肿瘤干细胞标志物ALDH1A1通过重塑免疫微环境促进乳腺癌进展  

ALDH1A1 Activity in Cancer Stem Cells Remodels Immune-Microenvironment to Promote Breast Cancer Progression

作　　者：刘翠翠 张立行 柳素玲 LIU Cuicui;Zhang Lixing;LIU Suling(Fudan University Shanghai Cancer Center&Institutes of Biomedical Sciences,Key Laboratory of Breast Cancer in Shanghai,Shanghai Medical College,Fudan University,Shanghai 200032,China)

机构地区：[1]复旦大学附属肿瘤医院肿瘤研究所&生物医学研究院上海医学院上海市乳腺肿瘤重点实验室,上海200032

出　　处：《中国细胞生物学学报》2022年第3期405-412,共8页Chinese Journal of Cell Biology

摘　　要：醛脱氢酶1A1(ALDH1A1)是包括乳腺癌在内的多种癌症中肿瘤干细胞的功能性标志物,在肿瘤发生发展过程中扮演了重要角色。但是,ALDH1A1对肿瘤免疫微环境的影响及其调控机制尚不明确。该研究发现,ALDH1A1依赖于其酶活性促进乳腺肿瘤干细胞的自我更新以及肿瘤生长,同时肿瘤细胞中具有酶活性的ALDH1A1还可以促进肿瘤微环境中骨髓来源的免疫抑制细胞(MDSCs)的富集并抑制抗肿瘤免疫细胞活性。机制上,该团队发现具有酶活性的ALDH1A1可以通过降低肿瘤细胞内的pH值来激活TAK1-NFκB信号通路,激活的TAK1-NFκB信号通路通过上调粒细胞巨噬细胞刺激因子(GM-CSF)的分泌增加MDSCs在乳腺癌免疫微环境中的富集比例以及增强对杀伤性T细胞增殖和活化的抑制作用,从而促进肿瘤的生长。针对这一调控机制,该团队设计了具有MDSCs清除作用的化疗药物吉西他滨和ALDH1A1酶活性抑制剂双硫仑的联合治疗思路。免疫健全小鼠体内实验结果显示,二者联合可以更好地抑制乳腺癌的生长。这些研究结果进一步阐明了肿瘤干细胞标志物ALDH1A1对乳腺癌发生发展的影响及其发挥作用的具体分子机制,并揭示了ALDH^(+)乳腺肿瘤干细胞对MDSCs富集的调控作用,为乳腺癌的临床治疗提供了新的思路。CSCs(cancer stem cells)are associated with tumor initiation,growth,metastasis and recurrence.ALDH1A1(Aldehyde dehydrogenase 1A1)is a CSC marker in many cancers,including breast cancer,however the molecular mechanisms of ALDH1A1 functioning in solid tumors remain largely unknown.Here,the studies by LIU and colleagues demonstrate that ALDH1A1,solely relying on its enzymatic activity,decrease the intracellular pH of breast cancer cells to promote the phosphorylation of TAK1 and activate NFκB signaling pathway and then increase the secretion of GM-CSF(granulocyte macrophage colony-stimulating factor),which lead to MDSCs(myeloid derived suppressor cells)expansion and anti-tumor immunity suppression to facilitate breast tumor growth.Furthermore,the combination of ALDH1A1 inhibitor DSF(disulfiram)and chemotherapeutic agent GEM(gemcitabine)could cooperatively inhibit breast tumor growth and tumorigenesis by purging ALDH^(+)breast CSCs and activating T cell immunity.These findings elucidate the mechanisms of how active ALDH1A1 modulates tumor immunity to promote tumor development,which will shed light on new therapeutic strategies for malignant breast tumor.

关 键 词：乳腺癌 肿瘤干细胞 ALDH1A1 骨髓来源的免疫抑制细胞 细胞内pH TAK1 NFΚB GM-CSF 

分 类 号：R737.9[医药卫生—肿瘤]