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

集落刺激因子-1（CSF-1）是调节巨噬细胞存活、增殖和凋亡的主要生长因子 和分化以及形态、粘附和运动。巨噬细胞的CSF-1调节在 在促进实体瘤的进展和转移中起重要作用。CSF-1的表达和 人乳腺癌中肿瘤相关巨噬细胞（TAM）的存在与不良的 预后巨噬细胞耗尽的CSF-1缺陷型乳腺癌患者的乳腺肿瘤转移严重减少。 （Csf-1 op/Csf-1 op）小鼠。此外，在乳腺癌小鼠模型中，TAM、血管生成、转移 并且通过去除CSF-1可以减少血管内渗并延长荷瘤小鼠的生命，或者 阻断CSF-1 R。以前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 表明CSF-1通过调节巨噬细胞的趋化性发挥这些作用， 分泌血管生成和肿瘤细胞趋化因子。在本项目中，建议研究 来自调节这些过程的CSF-1受体的信号传导的分子机制。的理由 拟议的研究是，了解所涉及的分子机制将提供新的 乳腺癌的治疗靶点。 初步实验表明，CSF-1 R Y 721和Y 706下游的信号传导途径 磷酸化分别正向和负向调节巨噬细胞运动和肿瘤细胞侵袭 体外该提案的总体目标是阐明调节巨噬细胞的信号通路 运动和肿瘤细胞侵袭，并确定血管生成和肿瘤细胞趋化因子产生的 巨噬细胞，并评估其对肿瘤进展和转移的意义。具体目标 为： 目的1：确定基于CSF-1受体pY 721的增强巨噬细胞趋化性的信号通路。 目的2：鉴定肿瘤细胞趋化因子和血管生成因子， 巨噬细胞和调节其产生的CSF-1 R磷酸酪氨酸信号传导途径。 目的3：探讨CSF-1趋化信号通路与巨噬细胞趋化性的关系 肿瘤细胞趋化因子和血管生成因子在肿瘤进展和转移中的作用。 与公共卫生的相关性：乳腺癌是妇女的主要癌症。以前的研究已经表明 肿瘤微环境中的特定非肿瘤细胞（TAM）促进肿瘤进展， 转移本项目的重点是确定这种增强的基本机制， 发现新的治疗靶点

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.