β-Catenin-CCL2 feedback loop mediates crosstalk between cancer cells and macrophages that regulates breast cancer stem cells.
β-Catenin-CCL2 feedback loop mediates crosstalk between cancer cells and macrophages that regulates breast cancer stem cells.
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β-连环蛋白-CCL2 反馈环介导癌细胞和调节乳腺癌干细胞的巨噬细胞之间的串扰。
DOI：
10.1038/s41388-021-01986-0
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发表时间：
2021
期刊：
影响因子：
8
通讯作者：
Liu Hao
中科院分区：
文献类型：
--
作者：
Zhang Fan;Li Pan;Liu Shuang;Yang Mingqiang;Zeng Shanshan;Deng Junjian;Chen Danyang;Yi Yanmei;Liu Hao
乳腺癌是全世界妇女中最常见的癌症。虽然诊断和治疗的进步延长了乳腺癌患者的总生存期（OS），但转移仍然是提高乳腺癌患者生存率的主要障碍。乳腺癌干细胞的存在是导致肿瘤转移和复发的主要原因。因此，了解维持BCSC特性和靶向BCSC的分子途径将最终改善乳腺癌治疗。在本研究中，我们发现β-Catenin的激活直接在转录水平上调节CCL 2的表达，进而促进巨噬细胞浸润和M2极化。此外，与乳腺癌细胞共培养的巨噬细胞显示CCL 2表达显著增加并促进β-连环蛋白诱导的BCSC特性，而通过加入中和抗体耗尽CCL 2抑制BSCS特性。此外，我们发现β-Catenin介导的CCL 2分泌将巨噬细胞招募到肿瘤微环境中，并促进乳腺癌的体内生长和转移。临床上我们观察到β-Catenin、CCL 2和CD 163的表达之间存在显著的正相关性，并且β-Catenin、CCL 2和CD 163的表达增加预示着乳腺癌的不良预后。此外，CCR 2和β-连环蛋白的药理学抑制协同抑制BCSC特性和乳腺癌生长。总的来说，我们的研究结果表明，β-连环蛋白介导的CCL 2分泌在乳腺癌细胞和巨噬细胞之间形成了一个旁分泌反馈回路，这反过来又促进了BCSC的特性，并支持乳腺癌的生长和转移。靶向β-Catenin/CCL 2信号通路可能是乳腺癌治疗的有效策略。
Breast cancer is the most frequently diagnosed cancer among women worldwide. Though advances in diagnosis and treatment have prolonged overall survival (OS) for patients with breast cancer, metastasis remains the major obstacles to improved survival for breast cancer patients. The existence of breast cancer stem cells (BCSCs) is a major reason underlying cancer metastasis and recurrence. Therefore, understanding the molecular pathways sustaining BCSC properties and targeting BCSCs will ultimately improve breast cancer treatments. In this study, we found that activation of β-Catenin directly regulated CCL2 expression at the transcriptional level, and in turn promoted macrophages infiltration and M2 polarization. Moreover, macrophages co-cultured with breast cancer cells showed a significant increase in CCL2 expression and promoted β-Catenin-induced BCSCs properties, whereas depletion of CCL2 by adding neutralizing antibodies suppressed BSCSs properties. In addition, we found that β-Catenin-mediated CCL2 secretion recruited macrophages into tumor microenvironment and promoted breast cancer growth and metastasis in vivo. Clinically, we observed a significant positive correlation between β-Catenin, CCL2 and CD163 expression, and increased expression of β-Catenin, CCL2 and CD163 predicted poor prognosis in breast cancer. Furthermore, pharmacological inhibition of CCR2 and β-Catenin synergistically suppressed BCSC properties and breast cancer growth. Collectively, our findings suggested that β-Catenin-mediated CCL2 secretion forms a paracrine feedback loop between breast cancer cells and macrophages, which in turn promotes BCSC properties and supports breast cancer growth and metastasis. Targeting β-Catenin/CCL2 signaling might be an effective strategy for breast cancer therapy.