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: 7534104
• 负责人: E. RICHARD STANLEY
• 金额: $ 25.71万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7534104
• 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; novel therapeutics; outcome forecast; paracrine; programs; research study; therapeutic target; 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.

集落刺激因子-1是调节巨噬细胞存活、增殖的主要生长因子 分化以及形态、粘附性和运动性。巨噬细胞对CSF-1的调节作用 在促进实体瘤的进展和转移中起重要作用。脑脊液-1的表达与血管内皮细胞 乳腺癌中肿瘤相关巨噬细胞(TAM)的存在与不良相关 预后。在巨噬细胞耗竭的CSF-1缺陷中，乳腺肿瘤转移严重减少 (CSF-1op/csf-1op)小鼠。此外，在乳腺癌的小鼠模型中，TAMs、血管生成、转移 而去除脑脊液-1可以减少血管内皮细胞的侵入，延长荷瘤小鼠的寿命，或者 阻断CSF-1R以前对该程序的研究已经证明了旁分泌的存在 TAMs与癌细胞相互作用促进乳腺肿瘤侵袭的研究 提示，CSF-1通过调节巨噬细胞的趋化作用而发挥上述作用。 分泌血管生成因子和肿瘤细胞趋化因子。在本项目中，建议研究 调节这些过程的CSF-1受体信号的分子机制。其基本原理是 建议的研究是，对所涉及的分子机制的理解将提供新的 乳腺癌的治疗靶点。 初步实验表明，CSF-1R Y721和Y706下游的信号通路 磷酸化分别正向和负向调节巨噬细胞的运动和肿瘤细胞的侵袭 在试管中。该提案的总体目标是阐明调节巨噬细胞的信号通路。 运动与肿瘤细胞侵袭及鉴定血管生成因子和肿瘤细胞趋化因子 巨噬细胞，并评价它们在肿瘤进展和转移中的意义。具体目标 包括： 目的1：确定基于CSF-1受体pY721的增强巨噬细胞趋化作用的信号通路。 目的2：鉴定肿瘤细胞合成和分泌的趋化因子和血管生成因子 巨噬细胞和调节其产生的CSF-1R磷酸化酪氨酸信号通路。 目的3：确定已识别的CSF-1趋化信号通路和巨噬细胞的意义 肿瘤细胞趋化和血管生成因子在肿瘤进展和转移中的作用 与公共健康相关：乳腺癌是女性的主要癌症。此前的研究表明， 肿瘤微环境中特定的非肿瘤细胞(TAM)促进肿瘤进展和 转移。这个项目的重点是确定这一增强的潜在机制，目标是 寻找新的治疗靶点。