Osteoclast-Like Giant Cells in Malignant Melanoma: Unintentional Accident or Strategic Recruitment?
Osteoclast-like multinucleated giant cells have been infrequently noted to occur in malignant melanoma,1–3 although neither their origin nor function is well understood. Presumably, they represent either non-neoplastic, reactive by-standers tissue or malignant, osteoclastic/histiocytic transformation of melanoma cells. In this letter to the editor, we would like to review current understanding of the relationship between osteoclasts and malignant melanoma. We also suggest that the presence of osteoclast-like cells and expression of osteoclast marker genes may aid in the progression and metastatic potential of melanoma.
In addition to melanoma, osteoclast-like cells have been observed in a variety of nonskeletal malignancies including soft tissue, lung, kidney, thyroid, pancreas, breast, stomach, and cutaneous squamous cell carcinoma.3–7 Accordingly, the presence of osteoclast-like giant cells within a tumor should not be misconstrued as evidence of fibrohistiocytic or other mesenchymal lineage. In most reported cases of osteoclast-like cells in melanoma, the occurrence is rare and the prognosis is unclear. Histologically, these cells express CD68, a monocyte/macrophage lineage marker, but not melanocytic markers (HMB-45, Melan-A, and S100), implying that they derive from circulating monocyte/macrophages or represent transformed tumor-associated macrophages (TAMs).1 However, a recent study suggests that malignant melanocytes are capable of osteoclast-like differentiation. Such cells were noted to be reactive for HMB-45, Melan-A, and S100 in addition to CD68 and acid phosphatase, an enzyme present in normal osteoclasts.3
Although the occurrence of histologically evident osteoclast-like giant cells in melanoma is rare, the expression of osteoclast marker genes in melanoma tissue is much more common and thus more thoroughly studied. Osteoclasts express the transmembrane cytokine receptor RANK, which binds to RANKL and initiates expression of genes that can degrade bone matrix such as cathepsin K (CTSK), matrix metalloprotease 9 (MMP9), and tartrate-resistant acid phosphatase. Abnormal activation of the RANK-RANKL pathway has been shown to stimulate cancer metastasis in some malignancies such as breast cancer.8,9 In melanoma, RANK expression is found to be significantly increased in peripheral circulating cells and metastasis from patients with stage IV disease compared to those with less advanced stage I melanoma.10 Thus, it is conceivable that melanoma is able to hijack the osteoclast RANK-RANKL signaling pathway to further its own growth and metastasis.
Activation of the RANK-RANKL pathway in metastatic melanoma has been shown to upregulate downstream effector genes. One such product, CTSK, is a lysosomal cysteine protease present in most primary melanoma and all cutaneous melanoma metastasis. By contrast, benign melanocytic nevi stain for CTSK less intensely, suggesting a positive association of CTSK expression and development/progression of melanoma.11 In addition, inhibition of MMP9, a metalloproteinase that is necessary for degradation of extracellular matrix and that is tightly controlled by normal RANKL signaling suppresses melanoma cell invasion and migration in vitro and in vivo.12 CTSK and MMP9 are not exclusively expressed in osteoclasts, but their presence in melanoma is more likely to be associated with metastatic and late stage melanoma, pointing to the role of osteoclast and osteoclast marker genes in melanoma transformation.
Although this evidence is revealing, questions remain. How do osteoclasts develop within melanoma, and what role do they play in its pathogenesis? Osteoclasts are powerful extracellular matrix degraders—recruiting osteoclasts or even up-regulating a few osteoclast signature genes such as CTSK and MMP9 is likely to help melanomas metastasize. A descendent from the monocyte/macrophage lineage, osteoclasts can be easily differentiated from monocyte/macrophage precursor cells ex vivo with the addition of RANKL. Thus, it is not surprising that osteoclasts in melanoma could come from either circulating monocytes or TAMs on RANKL stimulation.