ALDH1A1 Activity in Cancer Stem Cells Remodels Immune-Microenvironment to Promote Breast Cancer Progression
LIU Cuicui, ZHANG Lixing, LIU Suling*
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.
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