title: Macrophage infiltration predicts a poor prognosis for human ewing sarcoma.
abstract: 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.
authors.affiliation: Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Fujiwara
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Fukushi
authors.forename: Shunsaku
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: Nokitaka
authors.initials: N
authors.lastname: Setsu
authors.forename: Yoshinao
authors.initials: Y
authors.lastname: Oda
authors.forename: Hisakata
authors.initials: H
authors.lastname: Yamada
authors.forename: Seiji
authors.initials: S
authors.lastname: Okada
authors.forename: Kosuke
authors.initials: K
authors.lastname: Watari
authors.forename: Mayumi
authors.initials: M
authors.lastname: Ono
authors.forename: Michihiko
authors.initials: M
authors.lastname: Kuwano
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kamura
authors.forename: Keiichiro
authors.initials: K
authors.lastname: Iida
authors.forename: Yuko
authors.initials: Y
authors.lastname: Okada
authors.forename: Mihoko
authors.initials: M
authors.lastname: Koga
authors.forename: Yukihide
authors.initials: Y
authors.lastname: Iwamoto
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D001859:Bone Neoplasms / Q000401:mortality / Q000473:pathology*; D045744:Cell Line, Tumor; D054442:Cell Migration Assays, Macrophage; D002471:Cell Transformation, Neoplastic / Q000473:pathology; D002648:Child; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008264:Macrophages / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D009368:Neoplasm Transplantation; D011379:Prognosis; D012512:Sarcoma, Ewing / Q000401:mortality / Q000473:pathology*; D014183:Transplantation, Heterologous; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D055815:Young Adult
chemical_list: D016207:Cytokines; D042461:Vascular Endothelial Growth Factor A