Abstract
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.
Highlights
Primary bone sarcomas are rare oncologic subtypes, accounting for less than 0.2% of the malignant tumors registered in the EUROCARE database [1]
tumor-associated macrophages (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
The tumor niche is defined as a specific microenvironment promoting the emergence of cancerinitiating cells, and providing all the factors required for their quiescence, proliferation and migration
Summary
Primary bone sarcomas are rare oncologic subtypes, accounting for less than 0.2% of the malignant tumors registered in the EUROCARE database [1]. These tumors are made up of a large number of distinct histological entities, especially osteosarcoma (OS), chondrosarcoma and Ewing sarcoma originating from mesenchymal stem cells [2, 3]. Secondary OS occurs in the elderly mainly after Paget disease or radiotherapy. Radiotherapy may www.impactjournals.com/oncotarget be used in palliation [1]. OS still has a poor prognosis and patient survival is strongly associated with the tumor cell response to chemotherapy, and metastatic status. Understanding the pathophysiology of OS and the metastatic process is a pre-requisite for future improvement in therapeutic approaches
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