Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Am J Pathol. 2011 Sep;179(3):1157-70. doi: 10.1016/j.ajpath.2011.05.034. Epub 2011 Jul 21.
Ewing sarcoma-primitive neuroectodermal tumor (EWS) is associated with the most unfavorable prognosis of all primary musculoskeletal tumors. The objective of the present study was to investigate whether tumor-associated macrophages (TAMs) affect the development of EWS. TAMs were isolated from mouse xenografts using CD11b magnetic beads and examined for their cytokine expression and osteoclastic differentiation. To evaluate the role of TAMs in xenograft formation, liposome-encapsulated clodronate was used to deplete TAMs in mice. Macrophage infiltration and tumor microvascular density were histologically evaluated in 41 patients with EWS, and association with prognosis was examined using Kaplan-Meier survival analysis. In mouse EWS xenografts, TAMs expressed higher concentrations of cytokines including interleukin-6, keratinocyte-derived chemokine, and monocyte chemotactic protein-1. TAMs were more capable than normal monocytes of differentiating into tartrate-resistant acid phosphatase-positive giant cells. Depleting macrophages using liposome-encapsulated clodronate significantly inhibited development of EWS xenografts. In human EWS samples, higher levels of CD68-positive macrophages were associated with poorer overall survival. In addition, enhanced vascularity, increase in the amount of C-reactive protein, and higher white blood cell counts were also associated with poor prognosis and macrophage infiltration. TAMs seem to enhance the progression of EWS by stimulating both angiogenesis and osteoclastogenesis. Further investigation of the behavior of TAMs may lead to development of biologically targeted therapies for EWS.
尤因肉瘤-原始神经外胚层肿瘤（EWS）与所有原发性肌肉骨骼肿瘤中最不利的预后相关。本研究的目的是探讨肿瘤相关巨噬细胞（TAMs）是否影响 EWS 的发展。使用 CD11b 磁珠从小鼠异种移植物中分离 TAMs，并检查其细胞因子表达和破骨细胞分化。为了评估 TAMs 在异种移植物形成中的作用，使用脂质体包裹的氯膦酸盐在小鼠中耗尽 TAMs。在 41 例 EWS 患者中评估 TAMs 浸润和肿瘤微血管密度，并使用 Kaplan-Meier 生存分析检查与预后的关联。在小鼠 EWS 异种移植物中，TAMs 表达更高浓度的细胞因子，包括白细胞介素-6、角质细胞衍生趋化因子和单核细胞趋化蛋白-1。TAMs 比正常单核细胞更能分化为抗酒石酸酸性磷酸酶阳性巨细胞。使用脂质体包裹的氯膦酸盐耗尽巨噬细胞可显著抑制 EWS 异种移植物的发展。在人类 EWS 样本中，CD68 阳性巨噬细胞水平较高与总生存率较差相关。此外，血管生成增加、C 反应蛋白增加和白细胞计数增加也与预后不良和巨噬细胞浸润相关。TAMs 通过刺激血管生成和破骨细胞生成似乎增强了 EWS 的进展。进一步研究 TAMs 的行为可能会导致开发针对 EWS 的生物靶向治疗。
