CXCL12/CXCR4 Axis in Tissue Targeting and Bone Destruction in Cancer and Multiple Myeloma

The chemokine CXCL12 (also known as stromal cell derived factor [SDF‐1]) and its receptor CXCR4 are strong candidates for regulating the mobilization and intravasation of primary cancer cells and their extravasation and formation of metastases in bone. CXCL12 has been reported to have chemo‐attractive effects on both solid tumor‐derived cancer cells(1) and multiple myeloma cells.(2,3) CXCL12 is produced in bone by bone marrow stromal cells, where it has a physiological role in establishing normal hematopoietic bone marrow colonization during development.(4) CXCL12 is a powerful chemo‐attractant for lymphocytes and monocytes. As such, CXCL12 can have the dual roles of attracting and retaining cells of these lineages in the bone environment. CXCL12 has also been implicated as a regulator of bone resorption through control of the migration of osteoclast precursors to resorption sites(5) and their maintenance within the bone environment.(6) CXCR4 is highly expressed in pre‐osteoclasts and its expression decreases during the transition to mature osteoclasts.(7) CXCL12 has a role in attracting osteoclast precursors to areas of bone resorption through activation of the Akt signaling pathway(8) and may stimulate local proliferation and fusion of osteoclast precursors.(5) However, once osteoclast precursors are located in bone, RANKL seems to initiate all aspects of the resorption process (osteoclast differentiation, TRACP activity, cathepsin K activity, bone pit formation), and these effects seem independent of CXCL12.(7)