Macrophage Infiltration Predicts a Poor Prognosis for Human Ewing Sarcoma
Macrophage Infiltration Predicts a Poor Prognosis for Human Ewing Sarcoma
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DOI：
10.1016/j.ajpath.2011.05.034
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发表时间：
2011-09-01
影响因子：
6
通讯作者：
Iwamoto, Yukihide
中科院分区：
文献类型：
--
作者：
Fujiwara, Toshifumi;Fukushi, Jun-ichi;Iwamoto, Yukihide
尤文肉瘤原始神经外胚层肿瘤（EWS）是所有原发性肌肉骨骼肿瘤中预后最差的。本研究的目的是探讨肿瘤相关巨噬细胞（TAM）是否影响EWS的发展。使用CD 11b磁珠从小鼠异种移植物中分离TAM，并检查其细胞因子表达和骨细胞分化。为了评估TAM在异种移植物形成中的作用，使用脂质体包封的氯膦酸盐来消耗小鼠中的TAM。对41例EWS患者的巨噬细胞浸润和肿瘤微血管密度进行了组织学评价，并使用Kaplan-Meier生存分析研究了其与预后的关系。在小鼠EWS异种移植物中，TAM表达更高浓度的细胞因子，包括白细胞介素-6、角质形成细胞衍生的趋化因子和单核细胞趋化蛋白-1。TAM比正常单核细胞更有能力分化为抗酒石酸酸性磷酸酶阳性巨细胞。使用脂质体包封的氯膦酸盐消耗巨噬细胞显著抑制EWS异种移植物的发育。在人类EWS样本中，较高水平的CD 68阳性巨噬细胞与较差的总生存期相关。此外，血管分布增强、C反应蛋白量增加和较高的白色血细胞计数也与预后不良和巨噬细胞浸润相关。TAM似乎通过刺激血管生成和破骨细胞生成来增强EWS的进展。对TAM行为的进一步研究可能会导致EWS生物靶向治疗的发展。(Am J Pathol 2011，170：1157-1170; 10.1016/j.ajpath.2011.05.034）
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. (Am J Pathol 2011, 170:1157-1170; 10.1016/j.ajpath.2011.05.034)