Bortezomib Inhibits Giant Cell Tumor of Bone through Induction of Cell Apoptosis and Inhibition of Osteoclast Recruitment, Giant Cell Formation, and Bone Resorption.

Jishen Zhang,Xinghai Yang,Jian Luo,Mingyao Liu,Rongrong Jin,Shichang Li,Jianru Xiao,Wei Wan,Peng Sun,Leqin Xu,Zhengfeng Yang,Zhiying Yue

doi:10.1158/1535-7163.mct-15-0669

Abstract

Giant cell tumor of bone (GCTB) is a rare and highly osteolytic bone tumor that usually leads to an extensive bone lesion. The purpose of this study was to discover novel therapeutic targets and identify potential agents for treating GCTB. After screening the serum cytokine profiles in 52 GCTB patients and 10 normal individuals using the ELISA assay, we found that NF-κB signaling-related cytokines, including TNFα, MCP-1, IL1α, and IL17A, were significantly increased in GCTB patients. The results were confirmed by IHC that the expression and activity of p65 were significantly increased in GCTB patients. Moreover, all of the NF-κB inhibitors tested suppressed GCTB cell growth, and bortezomib (Velcade), a well-known proteasome inhibitor, was the most potent inhibitor in blocking GCTB cells growth. Our results showed that bortezomib not only induced GCTB neoplastic stromal cell (NSC) apoptosis, but also suppressed GCTB NSC-induced giant cell differentiation, formation, and resorption. Moreover, bortezomib specifically suppressed GCTB NSC-induced preosteoclast recruitment. Furthermore, bortezomib ameliorated GCTB cell-induced bone destruction in vivo As a result, bortezomib suppressed NF-κB-regulated gene expression in GCTB NSC apoptosis, monocyte migration, angiogenesis, and osteoclastogenesis. Particularly, the inhibitory effects of bortezomib were much better than zoledronic acid, a drug currently used in treating GCTB, in our in vitro experimental paradigms. Together, our results demonstrated that NF-κB signaling pathway is highly activated in GCTB, and bortezomib could suppress GCTB and osteolysis in vivo and in vitro, indicating that bortezomib is a potential agent in the treatment of GCTB. Mol Cancer Ther; 15(5); 854-65. ©2016 AACR.

Highlights

Giant cell tumor of bone (GCTB) is a rare, benign, highly osteolytic bone tumor with unpredictable behavior, which accounts for approximately 5% of primary bone tumors and 20% of benign bone tumors [1, 2]
Our results showed that bortezomib induced neoplastic stromal cell (NSC) apoptosis, and suppressed GCTB NSC–induced monocyte migration, giant cell differentiation, formation, and resorption
The expression of p65 was strikingly increased in both GCTB multinucleated giant cells and NSCs (Fig. 1B and C), which is indicated by Hematoxylin and eosin (H&E) and Tartrate-resistant acidic phosphatase (TRAP) staining (Fig. 1B)

Summary

Introduction

Giant cell tumor of bone (GCTB) is a rare, benign, highly osteolytic bone tumor with unpredictable behavior, which accounts for approximately 5% of primary bone tumors and 20% of benign bone tumors [1, 2]. As many as 6% of patients develop metastases, most frequently in the pulmonary parenchyma [3]. The cellular elements of GCTB include three major cell types: the multinucleated osteoclast–like giant cells, the round-shaped monocyte/macrophage origin mononuclear cells, and the spindle-shaped, fibroblast-like neoplastic stromal cells The NSCs are the only proliferating population and represent the neoplastic component, which express high concentrations of receptor activator of nuclear factor-k B ligand (RANKL), and attract and activate monocyte/ macrophage mononuclear cells to differentiate into osteoclastlike giant cells [5,6,7,8,9,10]. 27% to 65% of patients following primary surgical treatments still develop local recurrences or metastasis [11].

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