Abstract
Giant cell tumors of bone (GCTB) exhibit aggressive bone lytic behavior. Studies have shown that interleukin 17A (IL-17A) is involved pathologic bone resorption in various skeletal disorders. Thus, we have investigated the role of IL-17A in GCTBs. We evaluated the progression of GCTBs using Campanacci grading and Enneking staging systems in 74 patients with GCTB. The expression of IL-17A and the IL-17A receptor A (IL-17RA) was assessed in GCTB tissues and in both multinucleated giant cells (MNGC) and stromal cells cultured in vitro using immunostaining and reverse transcription PCR (RT-PCR). The effects of IL-17A on the osteolytic activity of the MNGCs and the proliferation of the stromal cells were investigated using the "pit" formation and MTT assays, respectively. The effects of IL-17A on the expression of proosteolytic factors were examined in primary cultured MNGCs and stromal cells using RT-PCR, Western blotting, and gene expression microarrays. In GCTBs, we detected abundant levels of IL-17A, which were associated with tumor extension and grade. IL-17A is predominantly produced by MNGCs, whereas IL-17RA is expressed by both MNGCs and stromal cells in GCTBs. In the MNGCs, the IL-17A increased the mRNA expression of IL-17A and proosteolytic enzymes, and also enhanced osteolytic ability. In the stromal cells, the IL-17A stimulated cellular proliferation and the expression of proosteolytic factors, including RANKL through myc and STAT3, respectively. In addition, IL-17A stimulated in vivo tumor growth and the extent of angiogenesis in GCTBs. IL-17A stimulates the progression of GCTBs and might represent a useful candidate marker for progression and as a therapeutic target for GCTBs.
Highlights
Giant cell tumor of bone (GCTB) is a benign, locally aggressive, osteolytic tumor that causes significant bone destruction at the epiphysis of long bones
interleukin 17A (IL-17A) is predominantly produced by multinucleated giant cells (MNGC), whereas IL-17A receptor A (IL-17RA) is expressed by both MNGCs and stromal cells in GCTBs
Our results show that the IL-17A mRNA expression levels found in using GCTB tissues are similar to those in the rheumatoid arthritis tissues but higher than those in the osteosarcoma tissues (Fig. 1C)
Summary
Giant cell tumor of bone (GCTB) is a benign, locally aggressive, osteolytic tumor that causes significant bone destruction at the epiphysis of long bones. GCTBs exhibit local recurrence in 8% to 62% of patients following primary surgical treatments, and up to Authors' Affiliations: Departments of 1Orthopaedics and 2Pathology, The General Hospital of Chinese People's Liberation Army; 3Center of Therapeutic Research for Hepatocellular Carcinoma, Beijing 302 Hospital, Beijing; 4International Joint Cancer Institute, The Second Military Medical University, Shanghai, China; and 5Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).
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