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Neutrophil-Mediated Melanoma Cell Adhesion and Migration

中性粒细胞介导的黑色素瘤细胞粘附和迁移

基本信息

批准号：
7078583
负责人：
CHENG DONG
金额：
$ 26.96万
依托单位：
PENNSYLVANIA STATE UNIVERSITY, THE
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-07-01 至 2008-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The events that mediate the initial steps in melanoma extravasation, adhesion of melanoma cancer cells to the endothelium within the dynamic circulation, are not well defined. Studies from our group, as well as others, have suggested that melanoma cell lines inefficiently bind endothelial cells underflow conditions and may require assistance for adhesion. We propose that neutrophils (PMNs), through direct cell-cell interaetions and the elaboration of soluble factors, directly participate in this process by inducing tumor cell expression of chemokines and cellular adhesion molecules. These tumor-derived factors contribute to a microenvironment that enhances the ability of melanoma cells to adhere to endothelium within the circulation. Preliminary data are presented that support this model including results that show PMNs aggregate with melanoma cells, PMNs stimulate IL-8 production in melanoma cell lines and, most importantly, PMNs facilitate melanoma cell adhesion to endothelial molecules under flow conditions and subsequent extravasation. We aim to extend these studies by (1) developing an experimental system that will permit in vitro investigations of melanoma cell adhesion to endothelium and subsequent transmigration, especially in the presence of PMNs under flow conditions; (2) determining what cytokines and chemokines are produced by melanoma cells following PMN induction and their role in mediating tumor cell adhesion and migration; and (3) characterizing the signal transduction cascades and transcriptional activators in melanoma cells induced by PMNs that facilitate melanoma adhesion and migration under flow conditions. We wilI also examine the effect of endothelial activation on regulating melanoma cell adhesion and migration, especially under the influence of PMNs. Therefore, these studies will provide a better understanding of the potential accessory role of PMNs in melanoma cell binding and insight into general mechanisms of tumor cell adhesion under dynamic flow conditions that mimic a blood capillary. Furthermore, since adhesion is a critical step in tumor metastasis these studies may identify novel therapeutic targets against invasive melanomas.

描述(由申请人提供)：在黑色素瘤外渗的初始步骤，即黑色素瘤癌细胞与动态循环内的内皮细胞的黏附中，调节的事件还没有很好的定义。我们小组和其他人的研究表明，黑色素瘤细胞系在底流条件下与内皮细胞低效结合，可能需要帮助才能黏附。我们认为，中性粒细胞(PMN)通过直接的细胞间相互作用和可溶性因子的阐述，通过诱导肿瘤细胞表达趋化因子和细胞黏附分子，直接参与这一过程。这些肿瘤衍生因子有助于增强黑色素瘤细胞与循环内血管内皮细胞黏附能力的微环境。提供了支持这一模型的初步数据，包括结果显示PMN与黑色素瘤细胞聚集，PMN刺激黑色素瘤细胞系产生IL-8，最重要的是，PMN在流动条件下促进黑色素瘤细胞与内皮分子的黏附，以及随后的渗出。我们的目标是通过以下方式扩展这些研究：(1)开发一种实验系统，能够在体外研究黑色素瘤细胞与内皮细胞的黏附和随后的迁移，特别是在流动条件下PMN存在的情况下；(2)确定PMN诱导后黑色素瘤细胞产生什么细胞因子和趋化因子，以及它们在介导肿瘤细胞黏附和迁移中的作用；以及(3)表征PMN诱导的黑色素瘤细胞中促进流动条件下黑色素瘤黏附和迁移的信号转导通路和转录激活物。我们还将研究内皮激活在调节黑色素瘤细胞黏附和迁移中的作用，特别是在PMN的影响下。因此，这些研究将更好地理解PMN在黑色素瘤细胞结合中的潜在辅助作用，并深入了解在模拟毛细血管的动态流动条件下肿瘤细胞黏附的一般机制。此外，由于粘连是肿瘤转移的关键步骤，这些研究可能确定针对侵袭性黑色素瘤的新治疗靶点。