title: Tumour-associated macrophages correlate with poor prognosis in myxoid liposarcoma and promote cell motility and invasion via the HB-EGF-EGFR-PI3K/Akt pathways.
abstract: BACKGROUND
  Myxoid liposarcoma (MLS) is the second most common subtype of liposarcoma, and metastasis occurs in up to one-third of cases. However, the mechanisms of invasion and metastasis remain unclear. Tumour-associated macrophages (TAMs) have important roles in tumour invasion, metastasis, and/or poor prognosis. The aim of this study was to investigate the relationship between TAMs and MLS.
  
  
  METHODS
  Using 78 primary MLS samples, the association between clinical prognosis and macrophage infiltration was evaluated by immunochemistry. The effects of macrophages on cell growth, cell motility, and invasion of MLS cell lines were investigated in vitro. In addition, clinicopathological factors were analysed to assess their prognostic implications in MLS.
  
  
  RESULTS
  Higher levels of CD68-positive macrophages were associated with poorer overall survival in MLS samples. Macrophage-conditioned medium enhanced MLS cell motility and invasion by activating epidermal growth factor receptor (EGFR), with the key ligand suggested to be heparin-binding EGF-like growth factor (HB-EGF). The phosphoinositide 3-kinase/Akt pathway was mostly involved in HB-EGF-induced cell motility and invasion of MLS. The expression of phosphorylated EGFR in MLS clinical samples was associated with macrophage infiltration. In addition, more significant macrophage infiltration was associated with poor prognosis even in multivariate analysis.
  
  
  CONCLUSIONS
  Macrophage infiltration in MLS predicts poor prognosis, and the relationship between TAMs and MLS may be a new candidate for therapeutic targets of MLS.
authors.affiliation: Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, 812-8582 Fukuoka, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Nabeshima
authors.affiliation: Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, 812-8582 Fukuoka, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Matsumoto
authors.affiliation: Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, 812-8582 Fukuoka, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Fukushi
authors.affiliation: Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, 812-8582 Fukuoka, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Iura
authors.affiliation: Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, 812-8582 Fukuoka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Matsunobu
authors.affiliation: Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, 812-8582 Fukuoka, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Endo
authors.affiliation: Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, 812-8582 Fukuoka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Fujiwara
authors.affiliation: Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, 812-8582 Fukuoka, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Iida
authors.affiliation: Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, 812-8582 Fukuoka, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Fujiwara
authors.affiliation: Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, 812-8582 Fukuoka, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Hatano
authors.affiliation: Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, 812-8582 Fukuoka, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Yokoyama
authors.affiliation: Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, 812-8582 Fukuoka, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Fukushima
authors.affiliation: Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, 812-8582 Fukuoka, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Oda
authors.affiliation: Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, 812-8582 Fukuoka, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Iwamoto
mesh_terms: D000818:Animals; D002465:Cell Movement; D002478:Cells, Cultured; D066246:ErbB Receptors / Q000378:metabolism; D066257:Heparin-binding EGF-like Growth Factor / Q000378:metabolism; D006801:Humans; D018208:Liposarcoma, Myxoid / Q000473:pathology*; D008264:Macrophages / Q000473:pathology*; D051379:Mice; D009361:Neoplasm Invasiveness; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D020298:U937 Cells
chemical_list: D066257:Heparin-binding EGF-like Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt