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

• 批准号: 6614356
• 负责人: CHENG DONG
• 金额: $ 27.61万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6614356
• 关键词: RNase protection assay; biological signal transduction; cell adhesion; cell adhesion molecules; cell cell interaction; cell line; cell migration; chemokine; clinical research; enzyme linked immunosorbent assay; flow cytometry; human subject; interleukin 8; melanoma; neoplasm /cancer immunology; neoplasm /cancer invasiveness; neutrophil; shear stress; tissue /cell culture; transcription factor; vascular endothelium; western blottings

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）： 介导黑色素瘤外渗、黑色素瘤癌细胞在动态循环内粘附到内皮的初始步骤的事件尚不清楚。我们小组以及其他小组的研究表明，黑色素瘤细胞系在下溢条件下无法有效地结合内皮细胞，并且可能需要粘附辅助。我们提出，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加工，通过诱导肿瘤细胞表达趋化因子和细胞粘附分子来直接参与这一过程。这些肿瘤衍生因子有助于形成微环境，增强黑色素瘤细胞粘附到循环内内皮的能力。支持该模型的初步数据包括显示 PMN 与黑色素瘤细胞聚集的结果，PMN 刺激黑色素瘤细胞系中 IL-8 的产生，最重要的是，PMN 促进黑色素瘤细胞在流动条件下粘附到内皮分子并随后外渗。我们的目标是通过以下方式扩展这些研究：（1）开发一个实验系统，该系统将允许体外研究黑色素瘤细胞与内皮的粘附和随后的迁移，特别是在流动条件下存在中性粒细胞的情况下； (2)确定PMN诱导后黑色素瘤细胞产生哪些细胞因子和趋化因子及其在介导肿瘤细胞粘附和迁移中的作用； (3) 表征由 PMN 诱导的黑色素瘤细胞中的信号转导级联和转录激活因子，促进流动条件下黑色素瘤的粘附和迁移。我们还将检查内皮激活对调节黑色素瘤细胞粘附和迁移的影响，特别是在中性粒细胞的影响下。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，并深入了解模拟毛细血管的动态流动条件下肿瘤细胞粘附的一般机制。此外，由于粘附是肿瘤转移的关键步骤，这些研究可能会确定针对侵袭性黑色素瘤的新治疗靶点。