A growing body of research has shown that a small number of cells with particularly strong tumorigening ability, very low degree of differentiation, and self-renewal and multidirectional differentiation characteristics of stem cells in a variety of tumor tissues are called "Cancer Stem Cells". Aldehyde dehydrogenase 1A1 (ALDH1A1) is one of the important biomarkers for Breast Cancer Stem Cells (BCSCs). It has been found that ALDH1A1 is also a predictor of the development and poor prognosis of breast cancer, and its expression and enzyme activity have an important regulatory effect on tumorigenesis and development. However, the specific mechanisms by which ALDH1A1 promotes breast cancer progression and how to maintain the BCSC properties are unclear, and addressing this question will give us new hope for the design of specific antineoplastic drugs that target tumor stem cells.
On December 1, 2021, Suling Liu's team and collaborators from the Institute of Biomedical Research/Affiliated Cancer Hospital of Fudan University published an online article titled ALDH1A1 activity in tumor-initiating cells remodels myeloid-derived suppressor to promote breast cancer progression The research paper reveals the remodeling and pro-tumor effect of ALDH1A1 on the immune microenvironment of breast cancer and its specific molecular mechanisms, which helps us better elucidate the impact of the BCSC marker ALDH1A1 on the occurrence and development of breast tumors, and provides new ideas for the clinical treatment of malignant breast cancer.
In order to analyze the remodeling effect of ALDH1A1 on the immune microenvironment of breast cancer, the authors constructed a three-negative breast cancer stable cell line that expressed wild-type ALDH1A1 (with enzymatic activity) and K193Q/R mutants (without enzyme activity), and found that ALDH1A1 relied on its aldehyde dehydrogenase activity to promote BCSC self-renewal and tumor growth through in vitro cell proliferation function test and in vivo breast in situ transplant tumor test. Immune cell staining and flow cytometry showed that ALDH1A1-dependent enzyme activity promoted the enrichment of MDSCs in the tumor microenvironment, and MDSCs inhibited cd8+ T cell immune activity to promote tumor growth, and inhibited ALDH1A1 enzyme activity and knocked down its expression showed the opposite effect. Due to the low proliferation rate of CSCs and the high resistance to immune-mediated killing, when a large number of ordinary tumor cells are cleared by the immune system, CSCs can still evade the damage of the immune system, and in this process of immune escape, in addition to the continuous increase in tumor stem cell heterogeneity and genetic variation, the changes in the tumor immune microenvironment also play an indispensable role; this study found that the BCSC biomarker ALDH1A1 on MDSCs and active CD8+ T cells regulation.
Mechanically, they found that ALDH1A1 relies on its enzyme activity to reduce the pH value in tumor cells, thereby activating the TAK1-NFκB signaling pathway, which increases the secretion of granulocyte macrophage stimulating factor (GM-CSF) in tumor cells, and then induces an increase in MDSCs in the tumor microenvironment, and the increase in MDSCs ultimately inhibits the anti-tumor immune activity of CD8+ T cells to promote breast tumor growth.
Aiming at the specific mechanisms that ALDH1A1 exerts to promote breast cancer, they designed a combination therapy strategy to target malignant breast cancer more efficiently. They treated immunocompetent mouse models of immunocompetent mouse breast in situ transplant tumors and immunodeficient human breast tumor transplant tumors (PDX) alone or in combination, using gemcitabine, a chemotherapy drug that can eliminate MDSCs, and disulfiram, an inhibitor that inhibits the activity of the ALDH1A1 enzyme. The results showed that the combination therapy effect was better than that of any single drug treatment, and the combination use had a better anti-tumor effect and more effectively inhibited the growth of breast tumors; at the same time, the combination therapy could better inhibit the infiltration of ALDH+ BCSCs and MDSCs in the immune microenvironment in tumor tissues.
Overall, this study found that ALDH1A1 relies on enzyme activity to reduce intracellular pHi in breast tumor cells to activate the TAK1-NFκB signaling pathway, which in turn leads to increased GM-CSF secretion, induces MDSC amplification and reduces anti-tumor immunity, thereby promoting the development of breast tumors. These findings help us better elucidate the effect of the BCSC marker ALDH1A1 on the development of breast cancer and its specific molecular mechanisms, provide direct evidence for demonstrating the interaction of BCSC and MDSCs with ALDH enzyme activity, and provide a new and effective therapeutic target for the clinical treatment of breast cancer. As soon as the paper was published, Lorenzo Galluzzi et al. reviewed their work in the journal "MDSCs sneak CSCs out of immune-surveillance" in the journal "MDSCs sneak CSCs out of immune-surveillance", and gave them a high evaluation, arguing that this study provides a new perspective for breaking the vicious circle of CSCs recruiting MDSCs, which in turn promote the vicious circle of CSCs stem. Breaking this vicious cycle can reshape the body's immune surveillance of CSCs, thereby controlling tumor progression.
Liu Cuicui, a doctoral candidate in Liu Suling's research group, is the first author of the paper, professor Liu Suling, Zhang Lixing, associate researcher of Fudan University Affiliated Cancer Hospital, Professor Zhang Xiaoyong of Fudan University Institute of Brain Science, and Professor Shao Zhimin of Fudan University Affiliated Cancer Hospital are the co-corresponding authors of this paper.
Aldehyde dehydrogenase 1A1 (ALDH1A1) is a marker of tumor-initiating cells in many other solid tumors, though the molecular mechanisms of ALDH1A1 functioning remain elusive. The study by Liu and colleagues demonstrated that ALDH1A1 decreased the pHi of cancer cells by its enzyme activity to activate TAK1-NFκB signaling pathway, which led to the increased GM-CSF secretion and then MDSC expansion to reduce anti-tumor immunity and facilitate cancer progression. The combination of Gemcitabine (GEM) and Disulfiram (DSF) synergistically suppressed breast tumor growth by adjusting an immunomodulatory effect on CD8+ T cells. The image is inspired by the ancient novel Pilgrimage to the West, depicting that a novel therapeutic strategy to treat breast cancer by targeting ALDH+ BTICs (Black Bear Evil Monster with a Lance) and MDSCs (Snake Evil Monster) with GEM (Salix Leaf from the Bottle) and DSF (The Golden Cudgel). The Art was created by Chloe Liao.
Original link:
https://cancerres.aacrjournals.org/content/81/23/5919
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