FIGURE 4.

Osteoclasts and cancer cells: partners in crime in the vicious cycle. Three principal steps are necessary for a bone metastasis to occur: 1) escape of the cancer cell from primary tumor site, migration, and vascular permeabilization; 2) extravasation from blood stream and bone marrow seeding; and 3) colonization and homing to bone. Once engrafted in the bone, neoplastic cells secrete pro-osteoclastogenic factors, such as TNF-α, PTHrP, ILs, IGFs, M-CSF, and RANKL, promoting osteoclast differentiation and activity. Jagged1 expression by neoplastic cells fuels IL-6 secretion by osteoblasts, exacerbating osteoclastogenesis and tumor growth. Mature osteoclasts, in turn, free several pro-tumorigenic factors, such as TGF-β, VEGF, BMPs, PDGF, and Ca²⁺ ions, all capable of stimulating tumor growth. This leads to the instauration and fueling of the vicious cycle between cancer cells and active osteoclasts. TNF-α, tumor necrosis factor-α; PTHrP, parathyroid hormone-related protein; ILs, interleukins; IGFs, insulin-like growth factors; M-CSF, macrophage colony-stimulating factor; RANKL, receptor activator of nuclear factor kappa B ligand; TGF-β, transforming growth factor-β; VEGF, vascular endothelial growth factor; BMPs, bone morphogenetic proteins; PDGF, platelet-derived growth factor; Ca²⁺, calcium ion.