Figure 2.

IL-6 signaling in the tumor cell of the bone marrow niche. The bone marrow microenvironment augments MAPK and PI3K/Akt pathways resulting in anti-apoptotic and NF-κB signaling in multiple myeloma cells. Binding of IL-6 to IL-6R and Gp-130 co-receptors induces JAK-2 signaling. This signaling cascade diverges down STAT3/PI3K/Akt pathways and various MAPK pathways, including MEK/ERK. The former is associated with promoting anti-apoptotic proteins: MCL1, BCL-XL, BCL-2 and c-Myc, which contribute to drug resistance. STAT3/PI3K/Akt can also promote NF-κB signaling which results in release of angiogenic and inflammatory molecules, such as IL-6. This can feed into an autocrine positive feedback loop. IκBα can inhibit NFκB through coupling and this interaction can be maintained by certan signals, such as by estradiol. The IL-6 signaling pathway in MM cells is similar to that of bone marrow stromal cells and overall it promotes an inflammatory microenvironment in the bone which results in bone loss, increased tumor burden and disease progression. Bone marrow adipocytes (BMAs) are one cell within the bone microoenvironment thought to feed into this system through secretion of IL-6. This can promote anti-apoptosis and disease progrssion through NF-κB signaling. BMAs, thus, represent an ideal target for MM therapies in order to reduce drug resistance and relapse, instead of targeting the complicated, clonally expanding plasma cell.