Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, University of Heidelberg, and Center of Excellence in Dermatology, Mannheim, Germany.
Int J Cancer. 2011 Jul 1;129(1):122-32. doi: 10.1002/ijc.25657. Epub 2010 Nov 28.
Tumor-associated macrophages (TAMs) represent alternatively activated (M2) macrophages that support tumor growth. Previously, we have described a special LYVE-1(+) M2 TAM subset in vitro and in vivo; gene profiling of this TAM subset identified MS4A8A as a novel TAM molecule expressed in vivo by TAM in mammary carcinoma and malignant melanoma. In vitro, Ms4a8a mRNA and MS4A8A protein expression was strongly induced in bone marrow-derived macrophages (BMDMs) by combining M2 mediators (IL-4, glucocorticoids) and tumor-conditioned media (TCM). Admixture of MS4A8A(+) TCM/IL-4/GC-treated BMDM significantly enhanced the tumor growth rate of subcutaneously transplanted TS/A mammary carcinomas. Upon forced overexpression of MS4A8A, Raw 264.7 macrophage-like cells displayed a special gene signature. Admixture of these MS4A8A(+) Raw 264.7 cells also significantly enhanced the tumor growth rate of subcutaneously transplanted mammary carcinomas. To identify the signaling pathways involved in synergistic induction of MS4A8A, the major signaling cascades with known functions in TAM were analyzed. Although inhibitors of NF-κB activation and of the MAPK JNK and ERK did not show relevant effects, the p38α/β MAPK inhibitor SB203580 strongly and highly significantly (p > 0.001) inhibited MS4A8A expression on mRNA and protein level. In addition, MS4A8A expression was restricted in M2 BMDM from mice with defective GC receptor (GR) dimerization indicating that classical GR gene regulation is mandatory for MS4A8A induction. In conclusion, expression of MS4A8A within the complex signal integration during macrophage immune responses may act to fine tune gene regulation. Furthermore, MS4A8A(+) TAM may serve as a novel cellular target for selective cancer therapy.
肿瘤相关巨噬细胞（TAMs）代表了支持肿瘤生长的替代性激活（M2）巨噬细胞。之前，我们已经在体外和体内描述了一种特殊的 LYVE-1（+）M2 TAM 亚群；该 TAM 亚群的基因谱分析鉴定出 MS4A8A 是一种在乳腺癌和恶性黑色素瘤中由 TAM 在体内表达的新型 TAM 分子。在体外，通过将 M2 介质（IL-4、糖皮质激素）和肿瘤条件培养基（TCM）联合作用于骨髓来源的巨噬细胞（BMDM），强烈诱导 Ms4a8a mRNA 和 MS4A8A 蛋白表达。MS4A8A（+）TCM/IL-4/GC 处理的 BMDM 混合物显著增强了皮下移植的 TS/A 乳腺癌的肿瘤生长速度。当强制过表达 MS4A8A 时，Raw 264.7 巨噬样细胞显示出特殊的基因特征。这些 MS4A8A（+）Raw 264.7 细胞的混合物也显著增强了皮下移植的乳腺癌的肿瘤生长速度。为了确定参与 MS4A8A 协同诱导的信号通路，分析了已知在 TAM 中具有功能的主要信号级联。尽管 NF-κB 激活和 MAPK JNK 和 ERK 的抑制剂没有显示出相关作用，但 p38α/β MAPK 抑制剂 SB203580 强烈且高度显著（p > 0.001）抑制了 mRNA 和蛋白水平上的 MS4A8A 表达。此外，在 GC 受体（GR）二聚化缺陷的小鼠的 M2 BMDM 中，MS4A8A 的表达受到限制，表明经典的 GR 基因调控是 MS4A8A 诱导所必需的。总之，在巨噬细胞免疫反应过程中的复杂信号整合中，MS4A8A 的表达可能有助于精细调节基因调控。此外，MS4A8A（+）TAM 可能成为选择性癌症治疗的新型细胞靶标。
