Dumars Clotilde, Ngyuen Jean-Michel, Gaultier Aurélie, Lanel Rachel, Corradini Nadège, Gouin François, Heymann Dominique, Heymann Marie-Françoise
INSERM, UMR 957, Equipe LIGUE Nationale Contre le Cancer, Nantes, France.
Université de Nantes, Nantes atlantique universités, Pathophysiology of Bone Resorption and Therapy of Primary Bone Tumors, Nantes, France.
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.
骨肉瘤（OS）是青少年中最常见的骨肉瘤，预后较差。OS细胞与其微环境之间形成了一个恶性循环，以促进肿瘤生长和细胞扩散。目前的工作旨在更好地表征OS中的肿瘤微环境，以确定与转移过程相关的新治疗靶点。化疗前OS活检组织芯片用于通过免疫组织化学表征肿瘤微环境。研究参数包括：免疫细胞（肿瘤相关巨噬细胞（TAM）的M1、M2亚型；T、B淋巴细胞；肥大细胞）、血管生成（内皮细胞、血管周围细胞）、骨保护素（OPG）、核因子κB受体活化因子配体（RANKL）和有丝分裂指数。定义了两组患者，22例局限性OS（OS Meta-）和28例转移性OS（OS Meta+）。OS Meta-组的特征是诱导型一氧化氮合酶（INOS）+ M1极化巨噬细胞浸润较高且OPG免疫染色上调。OS Meta +肿瘤中CD146 +细胞显著增加。INOS + M1巨噬细胞与OPG染色相关，与转移灶的存在呈负相关。CD163 + M2巨噬细胞与CD146 +细胞呈正相关。在多变量分析中，INOS和OPG是转移的预测因素。年龄较大、非转移性肿瘤、对化疗反应良好以及巨噬细胞浸润较高与较好的总生存期显著相关。TAM与较好的总生存期相关，并且在非转移性OS中观察到M1/M2极化巨噬细胞失调，有利于M1亚型。
