Tumor-Conditioned Macrophages Secrete Migration-Stimulating Factor: A New Marker for M2-Polarization, Influencing Tumor Cell Motility
Tumor-Conditioned Macrophages Secrete Migration-Stimulating Factor: A New Marker for M2-Polarization, Influencing Tumor Cell Motility
复制标题
DOI：
10.4049/jimmunol.1000413
复制
发表时间：
2010-07-01
影响因子：
4.4
通讯作者：
Allavena, Paola
中科院分区：
文献类型：
--
作者：
Solinas, Graziella;Schiarea, Silvia;Allavena, Paola
肿瘤相关巨噬细胞（TAM）是肿瘤微环境的关键协调者，直接影响肿瘤细胞生长、新血管生成和细胞外基质重塑。反过来，肿瘤环境强烈影响TAM的成熟并形成其几个特征。为了解决恶性背景下的早期巨噬细胞（M phi）分化阶段，我们通过体外共培养人血单核细胞与来自不同癌细胞系的条件培养基来模拟肿瘤微环境。16个肿瘤细胞系中只有2个由于分泌的M-CSF同种型（包括高分子量物质）而诱导M phi分化。进行肿瘤条件M phi的全局基因谱分析。与其他数据集（极化M1-M phi、M2-M phi和从人类肿瘤中分离的TAM）的比较突出了TAM和M2-极化M phi也共有的几个基因的上调。表达最多的基因是硒蛋白1、骨激活素、骨桥蛋白，有趣的是，还有迁移刺激因子（MSF），一种研究较少的癌胚纤维连接蛋白亚型。MSF（存在于胎儿/癌上皮细胞和基质细胞中，但不存在于健康组织中）从未在M phi中鉴定出。通过免疫组织化学在人TAM中确认MSF产生。MSF由M-CSF、IL-4和TGF β诱导，但不由促炎刺激诱导。RNA和蛋白质分析清楚地表明，它与M phi的M2极化特异性相关。肿瘤条件M φ衍生的MSF强烈刺激肿瘤细胞迁移，从而有助于肿瘤细胞的运动表型。总之，MSF是与M phi的M2极化相关并由TAM表达的新分子。其生物学功能可能与M phi介导的促进癌细胞侵袭和转移有关。免疫学杂志，2010，185：642-652。
Tumor-associated macrophages (TAMs) are key orchestrators of the tumor microenvironment directly affecting neoplastic cell growth, neoangiogenesis, and extracellular matrix remodeling. In turn, the tumor milieu strongly influences maturation of TAMs and shapes several of their features. To address the early macrophage (M phi) differentiation phase in a malignant context, we mimicked a tumor microenvironment by in vitro coculturing human blood monocytes with conditioned media from different cancer cell lines. Only 2 out of 16 tumor cell lines induced M phi differentiation due to secreted M-CSF isoforms, including high molecular mass species. A global gene profiling of tumor-conditioned M phi was performed. Comparison with other datasets (polarized M1-M phi, M2-M phi, and TAMs isolated from human tumors) highlighted the upregulation of several genes also shared by TAM and M2-polarized M phi. The most expressed genes were selenoprotein 1, osteoactivin, osteopontin, and, interestingly, migration-stimulating factor (MSF), a poorly studied oncofoetal isoform of fibronectin. MSF (present in fetal/cancer epithelial and stromal cells but not in healthy tissues) was never identified in M phi. MSF production was confirmed by immunohistochemistry in human TAMs. MSF was induced by M-CSF, IL-4, and TGF beta but not by proinflammatory stimuli. RNA and protein analysis clearly demonstrated that it is specifically associated with the M2 polarization of M phi. Tumor-conditioned M phi-derived MSFs strongly stimulated tumor cell migration, thus contributing to the motile phenotype of neoplastic cells. In conclusion, MSF is a new molecule associated with the M2 polarization of M phi and expressed by TAMs. Its biological function may contribute to M phi-mediated promotion of cancer cell invasion and metastasis. The Journal of Immunology, 2010, 185: 642-652.