Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Integration of Chinese and Western Medicine, Peking University Cancer Hospital and Institute, Beijing, 100142, PR China; Ningxia Medical University Pharmacy College, Key Laboratory of Hui Ethnic Medicine Modernization, Ministry of Education, Ningxia Research Center of Modern Hui Medicine Engineering and Technology, Yinchuan, 750004, PR China.
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Integration of Chinese and Western Medicine, Peking University Cancer Hospital and Institute, Beijing, 100142, PR China.
J Ethnopharmacol. 2021 Jun 28;274:113978. doi: 10.1016/j.jep.2021.113978. Epub 2021 Mar 11.
ETHNOPHARMACOLOGICAL RELEVANCE: Triple-negative breast cancer (TNBC) is the most aggressive and the worst prognosis breast cancer with limited treatment options. Taraxacum mongolicum (also called dandelion) is a traditional Chinese medicine has been used to treat mastitis, breast abscess, and hyperplasia of mammary glands since ancient times. In modern pharmacological research, dandelion has been proven with anti-breast cancer activities. We previously reported that dandelion extract could induce apoptosis in TNBC cells. However, its anti-tumor effects and mechanisms in the tumor microenvironment have not yet been elucidated. AIM OF THE STUDY: Tumor-associated macrophages (TAMs) play an important role in regulating the interaction between tumor cells and the immune system. The present study aimed to investigate the effects and mechanisms of dandelion extract on TNBC cells under the microenvironment of TAMs, as well as its influence on the polarization of M2 macrophages. MATERIALS AND METHODS: M2 macrophages were induced by phorbol-12-myristate 13-acetate (PMA) and interleukin 4 (IL-4), and verified by flow cytometry, quantitative RT-PCR (qRT-PCR), Western blotting, and ELISA. MDA-MB-231 and MDA-MB-468 TNBC cells were co-cultured with the supernatant of M2 macrophage which providing the TAMs microenvironment. The antitumor activity of dandelion extract in TNBC cells was evaluated by MTT assay. The invasive and migratory capacity of TNBC cells was measured by transwell assays. The expression of protein and gene was assessed by Western blotting and qRT-PCR, respectively. RESULTS: TAMs microenvironment promoted the proliferation, migration, and invasion of TNBC cells. However, dandelion extract inhibited the malignant property of MDA-MB-231 and MDA-MB-468 cells induced by TAMs. Both of TAMs and IL-10 caused STAT3 activation and PD-L1 higher expression, the immunosuppressive molecules in TNBC cells, and this effect can be attenuated by IL-10 neutralizing antibody. Dandelion extract exerted inhibition on STAT3 and PD-L1 in TNBC cells under TAMs microenvironment. Furthermore, in M2 macrophages, dandelion extract remarkably promoted the expression of M1-like marker TNF-α, IL-8, and iNOS, but reduced M2-like marker IL-10, CD206, Arginase-1, and TGF-β. CONCLUSION: Dandelion extract inhibited the proliferation, migration and invasion of TNBC cells in TAMs microenvironment through suppressing IL-10/STAT3/PD-L1 immunosuppressive signaling pathway. Furthermore, dandelion extract promoted the polarization of macrophages from M2 to M1 phenotype. Thus, our results indicated that dandelion may serve as a promising therapeutic strategy for TNBC by modulating tumor immune microenvironment.
民族药理学相关性：三阴性乳腺癌（TNBC）是最具侵袭性和预后最差的乳腺癌，治疗选择有限。蒲公英（又称蒲公英）是一种传统中药，自古以来一直用于治疗乳腺炎、乳腺脓肿和乳腺增生。在现代药理学研究中，蒲公英已被证明具有抗乳腺癌活性。我们之前的研究报告表明，蒲公英提取物可诱导 TNBC 细胞凋亡。然而，其在肿瘤微环境中的抗肿瘤作用及其机制尚未阐明。
研究目的：肿瘤相关巨噬细胞（TAMs）在调节肿瘤细胞与免疫系统之间的相互作用中起着重要作用。本研究旨在探讨蒲公英提取物在 TAMs 微环境下对 TNBC 细胞的作用及其机制，以及对 M2 巨噬细胞极化的影响。
材料和方法：用佛波醇 12-肉豆蔻酸 13-乙酸酯（PMA）和白细胞介素 4（IL-4）诱导 M2 巨噬细胞，并用流式细胞术、定量 RT-PCR（qRT-PCR）、Western blot 和 ELISA 进行验证。将 MDA-MB-231 和 MDA-MB-468 TNBC 细胞与提供 TAMs 微环境的 M2 巨噬细胞上清液共培养。用 MTT 法评估蒲公英提取物对 TNBC 细胞的抗肿瘤活性。Transwell 测定 TNBC 细胞的侵袭和迁移能力。Western blot 和 qRT-PCR 分别评估蛋白和基因的表达。
结果：TAMs 微环境促进了 TNBC 细胞的增殖、迁移和侵袭。然而，蒲公英提取物抑制了 TAMs 诱导的 MDA-MB-231 和 MDA-MB-468 细胞的恶性表型。TAMs 和白细胞介素 10（IL-10）均导致 STAT3 激活和 PD-L1 高表达，这是 TNBC 细胞中的免疫抑制分子，而 IL-10 中和抗体可减弱这种作用。蒲公英提取物在 TAMs 微环境下对 TNBC 细胞中的 STAT3 和 PD-L1 发挥抑制作用。此外，在 M2 巨噬细胞中，蒲公英提取物显著促进 TNF-α、IL-8 和 iNOS 等 M1 样标记物的表达，但降低 IL-10、CD206、精氨酸酶 1 和 TGF-β等 M2 样标记物的表达。
结论：蒲公英提取物通过抑制 IL-10/STAT3/PD-L1 免疫抑制信号通路抑制 TNBC 细胞在 TAMs 微环境中的增殖、迁移和侵袭。此外，蒲公英提取物促进了 M2 型向 M1 型表型的巨噬细胞极化。因此，我们的研究结果表明，蒲公英提取物通过调节肿瘤免疫微环境，可能成为治疗 TNBC 的一种有前途的治疗策略。
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