Upregulation of HMGB1 in tumor-associated macrophages induced by tumor cell-derived lactate further promotes colorectal cancer progression

Journal of Translational Medicine

Research

Shiqi Zhou¹  Zhaofu Qin¹  Xinyi Gao²  Dechuan Li³  Yuping Zhu³  Dening Ma⁴ 

[1] Department of Colorectal Surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), 1 Banshan East Road, 310022, Hangzhou, Zhejiang, People’s Republic of China;Department of Radiology, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), 1 Banshan East Road, 310022, Hangzhou, Zhejiang, People’s Republic of China;Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, 1 Banshan East Road, 310022, Hangzhou, Zhejiang, People’s Republic of China;Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, 1 Banshan East Road, 310022, Hangzhou, Zhejiang, People’s Republic of China;Department of Colorectal Surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), 1 Banshan East Road, 310022, Hangzhou, Zhejiang, People’s Republic of China;Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, 1 Banshan East Road, 310022, Hangzhou, Zhejiang, People’s Republic of China;Department of Colorectal Surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), 1 Banshan East Road, 310022, Hangzhou, Zhejiang, People’s Republic of China;Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, 310022, Hangzhou, China;

关键词: Colorectal cancer;    Tumor-associated macrophages;    HMGB1;    Lactate;   

DOI  :  10.1186/s12967-023-03918-w

 received in 2022-11-20, accepted in 2023-01-23,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundLactate accumulation leads to an acidic tumor microenvironment (TME), in turn promoting colorectal cancer (CRC) progression. Tumor-associated macrophages (TAMs) are the predominant cells in TME. This study aimed to reveal the regulation mechanism of CRC cell-derived lactate on TAMs and explore the mechanism underlying lactate accumulation-induced aggravation in CRC.MethodsCell growth and metastasis were evaluated by colony formation, Transwell, and wound healing assays. Western blot and RT-qPCR were applied to determine the protein and mRNA expression. Flow cytometry was used to analyze the polarization state and apoptotic rate of macrophages induced in THP-1 cells. The lactate in the cell supernatant was quantified using an ELISA kit. Immunofluorescence was performed to visualize the location of High Mobility Group Box 1 (HMGB1). H&E and Ki67 staining assays were used to assess tumorigenesis in nude mice bearing ectopic tumors.ResultsCell growth and metastasis were promoted in the hypoxic CRC cells. The hypoxic cell supernatant stimulated the M2-type polarization of macrophages. The lactate level increased in hypoxic cancer cells. However, the inhibition of lactate using 3-hydroxy-butyrate (3-OBA) reversed the effects of hypoxia. Also, macrophages showed no promoting effect on cancer cell growth and migration in the presence of 3-OBA. HMGB1 was secreted into the extracellular space of lactate-induced macrophages, further enhancing the malignant behaviors of cancer cells. ERK, EMT, and Wnt signaling pathways were activated in cancer cells due to HMGB1 upregulation.ConclusionsThe lactate metabolized by cancer cells stimulated M2 polarization and HMGB1 secretion by macrophages, aggravating the carcinogenic behaviors of cancer cells.

【 授权许可】

CC BY   
© The Author(s) 2023

【 图 表 】

Fig. 5

40249_2022_1049_Article_IEq8.gif

Fig. 1

Fig. 3

Fig. 2