Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022 Wuhan, China.
Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022 Wuhan, China.
Int Immunopharmacol. 2019 Nov;76:105864. doi: 10.1016/j.intimp.2019.105864. Epub 2019 Aug 31.
Tumor-associated macrophages (TAMs) are closely related to poor prognosis in triple-negative breast cancer (TNBC). Thus, gaining insight into how TAMs support cancer progression could contribute to effective therapies. We utilized the 4 T1 murine TNBC cell line and murine bone marrow-derived macrophages to assess TAM-mediated pro-proliferative effects in vivo and in vitro. Further, Transcriptional analysis was performed to identify pathways activated in TAM-stimulated 4 T1 cells. We also explored the therapeutic efficacy of combining a mitogen-activated protein kinase kinase (MEK) inhibitor with TAM-targeted therapy using a TNBC mouse model. We found that the presence of TAMs was significantly associated with proliferating cancer cells in a TNBC mouse model. Moreover, RNA sequencing analysis showed that TAMs could enhance mitogen-activated protein kinase (MAPK) pathway activation in 4 T1 cells compared to that in control cells. Further, the depletion of TAMs by clodronate liposomes significantly reduced MAPK pathway activation in vivo. In addition, the blockade of MAPK signaling by a MEK inhibitor repressed TAM-mediated cancer cell proliferation. Most importantly, MEK inhibition combined with macrophage depletion significantly suppressed tumor growth and increased T lymphocyte infiltration in a TNBC model. Our study suggests the possibility that TAM-induced MAPK pathway activation promotes cancer cell proliferation. Thus, MEK inhibition combined with macrophage depletion might represent an effective treatment for TNBC.
肿瘤相关巨噬细胞（TAMs）与三阴性乳腺癌（TNBC）的预后不良密切相关。因此，深入了解 TAMs 如何支持癌症进展可能有助于开发有效的治疗方法。我们利用 4T1 鼠 TNBC 细胞系和鼠骨髓来源的巨噬细胞，评估了 TAMs 在体内和体外介导的促增殖作用。此外，我们进行了转录分析，以鉴定 TAM 刺激的 4T1 细胞中激活的途径。我们还探索了在 TNBC 小鼠模型中，将丝裂原活化蛋白激酶激酶（MEK）抑制剂与 TAM 靶向治疗相结合的治疗效果。我们发现，在 TNBC 小鼠模型中，TAMs 的存在与增殖的癌细胞显著相关。此外，RNA 测序分析表明，与对照细胞相比，TAMs 可以增强 4T1 细胞中丝裂原活化蛋白激酶（MAPK）途径的激活。此外，用氯膦酸盐脂质体耗竭 TAMs 可显著减少体内 MAPK 途径的激活。此外，MEK 抑制剂阻断 MAPK 信号通路可抑制 TAM 介导的癌细胞增殖。最重要的是，MEK 抑制联合巨噬细胞耗竭可显著抑制 TNBC 模型中的肿瘤生长并增加 T 淋巴细胞浸润。我们的研究表明，TAM 诱导的 MAPK 途径激活促进了癌细胞的增殖。因此，MEK 抑制联合巨噬细胞耗竭可能是治疗 TNBC 的一种有效方法。
