肿瘤细胞源性乳酸诱导的肿瘤相关巨噬细胞中HMGB1的上调进一步促进结直肠癌的进展 二维码
发表时间:2024-08-28 14:19 2023年1月,中国科学院大学肿瘤医院(浙江省肿瘤医院)放射科;中国科学院基础医学与肿瘤研究所,中国科学院大学肿瘤医院(浙江省肿瘤医院)结直肠外科;浙江省上消化道肿瘤防治重点实验室 (Department of Radiology, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), 1 Banshan East Road, Hangzhou 310022, Zhejiang,People’s Republic of China;Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, 1 Banshan East Road, Hangzhou 310022, Zhejiang, People’sRepublic of China;Department of Colorectal Surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), 1 Banshan East Road, Hangzhou 310022, Zhejiang, People’s Republic of China;Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou 310022, China) Xinyi Gao老师研究团队在《Journal of Translational Medicine》上发表论文: “Upregulation of HMGB1 in tumor-associated macrophages induced by tumor cell-derived lactate further promotes colorectal cancer progression” “肿瘤细胞源性乳酸诱导的肿瘤相关巨噬细胞中HMGB1的上调进一步促进结直肠癌的进展” Abstract: Background: Lactate 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. Methods: Cell 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. Results: Cell 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. Conclusions: The lactate metabolized by cancer cells stimulated M2 polarization and HMGB1 secretion by macrophages, aggravating the carcinogenic behaviors of cancer cells. 摘要: 背景 乳酸积累导致酸性肿瘤微环境(TME),进而促进结直肠癌(CRC)的进展。肿瘤相关巨噬细胞(TAMs)是TME的主要细胞。本研究旨在揭示CRC细胞源性乳酸对TAMs的调控机制,探讨乳酸积累诱导CRC加重的机制。 方法 通过菌落形成、Transwell和伤口愈合试验来评估细胞生长和转移。Western blot和RT-qPCR检测蛋白和mRNA的表达。采用流式细胞术分析THP-1细胞诱导巨噬细胞极化状态及凋亡率。用ELISA试剂盒定量细胞上清液中的乳酸。采用免疫荧光法观察高迁移率组盒1 (HMGB1)的位置。采用H&E和Ki67染色法评价异位瘤裸鼠的肿瘤发生情况。 结果 低氧CRC细胞促进细胞生长和转移。低氧细胞上清刺激巨噬细胞的m2型极化。缺氧癌细胞中乳酸水平升高。然而,使用3-羟基丁酸(3-OBA)抑制乳酸逆转了缺氧的影响。此外,巨噬细胞在3-OBA存在下对癌细胞的生长和迁移没有促进作用。HMGB1分泌到乳酸诱导的巨噬细胞胞外间隙,进一步增强了癌细胞的恶性行为。由于HMGB1的上调,癌细胞中的ERK、EMT和Wnt信号通路被激活。 结论 癌细胞代谢的乳酸刺激巨噬细胞M2极化和HMGB1分泌,加重了癌细胞的致癌行为。 该论文中,SW480 (AW-CCH107)、HT29 (AW-CCH054)和THP-1 (AW-CCH098)及其经过体外刺激诱导的细胞的体外培养是使用Ausbian特级胎牛血清完成的。欲了解或购买Ausbian特级胎牛血清可以联系北京缔一生物400-166-8600. |
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