subsequently capturing melanoma cells and maintaining them in close proximity to the EC. Results have indicated a novel finding and led to an important hypothesis that PMN-facilitated melanoma cell arrest on the EC is mediated by intercellular adhesion molecule-1 (ICAM-1)/beta2-integrin binding and is influenced by hydrodynamic shear rates and heterotypic cell populations. The rationale for this research is to generate computational tools using innovative multi-scale computational fluid dynamics (CFD) and population balance (PB) modeling to study the heterotypic cell-cell interactions that facilitate tumor cell adhesion to the EC and subsequent extravasation. Specific aims are: 1) develop a PB model to simulate the shear-induced collision/aggregation of melanoma cells to PMNs near the EC in a statistical manner; 2) develop a 3-D CFD simulation to assess the role of PMN-melanoma cell interaction in melanoma arrest on the EC; 3) validate the models by using in vitro flow experiments and use the models to expand the current knowledge of the molecular mechanisms of tumor cell adhesion under flow conditions. This study will yield new evidence for the complex role of hemodynamics, heterotypic cell populations, and PMN-melanoma adhesion in the recruitment of metastatic cancer cells to the EC in the microcirculation during metastasis, which will be significant in fostering new cross-disciplinary approaches to cancer treatment.

描述（由申请人提供）：计算工具在推动生物医学研究取得进展方面变得越来越重要。该提案的目的是应用新兴技术开发多尺度计算方法，用于研究动态剪切力下近壁区域的异型细胞碰撞和粘附。我们特别关注非线性剪切流中白细胞（PMN）-黑色素瘤细胞栓塞的形成，以及随后由于细胞-细胞聚集而束缚到血管内皮（EC）上。肿瘤细胞粘附到血管壁的程度由受体-配体键的动力学形成/破坏、流体动力剪切环境和循环内的异型细胞群控制。初步研究发现，PMN 增加了黑色素瘤细胞的外渗，这涉及 PMN 最初束缚在 EC 上，随后捕获黑色素瘤细胞并将其保持在靠近 EC 的位置。结果表明了一项新的发现，并得出了一个重要的假设，即 PMN 促进的黑色素瘤细胞在 EC 上的停滞是由细胞间粘附分子 1 (ICAM-1)/β2-整合素结合介导的，并受到流体动力学剪切速率和异型细胞群的影响。这项研究的基本原理是使用创新的多尺度计算流体动力学 (CFD) 和群体平衡 (PB) 模型生成计算工具，以研究促进肿瘤细胞粘附到 EC 和随后外渗的异型细胞间相互作用。具体目标是：1）开发PB模型，以统计方式模拟剪切诱导的黑色素瘤细胞与EC附近的PMN的碰撞/聚集； 2) 开发 3-D CFD 模拟来评估 PMN-黑色素瘤细胞相互作用在 EC 黑色素瘤停滞中的作用； 3）利用体外流动实验验证模型，并利用模型扩展目前对流动条件下肿瘤细胞粘附分子机制的认识。这项研究将为血流动力学、异型细胞群和中性粒细胞-黑色素瘤粘附在转移过程中微循环中转移性癌细胞募集到内皮细胞中的复杂作用提供新的证据，这对于培育新的跨学科癌症治疗方法具有重要意义。