Macrophage Signaling Pathways Enhancing Tumor Progression

促进肿瘤进展的巨噬细胞信号通路

• 批准号: 8669392
• 负责人: E. RICHARD STANLEY
• 金额: $ 25.58万
• 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 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8669392
• 关键词: Adopted; Adoptive Transfer; Angiogenic Factor; Anti-Inflammatory Agents; Anti-inflammatory; Biological Assay; Cells; Collaborations; Data; Dependence; Development; Diagnostic tests; EGF gene; Event; Extravasation; Generations; Genes; Hematopoietic; Hematopoietic stem cells; Human; Hybrids; Image; Immune; Immunohistochemistry; In Vitro; Incidence; Instruction; Investigation; Lead; Location; LoxP-flanked allele; Macrophage Colony-Stimulating Factor; Macrophage Colony-Stimulating Factor Receptor; Malignant Epithelial Cell; Malignant Neoplasms; Mammary Neoplasms; Mediating; Morphology; Mouse Mammary Tumor Virus; Mus; Mutation; Neoplasm Metastasis; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Phosphotransferases; Production; Regulation; Resolution; Role; Sampling; Signal Pathway; Signal Transduction; Signaling Molecule; System; Testing; Time; Tissue Microarray; Work; angiogenesis; base; cell motility; clinically significant; cytokine; in vitro Assay; in vivo; inhibitor/antagonist; intravital imaging; knock-down; macrophage; malignant breast neoplasm; man; migration; mouse model; mutant; neoplastic cell; novel; novel therapeutic intervention; paracrine; preclinical study; programs; small hairpin RNA; tumor; tumor microenvironment; tumor progression; vector

The colony stimulating factor-1 (CSF-1) receptor (CSF-IR) kinase instructs multipotent hematopoietic cells to adopt a macrophage fate and regulates the functions of differentiated cells. Previous results from this program have shown that CSF-1-driven tumor-associated macrophages (TAMs) regulate angiogenesis, carcinoma cell invasion, intravasation and metastasis in mouse models of breast cancer. TAM production of angiogenic factors and cytokines, TAM migration and TAM promotion of carcinoma cell migration have been identified as important CSF-1 R-mediated events. Our analysis of macrophage CSF-IR phosphotyrosyl (pTyr) signaling pathways has shown that CSF-1 R pTyr pathways control CSF-1-regulated proliferation, whereas other pTyr pathways regulate differentiation, morphology and motility. In particular, we have shown that the pTyr-721 pathway is critical for the paracrine interaction between macrophages and carcinoma cells in vitro and for macrophage motility within the tumor in vivo, for the production of angiogenic factors and for the release of EGF that participates in a paracrine loop to activate tumor cell invasiveness. Thus we hvpothesize that the CSF-IR pTyr-721 signaling pathways function in TAMs to regulate TAM promotion of carcinoma cell progression and metastasis. The overall aim of Proiect 2 is to confirm this by direct in vivo analysis, to determine when and where macrophage enhancement of tumor progression mediated by CSF- 1R pTyr-721 signaling is occurring and to identify the downstream pathways involved. To test this hypothesis, we propose a comprehensive approach involving three specific alms. In the first aim, we will establish the in vivo roles of CSF-1 R pTyr-721 signaling in mouse mammary tumor progression and metastasis using novel imaging approaches. In the second aim, CSF-IR pTyr-721-dependent signaling molecules and macrophage-produced cytokines that have been identified using combination of approaches will be examined in vitro using newly developed assays that accurately mimic the paracrine interaction and TAM-mediated tumor cell Intravasation and extravasation. In the third aim, molecules selected on the basis of these in vitro functional assays will be examined for their in vivo roles In tumor progression and metastasis. Their clinical significance will be determined by immunohistochemistry of human CDP Breast Cancer Progression Tissue Microarrays (TMA) and using patient samples in collaboration with Project 5. These studies are expected to provide in vivo data concerning the function of selected signaling molecules that act in CSF-IR downstream signaling pathways in TAMs to effect tumor progression and metastasis. RELEVANCE (See instructions): The results of the proposed work will enhance our understanding of why anti-inflammatory drugs (e.g. CSF-IR inhibitors) are protective against cancer incidence and progression and are expected to provide in vivo data concerning the function of signaling molecules that act in TAMs to effect tumor progression and metastasis. They are also expected to lead to the identification of new targets for diagnostic tests in man and to preclinical studies testing novel therapeutic approaches.

菌落刺激因子-1（CSF-1）受体（CSF-IR）激酶教学多动造血细胞 采用巨噬细胞命运并调节分化细胞的功能。以前的结果 计划表明，与CSF-1驱动的肿瘤相关巨噬细胞（TAM）调节血管生成， 乳腺癌小鼠模型中的癌细胞侵袭，插入和转移。 TAM生产 血管生成因子和细胞因子，癌细胞迁移的TAM迁移和TAM促进一直是 被确定为重要的CSF-1 R介导的事件。我们对巨噬细胞CSF-IR磷酸酪糖基的分析 （PTYR）信号通路表明，CSF-1 R PTYR途径控制CSF-1调节的增殖， 而其他PTYR途径则调节分化，形态和运动。特别是，我们已经表明 PTYR-721途径对于巨噬细胞和癌细胞之间的旁分泌相互作用至关重要 体内肿瘤内的体外和巨噬细胞运动，用于产生血管生成因子和用于 参与旁分泌环以激活肿瘤细胞侵袭性的EGF的释放。因此我们 hvpothes，CSF-IR PTYR-721信号通路在TAM中起作用以调节TAM促进 癌细胞进展和转移。 PROUECT 2的总体目的是通过直接体内确认这一点 分析，以确定巨噬细胞在何时何地增强肿瘤进展的介导的CSF- 1R PTYR-721信号传导正在发生，并确定涉及的下游途径。测试这个 假设，我们提出了一种涉及三个特定施舍的综合方法。在第一个目标中，我们将 建立CSF-1 R PTYR-721信号在小鼠乳腺肿瘤进展和 使用新型成像方法转移。在第二个目标中，CSF-IR PTYR-721依赖性信号传导 分子和巨噬细胞生产的细胞因子已通过方法组合鉴定 将使用新开发的测定法对旁分泌相互作用和 TAM介导的肿瘤细胞插入和渗出。在第三个目标中，分子根据 这些体外功能测定中将检查其在肿瘤进展中的体内作用和 转移。它们的临床意义将由人CDP乳房的免疫组织化学确定 癌症进展组织微阵列（TMA）和使用患者样品与项目5合作。 这些研究有望提供有关选定信号分子功能的体内数据 该作用在TAM中的CSF-IR下游信号通路中作用，以实现肿瘤进展和转移。 相关性（请参阅说明）： 拟议工作的结果将增强我们对抗炎药为什么的理解（例如 CSF-IR抑制剂）可防止癌症发病率和进展，预计将提供 有关在TAM中作用以实现肿瘤进展和 转移。他们还期望他们能够确定人类诊断测试的新目标 临床前研究测试新型治疗方法。