TGF-β2-induced ANGPTL4 expression promotes tumor progression and osteoclast differentiation in giant cell tumor of bone.

Bo Li,Hao Cao,Haifeng Wei,Zhipeng Wu,Tianyi Ma,Tianrui Chen,Qi Jia,Ming Qian,Xinghai Yang,Jianru Xiao

doi:10.18632/oncotarget.18629

Bo Li, Hao Cao + Show 8 more

Open Access

https://doi.org/10.18632/oncotarget.18629

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Abstract

Although emerging studies have implicated that Aiopoietin-like 4 Protein (ANGPTL4) is related to the aggressiveness and metastasis of many tumors, the role of ANGPLT4 in giant cell tumor (GCT) of bone was rarely investigated. The mechanism of ANGPLT4 in tumor-induced osteoclastogenesis still remains unclear. In this study, we first demonstrated that ANGPTL4 was highly expressed in GCT compared to normal tissues, while we showed that TGF-β2 released by osteoclasts induced bone resorption could increase the expression of ANGPTL4 in GCTSCs. By using the luciferase reporter assay, we found that two downstreams of TGF-β2, Smad3 and Smad4, could directly activate the promoter of ANGPTL4, which might explain the mechanism of TGF-β2-induced ANGPLT4 expression. Moreover, knockout of ANGPTL4 by TALENs in GCTSCs inhibited tumor growth, angiogenesis and osteoclastogenesis in GCT in vitro. By using the chick chorio-allantoic membrane (CAM) models, we further showed that inhibition of ANGPTL4 suppressed tumor growth and giant cell formation in vivo. In addition, some new pathways involved in ANGPTL4 application were identified through microarray assay, which may partly explain the mechanism of ANGPTL4 in GCT. Taken together, our study for the first time identified the role of ANGPLT4 in GCT of bone, which may provide a new target for the diagnosis and treatment of GCT.

Highlights

Giant cell tumor (GCT) of bone is a common primary bone tumor which typically occurs in the epiphyseal end of long bones and less locates in sacrum, pelvis and spine [1,2,3]
We first demonstrated that Angiopoietin-like 4 Protein (ANGPTL4) was highly expressed in giant cell tumor (GCT) compared to normal tissues, while we showed that TGF-β2 released by osteoclasts induced bone resorption could increase the expression of ANGPTL4 in GCTSCs
These results suggested that GCTSCs could contribute to the high level of ANGPTL4 in GCT

Summary

Introduction

Giant cell tumor (GCT) of bone is a common primary bone tumor which typically occurs in the epiphyseal end of long bones and less locates in sacrum, pelvis and spine [1,2,3]. GCT predominantly occurs in the third and fourth decade of life with a slight predilection for females [4, 5]. The tumor is composed of osteoclastlike multinucleated giant cells, spindle-shaped stromal cells and mononuclear precursor cells [6]. Spindleshaped stromal cells of GCT (GCTSCs) originated from mesenchymal stem cells in bone marrow play a neoplastic role in GCT [7, 8]. GCT is classified as a benign tumor with a potentially aggressive behavior, malignant transformation and metastasis are not common [9, 10]. Further understanding the biology of GCT is critically important

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