Department of Immunology and Inflammation, Clinical Institute Humanitas, Rozzano, Italy.
J Immunol. 2010 Jul 1;185(1):642-52. doi: 10.4049/jimmunol.1000413. Epub 2010 Jun 7.
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) 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 differentiation due to secreted M-CSF isoforms, including high molecular mass species. A global gene profiling of tumor-conditioned M was performed. Comparison with other datasets (polarized M1-M, M2-M, and TAMs isolated from human tumors) highlighted the upregulation of several genes also shared by TAM and M2-polarized M. 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. MSF production was confirmed by immunohistochemistry in human TAMs. MSF was induced by M-CSF, IL-4, and TGFbeta but not by proinflammatory stimuli. RNA and protein analysis clearly demonstrated that it is specifically associated with the M2 polarization of M. Tumor-conditioned M-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 and expressed by TAMs. Its biological function may contribute to M-mediated promotion of cancer cell invasion and metastasis.
肿瘤相关巨噬细胞（TAMs）是肿瘤微环境的关键调节者，直接影响肿瘤细胞的生长、新生血管形成和细胞外基质重塑。反过来，肿瘤微环境强烈影响 TAMs 的成熟，并塑造它们的几个特征。为了研究恶性环境中早期巨噬细胞（M）分化阶段，我们通过体外共培养人类血液单核细胞与不同癌细胞系的条件培养基来模拟肿瘤微环境。只有 2 种肿瘤细胞系通过分泌的 M-CSF 异构体（包括高分子量物种）诱导 M 分化。对肿瘤条件化 M 进行了全基因组基因谱分析。与其他数据集（极化的 M1-M、M2-M 和从人类肿瘤中分离的 TAMs）的比较突出了几个基因的上调，这些基因也与 TAM 和 M2 极化的 M 共享。表达最丰富的基因是硒蛋白 1、骨激活素、骨桥蛋白，有趣的是，还有迁移刺激因子（MSF），它是一种研究较少的纤维连接蛋白的癌胚型。MSF（存在于胎儿/癌细胞上皮和基质细胞中，但不存在于健康组织中）从未在 M 中被识别。免疫组织化学证实了人 TAMs 中 MSF 的产生。MSF 由 M-CSF、IL-4 和 TGFβ诱导，但不受促炎刺激诱导。RNA 和蛋白质分析清楚地表明，它与 M 的 M2 极化特异性相关。肿瘤条件化 M 衍生的 MSFs 强烈刺激肿瘤细胞迁移，从而促进肿瘤细胞的迁移表型。总之，MSF 是与 M 的 M2 极化相关的新分子，由 TAMs 表达。其生物学功能可能有助于 M 介导的促进癌细胞侵袭和转移。
