Figure 1.

Transforming growth factor-β (TGF-β) and receptor activator of nuclear factor kappa-B ligand (RANKL) cooperate to suppress the immune response in the bone marrow. 1. In bone-associated cancers, the activation of Notch may be promoted by Jagged1/2 ligands overexpressed by cancer cells; one of the outcomes of Notch overactivation is to increase RANKL expression (52). 2. RANKL represents the main osteoclastogenic factor and promotes osteoclasts (OCLs) differentiation and bone resorption (53). 3. In addition, RANKL plays immunoregulatory functions. RANKL may activate its receptor RANK, which is overexpressed by DCs and, in turn, boosts DCs ability to induce the expansion of the local Treg population promoting tolerance to tumor antigens (54). 4. One of the outcomes of the increased bone resorption is the release of TGF-β from the extracellular matrix (55). 5. TGF-β can be also secreted by tumor and stromal cells and by myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment (TME). Its immunosuppressive effects may be promoted by Notch signaling (see text for details) (41, 51). 6. In specific contexts, such as breast cancer-derived bone metastasis, TGF-β released by cancer cells mediates bone remodeling and stimulates the overexpression of Jagged1 in tumor cells. Jagged1 present on cancer cell surface, in turn, triggers Notch activation in OCLs and osteoblasts (OBLs), promoting the development of tumor-associated bone disease (56).