Cancer Res Liu Suling/Zhang Lixing/Shao Zhimin/Zhang Xiaoyong of Fudan University Reveal the Important Mechanism of ALDH1A1 Enzyme Activity Promotes Breast Tumor Growth

iNature tumor initiating cells (TICs) are involved in tumor initiation, growth, metastasis and recurrence
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Aldehyde dehydrogenase 1A1 (ALDH1A1) is a TIC marker for many cancers, including breast cancer
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However, the molecular mechanisms by which ALDH1A1 functions in solid tumors remain unclear
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On December 1, 2021, Liu Suling/Zhang Lixing/Shao Zhimin of Fudan University Affiliated Cancer Hospital and Professor Zhang Xiaoyong of Fudan University Brain Science Research Institute jointly published an online publication entitled "ALDH1A1 activity in tumor-initiating" in the journal Cancer Research (IF=13).
cells remodels myeloid-derived suppressor to promote breast cancer progression ” research paper demonstrating that ALDH1A1 enzymatic activity promotes breast tumor growth
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Mechanistically, ALDH1A1 reduces intracellular pH in breast cancer cells, promotes the phosphorylation of TAK1, activates the NFkB signaling pathway, and increases the secretion of GM-CSF, resulting in the expansion of myeloid-derived suppressor cells and immunosuppression
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Furthermore, the ALDH1A1 inhibitor disulfiram and the chemotherapeutic drug gemcitabine synergistically inhibit breast tumor growth and tumorigenesis by clearing aldh1tic and activating T-cell immunity
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Taken together, this study elucidates how ALDH1A1 enzymatic activity modulates the immune system to promote tumor development, leading to the development of new therapeutic strategies for malignant breast cancer
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Compared with other breast cancer subtypes, triple-negative breast cancer (TNBC) has multiple aggressive clinical features, including high rates of metastasis, recurrence, poor survival, and high levels of breast tumor-initiating cells ( breast tumor-initiator cells, BTIC)
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Due to the lack of specific therapeutic targets, it is particularly urgent to find a reliable and effective strategy for TNBC
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Tumor-initiating cells, also known as tumor stem cells, refer to a subset of tumor cells that exist within the tumor mass, and have the characteristics of tumorigenesis, self-renewal, and resistance to chemotherapy
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They are associated with tumor initiation, growth and metastasis
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Unlike other TIC markers, aldehyde dehydrogenase (ALDH) is quite unique in that it detects endogenous enzymatic activity to characterize TIC stemness, rather than cell surface molecules such as CD133+ and CD24-/CD44+
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The ALDH family consists of 19 isozymes with important physiological and toxicological functions, and is a NADP-dependent superfamily capable of metabolizing endogenous and exogenous aldehydes to carboxylic acids
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ALDH1A1 was confirmed to be the first among most ALDH isozymes with enzymatic activity obtained in the ALDH substrate metabolism assay
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As a biomarker of breast cancer, prostate cancer, colon cancer, lung cancer and other tumors, ALDH1A1 plays an important role in promoting tumor angiogenesis, metastasis, and acquiring anti-tumor drug resistance
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Although ALDH1A1 has been reported to regulate retinoic acid (RA) biosynthesis and RA signaling in acute promyelocytic leukemia, all-transRA treatment of solid tumors was not as effective as APL treatment, suggesting that ALDH1A1 functions as a metabolic Enzymes, may have different molecular mechanisms in regulating the malignant phenotype of solid tumors
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Recent studies have shown that PD-L1 expression is abundant in ALDH1A1-expressing TNBC patient tissues, and ALDH1A1-expressing breast cancer cells have lower expression of antigen processing and presentation proteins (TAP-1 and TAP-2) and costimulatory molecules (CD80)
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Immune cells interact with cancer cells in the tumor microenvironment (TME), which can directly induce the BTIC phenotype and local immunosuppression, and promote tumorigenesis and development
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Furthermore, BTICs activate and recruit immunosuppressive cells, including myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs), to suppress immune responses
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MDSCs are the major immunosuppressive cells found in breast cancer and are defined as a heterogeneous cell population of myeloid origin consisting of myeloid progenitors, immature macrophages, immature granulocytes and immature dendritic cells composition
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Two major subpopulations of MDSCs have been identified: monocytes (M-MDSCs) and polymorphonuclear cells (PMN-MDSCs)
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However, whether and how the functional BTIC marker ALDH1A1 regulates the immunosuppressive TME to promote breast cancer development remains to be elucidated
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In this study, this study found that ALDH1A1 reduces intracellular pH in breast cancer cells through its enzymatic activity, increases TAK1 phosphorylation, activates NFkB signaling pathway, which in turn stimulates GMCSF secretion, induces MDSC expansion, which in turn reduces anti-tumor immunity and promotes breast cancer progression
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Therapeutic, ALDH1A1 inhibitor disulfiram (DSF) combined with the MDSC depleting agent gemcitabine (GEM) significantly inhibited breast tumor growth
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Mechanism of ALDH1A1 enzymatic activity in tumor-initiating cells suppressing immune processes (image courtesy of Cancer Research) In conclusion, this study elucidates the functional and molecular mechanism of ALDH1A1 regulating the interaction of BTICs and MDSCs to promote breast cancer development, which may provide evidence for malignant breast cancer.
provides a new therapeutic strategy
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Liu Cuicui, a doctoral student at Fudan University Affiliated Cancer Hospital, is the first author of the paper; Prof.
Liu Suling, Fudan University Biomedical Research Institute/Affiliated Cancer Hospital, Zhang Lixing, an associate researcher at Fudan University Affiliated Cancer Hospital, Prof.
Zhang Xiaoyong, Fudan University Brain Science Research Institute, and Fudan University Affiliated Cancer Institute Professor Shao Zhimin of the hospital is the co-corresponding author of this article
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Reference message: https://cancerres.
aacrjournals.
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