MOLECULAR MECHANISMS OF MULTINUCLEATED GIANT CELL FORMATION IN SOFT TISSUE SARCOMAS

Abstract

Introduction: Osteoclast-like multinucleated giant cells (MNGCs) are found in a number of soft tissue sarcomas including malignant fibrous histiocytoma and leiomyosarcoma. The nature of these MNGCs is poorly understood and the cellular mechanisms underlying their accumulation in sarcomas is not known.

Methods: We analysed by immunohistochemistry the expression of osteoclast, macrophage and smooth muscle markers by mononuclear and multinucleated cells in two cases of giant cell-rich leiomyosarcoma. We also characterised the role of mononuclear stromal cells and tumour-associated macrophages in the formation of MNGCs by RT-PCR, cell culture studies and immunohistochemistry/histochemistry for macrophage, osteoclast and smooth muscle markers

Results: MNCGs in giant cell-rich leiomyosarcoma expressed an osteoclast-like phenotype, being negative for smooth muscle actin and CD14 but positive for tartrate-resistant acid phophatase (TRAP), CD45, CD68 and vitronectin receptor (VNR). Scattered mononuclear cells expressing an osteoclast-like antigenic phenotype were also noted. An analysis of 25 conventional (non-giant cell-containing) leiomyosarcomas found isolated CD68+ MNGCs in three cases (approximately 12%); all of these cases were Grade-II/III leiomyosarcomas in which there was a prominent tumour-associated macrophage (TAM) infiltrate. Leiomyosarcoma TAMs isolated from two cases of conventional leiomyosarcoma and cultured in the presence of the osteoclastogenic factors RANKL and M-CSF differentiated into TRAP+/VNR+ MNGCs that were capable of lacunar resorption. RT-PCR studies showed that cultured leiomyosarcoma mononuclear stromal cells expressed RANKL, OPG and TRAIL.

Discussion: These findings show that the MNGCs which are found in leiomyosarcomas are osteoclast-like in nature and that these MNGCs are formed from TAMs by a RANKL dependent mechanism which involves an interaction with RANKL-expressing mononuclear stromal cells. A similar mechanism is likely to account for MNGC accumulation in other soft tissue sarcomas.