Adhesion of Metastatic Tumor Cells in the Bloodstream

循环肿瘤细胞(CTC)的黏附和渗出是流体动力剪切力和化学受体-配体结合动力学之间的复杂相互作用，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学扩散的关键。与这个拟议中心的总体组织框架一致，项目3将利用源自物理科学的实验和理论方法来解决血液中转移细胞黏附的复杂性。我们要解决的一个主要问题是：CTC与血管壁的黏附和渗出是否可以理解为一个多步骤的级联反应，类似于炎症中的白细胞募集？这项拟议的研究围绕三个具体目标展开。目的1：应用多尺度模型预测循环肿瘤细胞的滚动和牢固黏附。随机选择素：碳水化合物和MUC1：ICAM-1结合的多粒子黏附动力学模拟将使用从转移性癌症患者血液中分离的原代肿瘤细胞获得的输入参数。目的2：生理剪切力作用下CTCs与特定分子表面和内皮细胞单层的黏附特性。注入全血的癌细胞将通过微流体流室注入，以测试AIM 1的黏附预测，并识别来自不同组织的微血管内皮细胞之间的差异。目的3：在活体动物模型上研究CTC的黏附、机械堵塞和渗出。利用多光子活体显微镜在小鼠脑和头骨的微血管中观察到荧光标记的癌细胞，以确定黏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，例如对生物分子靶标的定量评估。破坏转移细胞的黏附。

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.