Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran.
Int Immunopharmacol. 2022 May;106:108581. doi: 10.1016/j.intimp.2022.108581. Epub 2022 Feb 8.
The compound "2-methylpyridine-1-ium-1-sulfonate" (MPS) is the active constituent of Allium hirtifolium Boiss. bulbs with potent anti-angiogenic and anti-cancer activities. Tumor microenvironment (TME) plays a key role in tumor progression via tumor derived exosome (TEX) mediated polarization of M2 type tumor associated macrophages (TAMs). In this study, we explored direct and colorectal cancer (CRC) exosome-mediated impacts of MPS on macrophage polarization to find out whether MPS could modify TEX in favor of anti-tumor M1-like macrophage polarization. After MPS isolation and characterization, first its direct anti-cancer effects were evaluated on HT-29 cells. Then, TEX were isolated from untreated (C-TEX) and MPS-treated (MPS-TEX) HT-29 cells. THP-1 M0 macrophages were incubated with MPS, C-TEX and MPS-TEX. Macrophage polarization was evaluated by flow cytometry, ELISA and gene expression analysis of several M1- and M2-related markers. MPS induced apoptosis and cell cycle arrest and reduced the migration ability of HT-29 cells. C-TEX polarized M0 macrophages toward a mixed M1-/M2-like phenotype with a high predominance of M2-like cells. Macrophage treatment with MPS was associated with the induction of M1-like phenotype. Also, MPS was demonstrated to ameliorate TEX-mediated effects in favor of M1-like polarization. In conclusion, our study addresses for the first time, the potential capability of MPS in skewing macrophages toward an anti-cancer M1-like phenotype both directly and in a TEX-dependent manner. Thus, in addition to its direct anti-cancer effects, this compound could also modify TME in favor of tumor eradication via its direct and TEX-mediated effects on macrophage polarization as a novel anti-cancer mechanism.
“2-甲基吡啶-1-磺酸根”（MPS）是具有强大抗血管生成和抗癌活性的葱属植物鳞茎的活性成分。肿瘤微环境（TME）通过肿瘤衍生的外泌体（TEX）介导的 M2 型肿瘤相关巨噬细胞（TAM）极化在肿瘤进展中起着关键作用。在这项研究中，我们探索了 MPS 对巨噬细胞极化的直接和结直肠癌（CRC）外泌体介导的影响，以确定 MPS 是否可以修饰 TEX，有利于抗肿瘤 M1 样巨噬细胞极化。在分离和表征 MPS 后，首先评估其对 HT-29 细胞的直接抗癌作用。然后，从未经处理的（C-TEX）和 MPS 处理的（MPS-TEX）HT-29 细胞中分离 TEX。将 THP-1 M0 巨噬细胞与 MPS、C-TEX 和 MPS-TEX 孵育。通过流式细胞术、ELISA 和几种 M1 和 M2 相关标志物的基因表达分析评估巨噬细胞极化。MPS 诱导 HT-29 细胞凋亡、细胞周期停滞和迁移能力降低。C-TEX 将 M0 巨噬细胞极化为混合的 M1-/M2 样表型，M2 样细胞占主导地位。巨噬细胞用 MPS 处理与诱导 M1 样表型有关。此外，还证明 MPS 可以改善 TEX 介导的作用，有利于 M1 样极化。总之，我们的研究首次表明，MPS 具有将巨噬细胞偏向抗癌 M1 样表型的潜力，无论是直接作用还是通过 TEX 依赖性作用。因此，除了直接的抗癌作用外，这种化合物还可以通过其对巨噬细胞极化的直接和 TEX 介导作用来修饰 TME，有利于通过肿瘤消除，作为一种新的抗癌机制。
