Macrophages promote fibroblast growth factor receptor-driven tumor cell migration and invasion in a CXCR2-dependent manner.
Macrophages promote fibroblast growth factor receptor-driven tumor cell migration and invasion in a CXCR2-dependent manner.
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DOI：
10.1158/1541-7786.mcr-12-0275
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发表时间：
2012-10
期刊：
影响因子：
--
通讯作者：
Schwertfeger KL
中科院分区：
文献类型：
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作者：
Bohrer LR;Schwertfeger KL
免疫细胞（特别是巨噬细胞）浸润到肿瘤微环境中与乳腺肿瘤形成和进展增加有关。乳腺上皮细胞内生长因子受体信号传导途径（如成纤维细胞生长因子受体1（FGFR 1）途径）的激活诱导巨噬细胞向乳腺上皮募集。这些巨噬细胞促进增加的上皮细胞增殖和血管生成。然而，这些巨噬细胞受癌前上皮细胞调节的具体机制以及巨噬细胞在发育中的FGFR 1驱动的肿瘤微环境中的作用机制仍然未知。在这项研究中，我们证明了乳腺中诱导型FGFR 1的激活导致与早期病变相关的巨噬细胞中转化生长因子β（TGFβ）/Smad 3途径的活性降低。进一步的研究表明，巨噬细胞在暴露于来自乳腺上皮细胞和肿瘤细胞的条件培养基（其中FGF途径已被激活）后，结合Cxcr 2的炎性趋化因子的表达增加。这些配体的增加在TGFβ途径活化后被抑制，表明TGFβ信号传导的减少有助于这些趋化因子的上调。使用共培养研究，我们进一步证明，巨噬细胞能够通过激活Cxcr 2促进上皮细胞和肿瘤细胞的迁移和侵袭。这些结果表明，巨噬细胞衍生的Cxcr 2配体可能是重要的促进乳腺肿瘤的形成FGFR信号调节。此外，这些结果表明，靶向Cxcr 2可能代表与高水平浸润性巨噬细胞相关的乳腺癌的新治疗策略。
Infiltration of immune cells, specifically macrophages, into the tumor microenvironment has been linked to increased mammary tumor formation and progression. Activation of growth factor receptor signaling pathways within mammary epithelial cells, such as the fibroblast growth factor receptor 1 (FGFR1) pathway, induces recruitment of macrophages to the mammary epithelium. These macrophages promote increased epithelial cell proliferation and angiogenesis. However, the specific mechanisms by which these macrophages are regulated by the preneoplastic epithelial cells and the mechanisms of action of the macrophages within the developing FGFR1-driven tumor microenvironment remain unknown. In this study, we demonstrate that activation of inducible FGFR1 in mammary glands leads to decreased activity of the transforming growth factor beta (TGFβ)/Smad3 pathway in macrophages associated with early stage lesions. Further studies demonstrate that macrophages have increased expression of inflammatory chemokines that bind Cxcr2 following exposure to conditioned media from mammary epithelial and tumor cells in which the FGF pathway had been activated. The increase in these ligands is inhibited following activation of the TGFβ pathway, suggesting that decreased TGFβ signaling contributes to the upregulation of these chemokines. Using co-culture studies, we further demonstrate that macrophages are capable of promoting epithelial and tumor cell migration and invasion through activation of Cxcr2. These results indicate that macrophage-derived Cxcr2 ligands may be important for promoting mammary tumor formation regulated by FGFR signaling. Furthermore, these results suggest that targeting Cxcr2 may represent a novel therapeutic strategy for breast cancers that are associated with high levels of infiltrating macrophages.