Human Cancer Biology IL-17A Stimulates the Progression of Giant Cell Tumors of Bone

Purpose: 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. Experimental Design:We evaluated the progression of GCTBs using Campanacci grading and Enneking staging systems in 74 patients withGCTB. 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 andMTT 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. Results: 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 throughmyc and STAT3, respectively. In addition, IL-17A stimulated in vivo tumor growth and the extent of angiogenesis in GCTBs. Conclusion: IL-17A stimulates the progression of GCTBs andmight represent a useful candidate marker for progression and as a therapeutic target for GCTBs. Clin Cancer Res; 19(17); 4697–705. 2013 AACR.