CSF-1R Signaling Pathways Regulating macrophage chemotaxis and angiogenic fac rel

CSF-1R 信号通路调节巨噬细胞趋化性和血管生成因子

• 批准号: 8097227
• 负责人: E. RICHARD STANLEY
• 金额: $ 26.79万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8097227
• 关键词: Adhesions; Angiogenic Factor; Chemotactic Factors; Chemotaxis; Goals; Growth Factor; Human; In Vitro; Life; Macrophage Colony-Stimulating Factor; Macrophage Colony-Stimulating Factor Receptor; Malignant Epithelial Cell; Malignant Neoplasms; Mammary Neoplasms; Molecular; Morphology; Mus; Neoplasm Metastasis; Phosphorylation; Phosphotyrosine; Play; Process; Production; Public Health; Regulation; Role; Signal Pathway; Signal Transduction; Solid Neoplasm; Tumor Cell Invasion; Woman; angiogenesis; base; cell motility; macrophage; malignant breast neoplasm; mouse model; neoplastic cell; new therapeutic target; outcome forecast; paracrine; programs; research study; tumor; tumor progression

Colony stimulating factor-1 (CSF-1) is the primary growth factor regulating macrophage survival, proliferation and differentiation as well as morphology, adhesion and motility. CSF-1 regulation of macrophages plays an important role in enhancing the progression and metastasis of solid tumors. CSF-1 expression and the presence of tumor-associated macrophages (TAMs) in human breast cancer are correlated with poor prognosis. Mammary tumor metastases are severely reduced in the macrophage-depleted CSF-1-deficient (Csf-1op/Csf-1op) mouse. Furthermore, in mouse models of breast cancer, TAMs, angiogenesis, metastasis and intravasation can be reduced and the life of tumor bearing mice prolonged by removing CSF-1, or blocking the CSF-1 R. Previous studies of this Program have demonstrated the existence of a paracrine interaction between TAMs and carcinoma cells necessary for the promotion of invasion of mammary tumor cells in mice and suggest that CSF-1 exerts these effects by regulating macrophage chemotaxis and the secretion of angiogenic and tumor cell chemotactic factors. In this project it is proposed to study the molecular mechanisms of signaling from the CSF-1 receptor that regulate these processes. The rationale for the proposed studies is that an understanding of the molecular mechanisms involved will provide novel therapeutic targets in breast cancer. Preliminary experiments indicate that the signaling pathways downstream of CSF-1 R Y721 and Y706 phosphorylation, respectively positively and negatively regulate macrophage motility and tumor cell invasion in vitro. The overall aim of the proposal is to elucidate the signaling pathways that regulate macrophage motility and tumor cell invasion and to identify the angiogenic and tumor cell chemotactic factors produced by macrophages and to evaluate their significance for tumor progression and metastasis. The specific aims are: Aim 1: To define CSF-1 receptor pY721-based signaling pathways that enhance macrophage chemotaxis. Aim 2: To identify the tumor cell chemotactic and angiogenic factors synthesized and secreted by macrophages and the CSF-1 R phosphotyrosine signaling pathways regulating their production. Aim 3: To determine the significance of identified CSF-1 chemotactic signaling pathways and macrophage tumor cell chemotactic and angiogenic factors in tumor progression and metastasis. Relevance to public health: Breast cancer is the leading cancer of women. Previous studies have shown that particular non-tumor cells (TAMs) in the tumor microenvironment enhance tumor progression and metastasis. This project focuses on identifying the underlying mechanisms of this enhancement with the goal of identifying novel therapeutic targets.

菌落刺激因子1（CSF-1）是调节巨噬细胞存活，增殖的主要生长因子 和分化以及形态，粘附和运动。巨噬细胞的CSF-1调节扮演 在增强实体瘤的进展和转移方面的重要作用。 CSF-1表达和 人乳腺癌中与肿瘤相关的巨噬细胞（TAM）的存在与较差 预后。巨噬细胞缺乏的CSF-1缺陷中，乳腺肿瘤转移量严重降低 （CSF-1OP/CSF-1OP）鼠标。此外，在乳腺癌的小鼠模型中，TAMS，血管生成，转移 并且可以降低侵入，并通过去除CSF-1或 阻止CSF-1R。对该程序的先前研究表明了旁分泌的存在 TAMS与癌细胞之间促进乳腺肿瘤所需的相互作用 小鼠中的细胞，建议CSF-1通过调节巨噬细胞趋化性和 血管生成和肿瘤细胞趋化因子的分泌。在这个项目中，建议研究 调节这些过程的CSF-1受体的信号传导的分子机制。理由 拟议的研究是，对所涉及的分子机制的理解将提供新颖 乳腺癌的治疗靶标。 初步实验表明CSF-1 R Y721和Y706的信号通路 磷酸化，分别对巨噬细胞运动和肿瘤细胞侵袭分别进行阳性和负调节 体外。该提案的总体目的是阐明调节巨噬细胞的信号通路 运动性和肿瘤细胞侵袭，并确定由 巨噬细胞并评估其对肿瘤进展和转移的重要性。具体目标 是： AIM 1：定义CSF-1受体PY721基于PY721的信号传导途径，以增强巨噬细胞趋化性。 目标2：确定由 巨噬细胞和CSF-1 R磷酸酪氨酸信号通路调节其产生。 目标3：确定已鉴定的CSF-1趋化信号通路和巨噬细胞的重要性 肿瘤细胞趋化因子和肿瘤进展和转移中的血管生成因子。 与公共卫生有关：乳腺癌是妇女的主要癌症。先前的研究表明 肿瘤微环境中特定的非肿瘤细胞（TAM）增强了肿瘤的进展和 转移。该项目着重于以目标确定这种增强的基本机制 确定新型治疗靶标。