Adhesion of Metastatic Tumor Cells in the Bloodstream

血流中转移性肿瘤细胞的粘附

• 批准号: 8534720
• 负责人: Michael R. King
• 金额: $ 31.76万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8534720
• 关键词: Address; Adhesions; Adhesives; Affect; Affinity; Animal Model; Behavior; Binding; Biological Assay; Blood; Blood Circulation; Blood Vessels; Blood capillaries; Blood flow; Blood specimen; Bone Marrow; Brain; Breast; Caliber; Cancer Biology; Cancer Patient; Cancer cell line; Carbohydrates; Cell Adhesion; Cell Adhesion Molecules; Cell Line; Cell Size; Cells; Chemicals; Colon; Complex; Computer Simulation; Development; Disseminated Malignant Neoplasm; Distant; Drug Targeting; E-Selectin; Endothelial Cells; Endothelium; Engineering; Environment; Extravasation; Goals; Growth Factor; Image; In Vitro; Inflammation; Intercellular adhesion molecule 1; Ischemia; Kinetics; Label; Lead; Leukocytes; Life; Ligand Binding; Ligands; Location; Malignant Neoplasms; Measures; Mechanics; Mediating; Methods; Microfabrication; Microfluidic Microchips; Microfluidics; Microtubules; Molecular; Morbidity - disease rate; Motion; Mucin-1 Staining Method; Mus; Myocardium; Neoplasm Circulating Cells; Neoplasm Metastasis; Normal Cell; Organ; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Physics; Physiological; Plug-in; Primary Neoplasm; Probability; Prostate; Quantitative Evaluations; Recruitment Activity; Relative (related person); Research; Retina; Retinoblastoma; Rheology; Scientist; Selectins; Site; Skin; Staining method; Stains; Stem cells; Surface; Taxane Compound; Testing; Tissues; Universities; Whole Blood; adhesion receptor; body system; bone; cancer cell; capillary; cell growth; chemokine; cranium; docetaxel; in vivo; intravital microscopy; migration; monolayer; mortality; multi-scale modeling; nano; neoplastic cell; novel; physical science; protein expression; receptor; receptor density; receptor expression; research study; response; shear stress; simulation; taxane

The adhesion to the vessel wall and extravasation of circulating tumor cells (CTC) is a complex interplay between hydrodynamic shear forces and chemical receptor-ligand binding kinetics, and is critical to the hematologic spread of many metastatic cancers including those originating from prostate, breast, colon, and skin. Consistent with the overarching organizational framework of this proposed Center, Project 3 will deconvolve the complexity of metastatic cell adhesion in the bloodstream by utilizing experimental and theoretical approaches derived from the physical sciences. A major question that we will address is: Can CTC adhesion to the vessel wall and extravasation be understood as a multistep cascade, similar to leukocyte recruitment in inflammation? The proposed research is organized around three specific aims. Aim 1: Application of a multiscale model to predict rolling and firm adhesion of circulating tumor cells. The multiparticle adhesive dynamics simulation with stochastic selectin:carbohydrate and MUC1:ICAM-1 binding will be used with input parameters obtained from primary tumor cells isolated from the blood of metastatic cancer patients. Aim 2: Characterization of the adhesion of CTCs to defined molecular surfaces and endothelial cell monolayers under physiological shear stress. Cancer cells spiked into whole blood will be perfused through microfluidic flow chambers to test adhesion predictions of Aim 1 and identify differences between microvascular endothelial cells from different tissues. Aim 3: Study of CTC adhesion, mechanical plugging and extravasation in a live animal model. Fluorescently labeled cancer cells will be observed in the microvessels of mouse brain and skull using multiphoton intravital microscopy, to determine the relative importance of adhesion receptors and mechanical plugging in tumor cell recruitment from the bloodstream. Taken together, the proposed research will lead to new pathways to intervene in the development of cancer, such as the quantitative evaluation of biomolecular targets for. disrupting metastatic cell adhesion.

循环肿瘤细胞（CTC）的血管壁粘附和外渗是流体动力学剪切力和化学受体-配体结合动力学之间复杂的相互作用，是许多转移性癌症（包括前列腺癌、乳腺癌、结肠癌和皮肤癌）血液扩散的关键。与该中心的总体组织框架一致，项目3将利用来自物理科学的实验和理论方法来解开血液中转移细胞粘附的复杂性。我们要解决的一个主要问题是：CTC粘附血管壁和外渗是否可以理解为一个多步骤级联，类似于炎症中的白细胞募集？拟议的研究是围绕三个具体目标组织的。目的1：应用多尺度模型预测循环肿瘤细胞滚动和牢固粘附。随机选择素：碳水化合物和MUC1:ICAM-1结合的多粒子粘附动力学模拟将使用从转移性癌症患者血液中分离的原发肿瘤细胞获得的输入参数。目的2：生理剪切应力下ctc与特定分子表面和内皮细胞单层的粘附特性。注入全血的癌细胞将通过微流体流动室进行灌注，以测试Aim 1的粘附预测，并确定来自不同组织的微血管内皮细胞之间的差异。目的3：活体动物模型中CTC黏附、机械堵塞和外渗的研究。使用多光子活体显微镜观察小鼠脑和颅骨微血管中荧光标记的癌细胞，以确定粘附受体和机械堵塞在肿瘤细胞从血液中募集中的相对重要性。综上所述，拟议的研究将导致干预癌症发展的新途径，如定量评估生物分子靶点。破坏转移细胞粘附。