COMPARATIVE EXPRESSION PROFILING IN HUMAN AND FELINE GIANT CELL TUMOR OF BONE.

We investigated molecules involved in the interaction between tumor cells, tumor-derived humoral factors and the bone marrow microenvironmental in human and feline giant cell tumors of bone (GCT). Expression of the key proteins of the RANK-RANKL signalling pathway and bone resorption, including TRAF6, IL-1a, enzymes involve in matrix degradation (MMP2, MMP9, UPA system, CA II) and c-fos, was analyzed in human and feline GCT specimens by tissue microarray analysis. There was frequent co- overexpression of uPA and uPAR in human GCTs , associated with increased expression of IL-1a , more invasive behaviour, and high potential for metatstasis Interestingly, when both RANKL and IL-1a were overexpressed on mononuclear cells (MCs), increased expression of TRAF6 and c-fos (>25% of MCs), MMP9 and CAII (>50% of GCs) were seen. In cats, MCs expressed strong and homogeneous positive membrane immunostaining for RANKL in all twelve cases examined, resulting in abundant large multinucleated osteoclast-like giant cells. The intracellular mediators TRAF6, IL1a and c-fos were weakly and focally positive, while MMP2 presented different expression patterns. A strong association between RANKL, large number of GCs, MMP9 and CAII, highly and predominantly expressed on the ruffled border of giant cells (>50%), confirmed the involvement of these proteolytic enzymes in osteoclast activity. The results indicate that activation of the RANK-RANKL pathway leads to increased production of MMP9 and CAII by multinucleated cells contributing to vascular invasion and local resorption in both feline and human GCTs. The intracellular mediators of proliferation pathways, TRAF6 and c-fos, appear to be involved in malignant progression of human GCTs, showing a direct correlation with grade and clinical course.