Dysregulation of macrophage polarization is associated with the metastatic process in osteosarcoma

Oncotarget. 2016 Nov 29;7(48):78343-78354. doi: 10.18632/oncotarget.13055.


Osteosarcoma (OS) is the most common bone sarcoma in adolescents, and has poor prognosis. A vicious cycle is established between OS cells and their microenvironment in order to facilitate the tumor growth and cell spreading. The present work aims to better characterize the tumor microenvironment in OS in order to identify new therapeutic targets relating to metastatic process. Tissue microarrays of pre-chemotherapy OS biopsies were used for characterizing the tumor niche by immunohistochemistry. Parameters studies included: immune cells (M1, M2-subtypes of tumor-associated macrophages (TAM); T, B lymphocytes; mast cells), vascularization (endothelial, perivascular cells), OPG, RANKL, and mitotic index. Two groups of patients were defined, 22 localized OS (OS Meta-) and 28 metastatic OS (OS Meta+). The OS Meta- group was characterized by a higher infiltration of INOS+ M1-polarizedmacrophages and upregulated OPG immunostaining. OS Meta+ tumors showed a significant increase in CD146+ cells. INOS+ M1-macrophages were correlated with OPG staining, and negatively with the presence of metastases. CD163+ M2-macrophages were positively correlated with CD146+ cells. In multivariate analysis, INOS and OPG were predictive factors for metastasis. An older age, non-metastatic tumor, good response to chemotherapy, and higher macrophage infiltration were significantly associated with better overall survival. TAMs are associated with better overall survival and a dysregulation of M1/M2 polarized-macrophages in favor of M1 subtype was observed in non-metastatic OS.

Keywords: Pathology Section; osteoprotegerin; osteosarcoma; tumour associated macrophage.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Antigens, CD / analysis
  • Antigens, Differentiation, Myelomonocytic / analysis
  • Biomarkers, Tumor / analysis
  • Bone Neoplasms / chemistry
  • Bone Neoplasms / mortality
  • Bone Neoplasms / pathology*
  • Bone Neoplasms / therapy
  • CD146 Antigen / analysis
  • Cell Plasticity*
  • Child
  • Humans
  • Immunohistochemistry
  • Logistic Models
  • Macrophages / chemistry
  • Macrophages / pathology*
  • Middle Aged
  • Multivariate Analysis
  • Nitric Oxide Synthase Type II / analysis
  • Odds Ratio
  • Osteopontin / analysis
  • Osteosarcoma / chemistry
  • Osteosarcoma / mortality
  • Osteosarcoma / secondary*
  • Osteosarcoma / therapy
  • Phenotype
  • Proportional Hazards Models
  • RANK Ligand / analysis
  • Receptors, Cell Surface / analysis
  • Risk Factors
  • Tissue Array Analysis
  • Treatment Outcome
  • Tumor Microenvironment
  • Young Adult


  • Antigens, CD
  • Antigens, Differentiation, Myelomonocytic
  • Biomarkers, Tumor
  • CD146 Antigen
  • CD163 antigen
  • MCAM protein, human
  • RANK Ligand
  • Receptors, Cell Surface
  • SPP1 protein, human
  • TNFSF11 protein, human
  • Osteopontin
  • NOS2 protein, human
  • Nitric Oxide Synthase Type II