Tumor-Infiltrating Macrophages Are Associated with Metastasis Suppression in High-Grade Osteosarcoma: A Rationale for Treatment with Macrophage-Activating Agents.
Emilie P Buddingh, Marieke L Kuijjer, Ronald Duim, Horst Burger, Konstantin Agelopoulos, Ola Myklebost, Massimo Serra, Fredrik Mertens, Pancras CW Hogendoorn, Arjan C Lankester, Anne-Marie Cleton-Jansen. Leiden University Medical Center, Netherlands; University of Münster, Germany; The Norwegian Radium Hospital, Oslo University Hospital, Norway; Istituto Ortopedico Rizzoli, Bologna, Italy; Lund University Hospital, Lund, Sweden
Background: High-grade osteosarcoma is a malignant primary bone tumor with a peak incidence in puberty. Overall survival of patients with resectable metastatic disease is approximately twenty percent. The exact mechanisms of development of metastases in osteosarcoma remain unclear. Most studies focus on tumor cells, but it is increasingly evident that stroma plays an important role in tumorigenesis and metastasis. We investigated the development of metastasis using an integrative approach, in which both stroma and tumor cells were studied.
Design: To identify gene signatures playing a role in metastasis, we performed genome-wide gene expression profiling on pre-chemotherapy biopsies of patients who did (n=34) and patients who did not (n=19) develop metastases within five years. Immunohistochemistry was performed on pre-treatment biopsies from two additional cohorts (n=63 and n=16), and on corresponding post-chemotherapy resections and metastases.
Results: 118/132 differentially expressed genes were upregulated in patients without metastases. Remarkably, almost half of these upregulated genes had immunological functions, particularly related to macrophages. Macrophage-associated genes were expressed by infiltrating cells and not by osteosarcoma cells. Tumor-associated macrophages (TAMs) were quantified with immunohistochemistry and were associated with significantly better overall survival in the additional patient cohorts. Osteosarcoma samples contained both M1 (CD14/HLA-DRα positive) and M2 type TAMs (CD14/CD163 positive and association with angiogenesis).
Conclusions: In contrast to most other tumor types, TAMs are associated with reduced metastasis and improved survival in high-grade osteosarcoma. This study provides a biological rationale for the adjuvant treatment of high-grade osteosarcoma patients with macrophage-activating agents, such as muramyl tripeptide.
Category: Bone & Soft Tissue
Tuesday, March 1, 2011 1:30 PM
Platform Session: Section E, Tuesday Afternoon