Interferon-gamma inhibits aldehyde dehydrogenasebright cancer stem cells in the 4T1 mouse model of breast cancer.
10.1097/CM9.0000000000001558
- Author:
Xiufen ZHUANG
1
;
Guilan SHI
2
;
Xiao HU
3
;
Huiru WANG
4
;
Wen SUN
1
;
Yanhong WU
5
Author Information
1. Department of Oncology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212000, China.
2. Department of Immunology, Zibo Vocational Institute Health School, Zibo, Shandong 255000, China.
3. Department of Oncology, Suqian First Hospital, Suqian, Jiangsu 223800, China.
4. Department of Blood Transfusion, The First Affiliated Hospital of USTC, Hefei, Anhui 230001, China.
5. Department of Medical Microbiology and Immunology, School of Basic Medical Sciences, Wannan Medical College, Wuhu, Anhui 241002, China.
- Publication Type:Journal Article
- MeSH:
Aldehydes;
Animals;
Breast Neoplasms;
Cell Line, Tumor;
Female;
Humans;
Interferon-gamma;
Mice;
Mice, Inbred BALB C;
Mice, Nude;
Neoplastic Stem Cells
- From:
Chinese Medical Journal
2021;135(2):194-204
- CountryChina
- Language:English
-
Abstract:
BACKGROUND:Despite improvements in disease diagnosis, treatment, and prognosis, breast cancer is still a leading cause of cancer death for women. Compelling evidence suggests that targeting cancer stem cells (CSCs) have a crucial impact on overcoming the current shortcomings of chemotherapy and radiotherapy. In the present study, we aimed to study the effects of T cells and a critical anti-tumor cytokine, interferon-gamma (IFN-γ), on breast cancer stem cells.
METHODS:BALB/c mice and BALB/c nude mice were subcutaneously injected with 4T1 tumor cells. Tumor growth and pulmonary metastasis were assessed. ALDEFLOUR™ assays were performed to identify aldehyde dehydrogenasebright (ALDHbr) tumor cells. ALDHbr cells as well as T cells from tumor-bearing BALB/c mice were analyzed using flow cytometry. The effects of CD8+ T cells on ALDHbr tumor cells were assessed in vitro and in vivo. The expression profiles of ALDHbr and ALDHdim 4T1 tumor cells were determined. The levels of plasma IFN-γ were measured by enzyme-linked immunosorbent assay, and their associations with the percentages of ALDHbr tumor cells were evaluated. The effects of IFN-γ on ALDH expression and the malignancy of 4T1 tumor cells were analyzed in vitro.
RESULTS:There were fewer metastatic nodules in tumor-bearing BALB/c mice than those in tumor-bearing BALB/c nude mice (25.40 vs. 54.67, P < 0.050). CD8+ T cells decreased the percentages of ALDHbr 4T1 tumor cells in vitro (control vs. effector to target ratio of 1:1, 10.15% vs. 5.76%, P < 0.050) and in vivo (control vs. CD8+ T cell depletion, 10.15% vs. 21.75%, P < 0.001). The functions of upregulated genes in ALDHbr 4T1 tumor cells were enriched in the pathway of response to IFN-γ. The levels of plasma IFN-γ decreased gradually in tumor-bearing BALB/c mice, while the percentages of ALDHbr tumor cells in primary tumors increased. IFN-γ at a concentration of 26.68 ng/mL decreased the percentages of ALDHbr 4T1 tumor cells (22.88% vs. 9.88%, P < 0.050) and the protein levels of aldehyde dehydrogenase 1 family member A1 in 4T1 tumor cells (0.86 vs. 0.49, P < 0.050) and inhibited the abilities of sphere formation (sphere diameter <200 μm, 159.50 vs. 72.0; ≥200 μm, 127.0 vs. 59.0; both P < 0.050) and invasion (89.67 vs. 67.67, P < 0.001) of 4T1 tumor cells.
CONCLUSION:CD8+ T cells and IFN-γ decreased CSC numbers in a 4T1 mouse model of breast cancer. The application of IFN-γ may be a potential strategy for reducing CSCs in breast cancer.
