Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands.
Clin Cancer Res. 2011 Apr 15;17(8):2110-9. doi: 10.1158/1078-0432.CCR-10-2047. Epub 2011 Mar 3.
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.
To identify gene signatures playing a role in metastasis, we carried out genome-wide gene expression profiling on prechemotherapy biopsies of patients who did (n = 34) and patients who did not (n = 19) develop metastases within 5 years. Immunohistochemistry (IHC) was performed on pretreatment biopsies from 2 additional cohorts (n = 63 and n = 16) and corresponding postchemotherapy resections and metastases.
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-DRα positive) and M2-type TAMs (CD14/CD163 positive and association with angiogenesis).
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.
高级别骨肉瘤是一种恶性原发性骨肿瘤，发病高峰在青少年时期。可切除转移性疾病患者的总生存率（OS）约为 20%。骨肉瘤转移的确切机制仍不清楚。大多数研究集中在肿瘤细胞上，但越来越明显的是，基质在肿瘤发生和转移中起着重要作用。我们通过研究肿瘤细胞及其基质环境来研究转移的发展。
为了确定在转移中起作用的基因特征，我们对在 5 年内未发生转移（n=34）和发生转移（n=19）的患者的化疗前活检进行了全基因组基因表达谱分析。对另外两个队列（n=63 和 n=16）的预处理活检和相应的化疗后切除物和转移进行了免疫组织化学（IHC）检测。
在无转移患者中，共有 118/132 个差异表达基因上调。值得注意的是，这些上调基因中几乎有一半具有免疫功能，特别是与巨噬细胞有关。巨噬细胞相关基因由浸润细胞表达，而不是由骨肉瘤细胞表达。用 IHC 对肿瘤相关巨噬细胞（TAM）进行了定量，并与另外两个患者队列的总生存率（OS）显著相关。骨肉瘤样本中同时含有 M1-（CD14/HLA-DRα 阳性）和 M2 型 TAMs（CD14/CD163 阳性，与血管生成有关）。
与大多数其他肿瘤类型相反，TAMs 与高级别骨肉瘤的转移减少和生存改善相关。这项研究为高级别骨肉瘤患者用巨噬细胞激活剂（如 muramyl tripeptide）进行辅助治疗提供了生物学依据。
