Tumor-Infiltrating Macrophages Are Associated with Metastasis Suppression in High-Grade Osteosarcoma: A Rationale for Treatment with Macrophage Activating Agents

Abstract

Purpose: High-grade osteosarcoma is a malignant primary bone tumor with a peak incidence in adolescence. Overall survival (OS) of patients with resectable metastatic disease is approximately 20%. 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 by studying tumor cells and their stromal context.Experimental Design: To identify gene signatures playing a role in metastasis, we carried out genomewide gene expression profiling on prechemotherapy biopsies of patients who did (n ¼ 34) and patients who did not (n ¼ 19) develop metastases within 5 years. Immunohistochemistry (IHC) was performed on pretreatment biopsies from 2 additional cohorts (n ¼ 63 and n ¼ 16) and corresponding postchemotherapy resections and metastases.Results: A total of 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 (TAM) were quantified with IHC and associated with significantly better overall survival (OS) in the additional patient cohorts. Osteosarcoma samples contained both M1-(CD14/HLA-DRa 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.

Alternate Splicing of the p53 Inhibitor HDMX Offers a Superior Prognostic Biomarker than p53 Mutation in Human Cancer

“…Clinicopathologic data of 51 patients with osteosarcoma are shown in Supplementary Table S1. Part of the samples was previously described (26). Biopsies were taken before preoperative chemotherapeutics were administered.…”

Identification of key biomarkers involved in osteosarcoma using altered modules

“…Approximately 30% of the patients with OS present clinically detectable metastatic disease at diagnosis (Kaste et al, 1999;Kager et al, 2003). So far, researchers have not thoroughly investigated treatment methods that could significantly increase survival, excluding preoperative chemotherapy (Buddingh et al, 2011).…”

Clinicopathological correlation of tumor-associated macrophages in Ewing sarcoma

“…In a cohort of 53 high-grade osteosarcomas, the number of CD14-positive TAMs was associated with reduced metastasis and improved survival, whereas the phenotype CD14/CD163 did not show this relationship 18 . The significance of CD68 and CD163 positive cells was also investigated in 149 samples of leiomyosarcomas.…”

“…[13][14][15][16] ). On the other hand, some studies have identified the effect of TAMs as tumor-suppressing [17][18][19][20] . This heterogeneity of the results is caused by the inability to clearly distinguish between TAM subtypes.…”

“…Some studies have proven a correlation between large number of TAMs and poor prognosis, advanced grade or stage of various cancers [13][14][15][16] . Other studies have produced contradictory results [17][18][19] , making this issue highly controversial 21 . The answer may reside in the fact that macrophages are highly plastic and can alter their phenotype flexibly according to local stimuli.…”