IL-17A stimulates the progression of giant cell tumors of bone

Clin Cancer Res. 2013 Sep 1;19(17):4697-705. doi: 10.1158/1078-0432.CCR-13-0251. Epub 2013 Jul 15.

Abstract

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 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.

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 through myc 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 and might represent a useful candidate marker for progression and as a therapeutic target for GCTBs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Bone Neoplasms / genetics*
  • Bone Neoplasms / metabolism
  • Bone Neoplasms / pathology
  • Carcinogenesis / genetics*
  • Cell Proliferation
  • Disease Progression
  • Female
  • Gene Expression Regulation, Neoplastic
  • Giant Cell Tumor of Bone / genetics*
  • Giant Cell Tumor of Bone / pathology
  • Humans
  • Interleukin-17 / biosynthesis*
  • Interleukin-17 / genetics
  • Male
  • Middle Aged
  • Neoplasm Staging
  • Oligonucleotide Array Sequence Analysis
  • Signal Transduction / genetics

Substances

  • IL17A protein, human
  • Interleukin-17