Department of Immunology, School of Medicine, Nankai University, Tianjin, People's Republic of China.
State Key Lab of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, People's Republic of China.
Stem Cells. 2017 Dec;35(12):2351-2365. doi: 10.1002/stem.2720.
As an important component of the tumor microenvironment, CD4 CD25 Tregs reduce antitumor immunity, promote angiogenesis and metastasis in breast cancer. However, their function in regulating the "stemness" of tumor cells and the communication between Tregs and cancer stem cells (CSCs) remain elusive. Here, we disclose that the primarily cultured Tregs isolated from breast-tumor-bearing Foxp3-EGFP mouse upregulate the stemness property of breast cancer cells. Tregs increased the side-population and the Aldehyde dehydrogenase-bright population of mouse breast cancer cells, promoted their sphere formation in a paracrine manner, and enhanced the expression of stemness genes, such as Sox2 and so forth. In addition, Tregs increased tumorigenesis, metastasis, and chemoresistance of breast cancer cells. Furthermore, Sox2-overexpression tumor cells activated NF-κB-CCL1 signaling to recruit Tregs through reducing the binding of H3K27Me3 on promoter regions of p65 and Ccl1. These findings reveal the functional interaction between Tregs and CSCs and indicate that targeting on the communication between them is a promising strategy in breast cancer therapy. Stem Cells 2017;35:2351-2365.
作为肿瘤微环境的重要组成部分，CD4+CD25+Tregs 降低了抗肿瘤免疫，促进了乳腺癌的血管生成和转移。然而，它们在调节肿瘤细胞“干性”以及 Tregs 和癌症干细胞（CSCs）之间的通讯方面的功能仍不清楚。在这里，我们揭示了从 Foxp3-EGFP 小鼠荷瘤组织中分离的原代培养 Tregs 可上调乳腺癌细胞的干性。Tregs 增加了小鼠乳腺癌细胞的侧群和醛脱氢酶亮细胞群，通过旁分泌方式促进其球体形成，并增强干性基因（如 Sox2 等）的表达。此外，Tregs 增加了乳腺癌细胞的致瘤性、转移和化疗耐药性。此外，Sox2 过表达肿瘤细胞通过减少 p65 和 Ccl1 启动子区域 H3K27Me3 的结合，激活 NF-κB-CCL1 信号以招募 Tregs。这些发现揭示了 Tregs 和 CSCs 之间的功能相互作用，并表明针对它们之间的通讯是乳腺癌治疗的一种有前途的策略。《干细胞》2017；35:2351-2365。
