miR-149 Suppresses Breast Cancer Metastasis by Blocking Paracrine Interactions with Macrophages
miR-149 Suppresses Breast Cancer Metastasis by Blocking Paracrine Interactions with Macrophages
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DOI：
10.1158/0008-5472.can-19-1934
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发表时间：
2020-03-15
期刊：
影响因子：
11.2
通讯作者：
Olayioye, Monilola A.
中科院分区：
文献类型：
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作者：
Sanchez-Gonzalez, Ismael;Bobien, Anja;Olayioye, Monilola A.
肿瘤微环境中细胞的旁分泌激活促进肿瘤进展和转移。在乳腺癌中，恶性细胞招募巨噬细胞并将其培养成 M2 肿瘤促进表型，支持癌细胞的转移扩散。在这里，我们证明 miR-149 通过限制巨噬细胞的集落刺激因子 1 (CSF1) 依赖性募集和 M2 极化，在乳腺癌细胞中发挥转移抑制 microRNA 的作用。在淋巴结阳性、三阴性乳腺癌 (TNBC) 组织中，低 miR-149 表达与巨噬细胞浸润相关，并降低患者生存率。通过直接靶向 CSF1，TNBC 细胞系（MDA-MB-231 和 BT-549）中的 miR-149 表达抑制人单核 THP-1 细胞和原代人巨噬细胞的募集。此外，在与表达miR-149的MDA-MB-231细胞共培养的巨噬细胞中，表皮生长因子（EGF）和双调蛋白的表达水平显着降低，导致癌细胞中EGF受体激活减少。在体内，miR-149 表达使原位 MDA-MB-231 肿瘤发生的肺转移减少了 75%，这与原发肿瘤的 M2 巨噬细胞浸润受损有关。这些数据表明，miR-149 下调通过将巨噬细胞募集到肿瘤并促进癌细胞和巨噬细胞之间的 CSF1 和 EGF 受体串扰，在功能上有助于乳腺肿瘤进展。意义：这些发现有助于理解肿瘤基质相互作用，因为 TNBC 中 miR-149 下调增强了巨噬细胞和癌细胞之间的相互生长因子信号传导，从而促进肿瘤进展和转移。
Paracrine activation of cells contained in the tumor microenvironment promotes tumor progression and metastasis. In breast cancer, malignant cells recruit and educate macrophages into a M2 tumor-promoting phenotype that supports the metastatic spread of cancer cells. Here, we show that miR-149 functions as a metastasis-suppressing microRNA in breast cancer cells by limiting colonystimulating factor-1 (CSF1)-dependent recruitment and M2 polarization of macrophages. In lymph node-positive, triple-negative breast cancer (TNBC) tissues, low miR-149 expression correlated with macrophage infiltration and reduced patient survival. By directly targeting CSF1, miR-149 expression in TNBC cell lines (MDA-MB-231 and BT-549) inhibited the recruitment of human monocytic THP-1 cells and primary human macrophages. Furthermore, in macrophages cocultured with MDA-MB-231 cells expressing miR-149, epidermal growth factor (EGF) and amphiregulin expression levels were strongly reduced, resulting in reduced EGF receptor activation in the cancer cells. In vivo, lung metastases developing from orthotopic MDA-MB-231 tumors were reduced by 75% by miR-149 expression, and this was associated with impaired M2 macrophage infiltration of the primary tumors. These data suggest that miR-149 downregulation functionally contributes to breast tumor progression by recruiting macrophages to the tumor and facilitating CSF1 and EGF receptor cross-talk between cancer cells and macrophages.Significance: These findings contribute to the understanding of tumor-stroma interactions by showing that miR-149 downregulation in TNBC enhances reciprocal growth factor signaling between macrophages and cancer cells, which promotes tumor progression and metastasis.