Role of immature myeloid cells in premetastatic lung

我们发现，在肿瘤细胞到达乳腺腺癌小鼠的肺部之前，Gr-1+CD11b+细胞显著增加。在转移前肺中，这些未成熟的骨髓细胞显著减少ifn - γ的产生并增加促炎细胞因子。此外，它们产生大量的MMP9，促进血管重塑。MMP9的缺失使转移前肺的异常血管系统正常化，并减少肺转移。MMP9的产生和活性选择性地局限于肺和具有大量Gr-1+CD11b+细胞的器官。我们的工作揭示了Gr-1+CD11b+细胞的一种新的促瘤机制，它将转移前肺改变为炎症和增殖环境，减少免疫保护，并通过异常的脉管系统形成促进转移。因此，抑制Gr-1+CD11b+细胞可使转移前肺环境正常化，改善宿主免疫监测，抑制肿瘤转移。我们目前正在研究骨髓特异性TGFbeta单点在转移过程中的作用。

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.