Figure 2. Vicious cycle between osteoclasts and cancer cells in bone.

Bone-derived growth factors (GFs) such as insulin-like growth factors (IGF) and transforming growth factor-β (TGF-β), promote proliferation and inhibit apoptosis and stimulate epithelial-mesenchymal transition (EMT) and production of bone-modifying cytokines such as parathyroid hormone-related protein (PTH-rP), prostaglandin E₂ (PGE₂) and interleukin-11 (IL-11) in bone-colonizing cancer cells, representing the concept of “Seed and Soil” theory proposed by Paget [81]. These bone-modifying factors further stimulate osteoclastic bone resorption via activation of receptor activator of nuclear factor-κB (RANKL)/RANK pathway in osteoblasts and osteoclasts, thereby further increasing release of bone-stored growth factors, thus establishing “vicious cycle” between bone-resorbing osteoclasts and bone-colonizing cancer cells [1, 17, 18]. Bone-colonizing cancer cells reside in stromal cell niche via cell-cell contact that is mediated by cell adhesion molecules (CAMs) and stay dormant or undergo EMT and acquire further aggressiveness. Role of osteocytes in bone metastasis and CABP needs to be elucidated. CAM: cell adhesion molecule, EMT: Epithelial-mesenchymal transition, RANK: receptor activation of NF-κB, RANKL: receptor activation of NF-κB ligand,