Role of immature myeloid cells in premetastatic lung

未成熟骨髓细胞在转移前肺中的作用

• 批准号: 8349363
• 负责人: Li Yang
• 金额: $ 28.05万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 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/8349363
• 关键词: Blood Vessels; Breast Adenocarcinoma; Cancer Patient; Cause of Death; Cells; Data; Distant; Environment; Goals; ITGAM gene; Immune; Immunologic Monitoring; Immunologic Surveillance; Inflammatory; Integration Host Factors; Interferon Type II; Lung; MMP9 gene; Malignant Neoplasms; Molecular; Mus; Myelogenous; Myeloid Cells; Neoplasm Metastasis; Organ; Phase; Predisposition; Primary Neoplasm; Process; Production; Research Personnel; Role; Signal Transduction; Site; Strategic Planning; Transforming Growth Factor beta; Travel; Vascular System; Vascular remodeling; Work; Yang; capillary bed; cytokine; effective therapy; improved; metastatic process; neoplastic cell; novel; tumor

We have found that Gr-1+CD11b+ cells are significantly increased in lungs of mice bearing mammary adenocarcinomas prior to tumor cell arrival. In the premetastatic lungs, these immature myeloid cells significantly decrease IFN-gamma production and increase pro-inflammatory cytokines. In addition, they produce large quantities of MMP9 and promote vascular remodeling. Deletion of MMP9 normalizes aberrant vasculature in the premetastatic lung, and diminishes lung metastasis. The production and activity of MMP9 is selectively restricted to lungs and organs with a large number of Gr-1+CD11b+ cells. Our work reveals a novel pro-tumor mechanism for Gr-1+CD11b+ cells that changes the premetastatic lung into an inflammatory and proliferative environment, diminishes immune protection and promotes metastasis through aberrant vasculature formation. Thus inhibition of Gr-1+CD11b+ cells could normalize the premetastatic lung environment, improve host immunosurveillance, and inhibit tumor metastasis. We are currently investigating the effect of myeloid specific TGFbeta singling in the metastatic process.

我们已经发现，Gr-1+ CD 11b+细胞显着增加，在肿瘤细胞到达之前，在小鼠乳腺癌的肺。在转移前的肺中，这些未成熟的髓样细胞显著减少IFN-γ的产生并增加促炎细胞因子。此外，它们产生大量的MMP 9并促进血管重塑。MMP 9的缺失使转移前肺中的异常脉管系统正常化，并减少肺转移。MMP 9的产生和活性选择性地局限于具有大量Gr-1+ CD 11b+细胞的肺和器官。我们的工作揭示了Gr-1+ CD 11b+细胞的一种新的促肿瘤机制，该机制将转移前肺改变为炎症和增殖环境，减少免疫保护并通过异常血管形成促进转移。因此，抑制Gr-1+ CD 11b+细胞可以使转移前肺环境正常化，改善宿主免疫监视，并抑制肿瘤转移。我们目前正在研究髓系特异性TGF β在转移过程中的作用。