Figure 1

Vicious cycles in bone metastasis. In the classic vicious cycle of bone metastasis [2], tumor cells stimulate osteolysis by releasing factors (such as interleukins and parathyroid hormone-related protein) that increase receptor activator of nuclear factor kappa-B (RANK) ligand (RANKL, shown as lollipops), which activates osteoclasts (by binding to the RANK receptor, shown as Y’s) to resorb bone. Bone resorption releases growth factors from matrix (such as transforming growth factor beta), which in turn stimulate tumor cells. In multiple myeloma (MM), an additional vicious cycle occurs. Active osteoblasts make new bone and secrete factors that antagonize tumor growth. MM and breast cancer cells secrete osteoblast blockers, such as sclerostin (Sost) and DKK1 (both inhibitors of the WNT pathway), thus potentially fending off osteoblast-mediated growth inhibition and causing increased bone loss, because tumor now increases osteoclastic bone destruction and suppresses compensatory new bone formation. The authors speculate that a similar secondary vicious cycle occurs in osteolytic bone metastases because of breast cancer. The role of abundant osteocytes in bone metastasis is unclear, although these cells are a major source of sclerostin and RANKL. FGFR, fibroblast growth factor receptor; mTOR, mammalian target of rapamycin.