Research Papers: Pathology:

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

Clotilde Dumars, Jean-Michel Ngyuen, Aurélie Gaultier, Rachel Lanel, Nadège Corradini, François Gouin, Dominique Heymann and Marie-Françoise Heymann _

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Oncotarget. 2016; 7:78343-78354. https://doi.org/10.18632/oncotarget.13055

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Clotilde Dumars1,2,3, Jean-Michel Ngyuen2,3, Aurélie Gaultier3, Rachel Lanel1,2, Nadège Corradini4, François Gouin1,2,3, Dominique Heymann1,2,3,5 and Marie-Françoise Heymann1,2,3,5

1 INSERM, UMR 957, Equipe LIGUE Nationale Contre le Cancer, Nantes, France

2 Université de Nantes, Nantes atlantique universités, Pathophysiology of Bone Resorption and Therapy of Primary Bone Tumors, Nantes, France

3 CHU de Nantes, Nantes University Hospital, France

4 Centre de Lutte Contre le Cancer, Léon Bérard, Lyon, France

5 INSERM, European Associated Laboratory “Sarcoma Research Unit”, Department of Oncology and Metabolism, University of Sheffield, Medical School, Sheffield, UK

Correspondence to:

Marie-Françoise Heymann, email:

Dominique Heymann, email:

Keywords: osteosarcoma, tumour associated macrophage, osteoprotegerin, Pathology Section

Received: September 24, 2016 Accepted: October 27, 2016 Published: November 13, 2016


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.

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