The Role of TWIST in Angiogenesis and Cell Migration in Giant Cell Tumor of Bone

Shalini Singh,Isabella W Y Mak,Michelle Ghert,Divya Handa

doi:10.1155/2014/903259

Abstract

Giant cell tumor of bone (GCT) is a bone tumor consisting of numerous multinucleated osteoclastic giant cells involved in bone resorption and neoplastic osteoblast-like stromal cells responsible for tumor growth. The tumor occasionally metastasizes to the lung; however, factors leading to metastasis in this tumor are unknown. The TWIST-1 protein (also referred to as TWIST) has been suggested to be involved in epithelial-mesenchymal transition (EMT) and tumor progression in some cancers. In this study we investigated the functional role of TWIST in GCT cell angiogenesis and migration. Overexpression of TWIST in neoplastic GCT stromal cells significantly increased mRNA and protein expression of VEGF and VEGFR1 in vitro, whereas knockdown of TWIST resulted in decreased VEGF and VEGFR1 expression. A stable cell line with TWIST overexpression resulted in features of EMT including increased cell migration and downregulation of E-cadherin. The results of our study indicate that TWIST may play an important role in angiogenesis and cell migration in GCT.

Highlights

Giant cell tumor of bone (GCT) is an aggressive bone tumor characterized by the presence of an abundance of reactive multinucleated giant cells surrounded by mesenchymal stromal cells
In order to determine whether TWIST plays a role in angiogenesis through vascular endothelial growth factor (VEGF) expression in GCT stromal cells, we generated 3 stable TWIST overexpressing cell lines (GCTT1 and GCTT2 and GCTT3) from three different patient specimens using a TWIST-pcDNA3.1 construct and compared them to pcDNA3.1 empty vector
Quantitative real time PCR showed that overexpression of TWIST significantly increased the mRNA expression of VEGF and VEGFR1 in GCT stromal cells (Figure 1(a), P < 0.05)

Summary

Introduction

Giant cell tumor of bone (GCT) is an aggressive bone tumor characterized by the presence of an abundance of reactive multinucleated giant cells surrounded by mesenchymal stromal cells. GCT is a highly vascular tumor and in several cases metastasizes to the lungs [2, 5, 6]. Bone tumors recruit new blood vessels from preexisting vessels of the host through factors secreted from either the tumor itself or the surrounding stromal cells [7, 8]. Tumor growth is dependent upon the growth of these new blood vessels. Activators of angiogenesis include growth factors, such as vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and hypoxic conditions that activate hypoxia-inducible factor-1 (HIF-1) which in turn upregulate angiogenic proteins as well as angiogenic oncogenes [9]

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Discussion

Conclusion