Tumor metastasis to bone

Abstract

Establishment of skeletal metastasis involves bidirectional interactions between the tumor cell and the cellular elements in the bone microenvironment. A better understanding of the pathophysiology of bone metastasis will be critical in developing the means to prevent bone metastasis or inhibit its progression. The receptor activator of nuclear factor-kappaB (RANK)/RANK ligand pathway has emerged as the key pathway regulating osteolysis in skeletal metastasis. A number of candidate factors, including the Wnt (wingless int) proteins, endothelin-1, and bone morphogenetic proteins, have been implicated in the establishment of osteoblastic metastasis. The complex nature of tumor-bone microenvironment interactions and the presence of multiple pathways that lead to bone metastasis suggests that simultaneous targeting of these pathways in the metastatic cascade are required for effective treatment. This review discusses current understanding of the pathophysiologic mechanisms that underlie the establishment of bone metastasis and potential molecular therapeutic strategies for prevention and treatment of bone metastasis.

Figure 1

Vicious cycle in osteolytic bone metastasis. The pro-osteolytic factors secreted by the tumor cells (PTHrP, IL-1, IL-8, IL-11, soluble RANKL, TNF-α, and PGE) promote osteolysis by stimulating osteoclast formation and maturation. The growth factors secreted following osteolysis (BMP, IGF, and TGF-β) are stimulatory for tumor growth, which results in increased tumor burden and eventually more osteolysis. The inset delineates the regulation of osteoclast formation and activation. RANKL on the osteoblast/stromal cells interacts with the RANK on the osteoclast precursors in the presence of M-CSF to stimulate their differentiation into mature osteoclasts. An alternate pathway (RANKL independent) of osteoclast differentiation (mediated by IL-1 and its receptor IL-1R on the osteoclast) is also shown. BMP, bone morphogenetic protein; IGF, insulin-like growth factor; M-CSF, macrophage colony-stimulating factor; OB, osteoblast; OCL, osteoclast; PG, prostaglandin; PTHrP, parathyroid hormone related peptide; IL, interleukin; RANKL, receptor activator of nuclear factor-κB ligand; TGF, transforming growth factor; TNF, tumor necrosis factor.