Figure 3.

The stimulation of bone cell activity by tumors in the bone marrow. Interactions between tumor cells, bone marrow components (for example, stromal cells, platelets, immune cells and hematopoietic progenitors) and resident bone cells results in activation of both osteoclasts and osteoblasts, causing bone resorption, as well as robust bone formation. Tumor-derived activation of host bone cells also supports the aggressive growth and behavior of tumor cells. (1) The release of tumor-derived factors, such as parathyroid hormone-related protein (PTHrP), interleukin 8 (IL-8), tumor necrosis factor (TNF), transforming growth factor β (TGF-β), heparanase and many others, enhances osteoclast activation and bone resorption via RANKL-dependent and RANKL-independent mechanisms. Bone resorption results in the release of bone-derived growth factors that support tumor proliferation. Tumor activation also drives the activation of local stromal cells and platelets that may also enhance tumor proliferation. (2) The production of growth factors such as fibroblast growth factors (FGFs), bone morphogenetic proteins (BMPs), TGF-β and Wnt family members by metastatic tumors stimulates osteoblast activity, leading to increased bone formation. The result of the enhanced osteoblast proliferation and activity is again tumor stimulation, as well as the normal coupling responses to help enhance osteoclastogenesis and bone resorption. Collectively, these numerous cellular interactions drive all of the well-described skeletal consequences of bone metastasis and result in the inappropriate bone formation and bone resorption characteristic of bone metastasis.