MOTILITY AND INVASION

运动性和入侵性

• 批准号: 7501536
• 负责人: JOHN S CONDEELIS
• 金额: $ 200.22万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7501536
• 关键词: MOTILITY; INVASION

DESCRIPTION (provided by applicant): Metastasis represents the major cause of mortality in, cancer patients. According to most current models of metastasis, interactions between tumor cells and the stromal microenvironment involving adhesion, proteolysis, growth factor and cytokine secretion and chemotaxis are key events at the cellular level driving the traversal of basement membrane barriers, migration and intravasation. Until recently, however, the technology has not existed to observe and manipulate these events at the cellular and molecular levels in vivo. The interdisciplinary projects and specialized cores of this program project, some with unique technologies, have provided the opportunity to investigate these events at the molecular and cellular levels in vivo. During the previous funding period the members of this program have demonstrated that macrophages are necessary for enhancing the motility and invasion of tumor cells in primary mammary tumors of rats and mice. We have shown how tumor cells and host macrophages both contribute, in a highly interactive process, to the intercellular signaling necessary for tumor cell motility, invasion, intravasation and metastasis. We have discovered the signaling pathways in macrophages and tumor cells that contribute to the signaling, motility and chemotaxis behaviors that generate the invasive phenotype and identified an invasion signature that uniquely defines invasive tumor cells in rat and mouse mammary tumors. In this competing continuation application we propose to extend and broaden the new insights derived during the previous funding period: 1) to identify the various subpopulations of macrophages present in primary tumors and metastatic tumors, and how they differentially affect angiogenesis, intravasation and extravasation; 2) to define, at the molecular level, the specific colony stimulating factor (CSF1) and erbB family phosphotyrosine-associated pathways that regulate growth factor production, chemotaxis, intravasation and metastasis; 3) to identify additional cytokines, growth factors, and stromal cells involved in initiating the paracrine loop between macrophages and tumor cells and the cellular sources of these cytokines and growth factors; 4) investigate chemotaxis and motility pathways in tumor cells and macrophages that determine cell polarity and migration efficiency at the molecular level; 5) extend the invasion signature discovered in rats and mice to human breast tumors by adapting the technology developed during the previous funding period to human cell line-derived tumors and human tumors from patients transplanted into mouse hosts; and 6) evaluate biomarkers derived from the human and mouse invasion signatures for their ability to define landmarks involved in invasion and intravasation in human breast tumors and predict the outcome of the disease.

描述（由申请人提供）：转移是癌症患者死亡的主要原因。根据大多数当前的转移模型，肿瘤细胞与基质微环境之间的相互作用（涉及粘附、蛋白水解、生长因子和细胞因子分泌以及趋化性）是细胞水平上驱动穿过基底膜屏障、迁移和内渗的关键事件。然而，直到最近，还没有在体内细胞和分子水平上观察和操纵这些事件的技术。该项目的跨学科项目和专业核心，其中一些具有独特的技术，提供了在体内分子和细胞水平上研究这些事件的机会。在之前的资助期间，该项目的成员已经证明，巨噬细胞对于增强大鼠和小鼠原发性乳腺肿瘤中肿瘤细胞的运动和侵袭是必需的。我们已经展示了肿瘤细胞和宿主巨噬细胞如何在高度相互作用的过程中共同促进肿瘤细胞运动、侵袭、内渗和转移所必需的细胞间信号传导。我们发现了巨噬细胞和肿瘤细胞中的信号通路，这些信号通路有助于产生侵袭性表型的信号传导、运动和趋化行为，并确定了独特定义大鼠和小鼠乳腺肿瘤中侵袭性肿瘤细胞的侵袭特征。在这个竞争性的延续申请中，我们建议扩展和拓宽在上一个资助期间获得的新见解：1）确定原发性肿瘤和转移性肿瘤中存在的巨噬细胞的各种亚群，以及它们如何不同地影响血管生成、内渗和外渗； 2）在分子水平上定义调节生长因子产生、趋化性、内渗和转移的特定集落刺激因子（CSF1）和erbB家族磷酸酪氨酸相关途径； 3) 鉴定参与启动巨噬细胞和肿瘤细胞之间的旁分泌循环的其他细胞因子、生长因子和基质细胞以及这些细胞因子和生长因子的细胞来源； 4) 研究肿瘤细胞和巨噬细胞的趋化性和运动途径，在分子水平上决定细胞极性和迁移效率； 5）通过将先前资助期间开发的技术应用于人类细胞系衍生肿瘤和移植到小鼠宿主的患者的人类肿瘤，将在大鼠和小鼠中发现的入侵特征扩展到人类乳腺肿瘤； 6) 评估源自人类和小鼠侵袭特征的生物标志物，以确定其定义与人类乳腺肿瘤侵袭和内渗相关的标志并预测疾病结果的能力。