Department of Laboratory Medicine and Pathology and Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
Mol Cancer Res. 2012 Oct;10(10):1294-305. doi: 10.1158/1541-7786.MCR-12-0275. Epub 2012 Aug 14.
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 show that activation of inducible FGFR1 in mammary glands leads to decreased activity of the TGFβ/Smad3 pathway in macrophages associated with early stage lesions. Further studies show 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 coculture studies, we further show 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.
免疫细胞（尤其是巨噬细胞）浸润肿瘤微环境与乳腺肿瘤的形成和进展增加有关。乳腺上皮细胞中生长因子受体信号通路的激活，如成纤维细胞生长因子受体 1（FGFR1）通路，会诱导巨噬细胞向乳腺上皮细胞募集。这些巨噬细胞促进上皮细胞增殖和血管生成。然而，这些巨噬细胞被肿瘤前上皮细胞调控的具体机制以及巨噬细胞在 FGFR1 驱动的肿瘤微环境中的作用机制尚不清楚。在这项研究中，我们表明，乳腺中诱导型 FGFR1 的激活导致与早期病变相关的巨噬细胞中 TGFβ/Smad3 通路活性降低。进一步的研究表明，巨噬细胞表达的炎症趋化因子增加，这些趋化因子在暴露于 FGFR 通路被激活的乳腺上皮细胞和肿瘤细胞的条件培养基后与 Cxcr2 结合。TGFβ 通路的激活抑制了这些配体的增加，表明 TGFβ 信号的降低有助于这些趋化因子的上调。通过共培养研究，我们进一步表明，巨噬细胞通过激活 Cxcr2 能够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 Cxcr2 配体可能是 FGFR 信号调控的乳腺肿瘤形成的重要因素。此外，这些结果表明，靶向 Cxcr2 可能是一种针对与浸润巨噬细胞水平高相关的乳腺癌的新的治疗策略。
