Cancer Therapy and Research Center, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021 Shandong, China.
Biomed Res Int. 2022 Apr 20;2022:9895504. doi: 10.1155/2022/9895504. eCollection 2022.
Metastasis is the major cause of cancer-related mortalities. A tumor-supportive microenvironment, also known as the premetastatic niche at secondary tumor sites, plays a crucial role in metastasis. Remodeling of the extracellular matrix (ECM) is essential for premetastatic niche formation, especially for circulating tumor cell colonization. However, the underlying molecular mechanism that contributes to this effect remains unclear. Here, we developed a lung metastasis model with 4T1 breast cancer cells and found that the metastasis critically depended on the early recruitment of macrophages to the lung. Disruption of macrophage recruitment reduced fibroblast activation and lung metastasis. Furthermore, we identified the secreted protein S100A4, which is produced by M2 macrophages and participates in fibroblast activation and ECM protein deposition via the ERK signaling pathway. Collectively, these results indicate that recruiting S100A4-expressing inflammatory macrophages plays a vital role in ECM remodeling in the premetastatic niche and may act as a potential therapeutic target for breast cancer lung metastasis.
转移是癌症相关死亡的主要原因。肿瘤支持的微环境，也称为次级肿瘤部位的前转移龛，在转移中起着至关重要的作用。细胞外基质 (ECM) 的重塑对于前转移龛的形成至关重要，特别是对于循环肿瘤细胞的定植。然而，导致这种效应的潜在分子机制尚不清楚。在这里，我们开发了一种带有 4T1 乳腺癌细胞的肺转移模型，发现转移严重依赖于巨噬细胞向肺部的早期募集。阻断巨噬细胞募集会减少成纤维细胞的激活和肺转移。此外，我们鉴定了一种分泌蛋白 S100A4，它由 M2 巨噬细胞产生，并通过 ERK 信号通路参与成纤维细胞激活和 ECM 蛋白沉积。综上所述，这些结果表明，招募表达 S100A4 的炎症性巨噬细胞在前转移龛的 ECM 重塑中起着至关重要的作用，可能成为乳腺癌肺转移的潜在治疗靶点。
