Receptor activator of nuclear factor kappa-B ligand (RANKL) is an essential mediator of osteoclast formation, function and survival. In patients with solid
tumor metastasis to the bone, targeting the bone microenvironment by inhibition of RANKL using
denosumab, a fully human
monoclonal antibody (mAb) specific to RANKL, has been demonstrated to prevent
tumor-induced
osteolysis and subsequent skeletal complications. Recently, a prominent functional role for the RANKL pathway has emerged in the primary bone
tumor giant cell tumor of bone (GCTB). Expression of both RANKL and RANK is extremely high in GCTB
tumors and
denosumab treatment was associated with
tumor regression and reduced
tumor-associated bone lysis in GCTB patients. In order to address the potential role of the RANKL pathway in another primary bone
tumor, this study assessed human RANKL and RANK expression in human primary
osteosarcoma (OS) using specific mAbs, validated and optimized for immunohistochemistry (IHC) or flow cytometry. Our results demonstrate RANKL expression was observed in the
tumor element in 68% of human OS using IHC. However, the staining intensity was relatively low and only 37% (29/79) of samples exhibited≥10% RANKL positive
tumor cells. RANK expression was not observed in OS
tumor cells. In contrast, RANK expression was clearly observed in other cells within OS samples, including the myeloid osteoclast precursor compartment, osteoclasts and in giant osteoclast cells. The intensity and frequency of RANKL and RANK staining in OS samples were substantially less than that observed in GCTB samples. The observation that RANKL is expressed in OS cells themselves suggests that these
tumors may mediate an osteoclastic response, and anti-RANKL
therapy may potentially be protective against bone pathologies in OS. However, the absence of RANK expression in primary human OS cells suggests that any autocrine RANKL/RANK signaling in human OS
tumor cells is not operative, and anti-RANKL
therapy would not directly affect the
tumor.