Macrophage Infiltration Predicts a Poor Prognosis for Human Ewing Sarcoma

• DOI: 10.1016/j.ajpath.2011.05.034
• Publication Date: 2011-07-24T19:32:26Z
• Authors: Toshifumi Fujiwara; Jun-ichi Fukushi; Shunsaku Yamamoto; Yoshihiro Matsumoto; Nokitaka Setsu; Yoshinao Oda; Hisakata Yamada; Seiji Okada; Kosuke Watari; Mayumi Ono; Michihiko Kuwano; Satoshi Kamura; Keiichiro Iida; Yuko Okada; Mihoko Koga; Yukihide Iwamoto
• Keywords: Adult; Cell Migration Assays, Macrophage; Male; Mice, Inbred BALB C; Adolescent; Macrophages; Bone Neoplasms; Kaplan-Meier Estimate; Middle Aged; Prognosis; 3. Good health; Mice; 03 medical and health sciences; Cell Transformation, Neoplastic; 0302 clinical medicine; Cell Line, Tumor; Animals; Cytokines; Humans; Female; Child; Neoplasm Transplantation; Aged

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.