Schematic representation of tumor-cell induced osteolysis. A tumor cell may release soluble mediators such as hormones (eg, PTHrP), eicosanoids, cytokines (eg, IL-6), or growth factors (eg, TGF-α) that act on an osteoblastic stromal cell. The stromal cell produces RANKL, which binds to its cognate receptor, RANK, expressed on osteoclast (Oc) precursors. In the presence of M-CSF, which acts on its receptor, c-fms, RANKL can enhance the formation of active osteoclasts that carry out bone resorption. Tumor cells have also been occasionally reported to directly release sRANKL, a soluble form of RANKL. Additionally, proteases can be produced by tumor cells and facilitate their invasion of nonmineralized tissue.