Adhesion of Metastatic Tumor Cells in the Bloodstream

循环肿瘤细胞（CTC）对血管壁的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的复杂相互作用，并且对于许多转移性癌症（包括源自前列腺、乳腺、结肠和皮肤的那些）的血液学扩散至关重要。与该中心的总体组织框架一致，项目3将通过利用物理科学的实验和理论方法来解卷积血流中转移性细胞粘附的复杂性。我们要解决的一个主要问题是：CTC与血管壁的粘附和外渗是否可以理解为一个多步级联反应，类似于炎症中的白细胞募集？拟议的研究围绕三个具体目标进行。目的1：应用多尺度模型预测循环肿瘤细胞的滚动和牢固粘附。随机选择素：碳水化合物和MUC 1：ICAM-1结合的多粒子粘附动力学模拟将与从转移性癌症患者血液中分离的原发性肿瘤细胞获得的输入参数一起使用。目的2：在生理剪切应力下表征CTC与限定的分子表面和内皮细胞单层的粘附。掺入全血中的癌细胞将通过微流体流动室灌注，以测试Aim 1的粘附预测并鉴定来自不同组织的微血管内皮细胞之间的差异。目的3：在活体动物模型中研究CTC粘附、机械堵塞和外渗。将使用多光子活体显微镜在小鼠脑和颅骨的微血管中观察荧光标记的癌细胞，以确定粘附受体和机械堵塞在肿瘤细胞从血流募集中的相对重要性。总的来说，拟议的研究将导致干预癌症发展的新途径，例如定量评估生物分子靶点。破坏转移性细胞粘附。

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.