Motta Juliana Maria, Rumjanek Vivian Mary, Mantovani Alberto, Locati Massimo
Instituto de Bioquímica Médica Leopoldo de Meis, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil.
Humanitas Clinical and Research Center-IRCCS, 20089 Rozzano, Italy.
Biomedicines. 2021 Oct 4;9(10):1387. doi: 10.3390/biomedicines9101387.
Macrophages play a central role within the tumor microenvironment, with relevant implications for tumor progression. The modulation of their phenotype is one of the mechanisms used by tumors to escape from effective immune responses. This study was designed to analyze the influence of soluble products released by tumors, here represented by the tumor-conditioned media of two tumor cell lines (3LL from Lewis lung carcinoma and MN/MCA from fibrosarcoma), on murine macrophage differentiation and polarization in vitro. Data revealed that tumor-conditioned media stimulated macrophage differentiation but influenced the expression levels of macrophage polarization markers, cytokine production, and microRNAs of relevance for macrophage biology. Interestingly, tumor-derived soluble products supported the survival and proliferation rate of bone marrow precursor cells, an effect observed even with mature macrophages in the presence of M2 but not M1 inducers. Despite presenting low concentrations of macrophage colony-stimulating factor (M-CSF), tumor-conditioned media alone also supported the proliferation of cells to a similar extent as exogenous M-CSF. This effect was only evident in cells positive for the expression of the M-CSF receptor (CD115) and occurred preferentially within the CD16 subset. Blocking CD115 partially reversed the effect on proliferation. These results suggest that tumors release soluble products that not only promote macrophage development from bone marrow precursors but also stimulate the proliferation of cells with specific phenotypes that could support protumoral functions.
巨噬细胞在肿瘤微环境中发挥核心作用，对肿瘤进展具有重要影响。其表型的调节是肿瘤逃避有效免疫反应所采用的机制之一。本研究旨在分析肿瘤释放的可溶性产物（此处以两种肿瘤细胞系的肿瘤条件培养基为代表，即Lewis肺癌的3LL和纤维肉瘤的MN/MCA）对小鼠巨噬细胞体外分化和极化的影响。数据显示，肿瘤条件培养基刺激巨噬细胞分化，但影响巨噬细胞极化标志物的表达水平、细胞因子产生以及与巨噬细胞生物学相关的微小RNA。有趣的是，肿瘤衍生的可溶性产物支持骨髓前体细胞的存活和增殖率，即使在存在M2而非M1诱导剂的情况下，成熟巨噬细胞也能观察到这种效应。尽管肿瘤条件培养基中巨噬细胞集落刺激因子（M-CSF）浓度较低，但单独的肿瘤条件培养基也能在与外源性M-CSF相似的程度上支持细胞增殖。这种效应仅在M-CSF受体（CD115）表达阳性的细胞中明显，且优先发生在CD16亚群内。阻断CD115可部分逆转对增殖的影响。这些结果表明，肿瘤释放可溶性产物，不仅促进骨髓前体细胞向巨噬细胞的发育，还刺激具有特定表型的细胞增殖，这些细胞可能支持肿瘤相关功能。
