Abstract
Amplification of the chemokines CXCL10 and RANKL has been suggested to promote osteoclast differentiation and osteolytic bone metastasis, but a function for endogenous CXCL10 in these processes is not well established. In this study, we show that endogenous CXCL10 is critical to recruit cancer cells to bone, support osteoclast differentiation and promote for the formation of osteolytic bone metastases. Neutralizing CXCL10 antibody reduced migration of cancer cells expressing the CXCL10 receptor CXCR3, and loss of CXCR3 or CXCL10 decreased bone tumor burden in vivo. Bone colonization augmented host production of CXCL10, which was required for cancer growth and subsequent osteolysis. Direct interactions between cancer cells and macrophages further stimulated CXCL10 production from macrophages. Growth of bone metastases required CXCL10-stimulated adhesion of cancer cells to type I collagen as well as RANKL-mediated osteoclast formation. Together, our findings show that CXCL10 facilitates trafficking of CXCR3-expressing cancer cells to bone, which augments its own production and promotes osteoclastic differentiation. CXCL10 therefore may represent a therapeutic target for osteolytic bone metastasis.
Highlights
The importance of the interaction between cancer cells and the surrounding environment in organ-specific metastasis has been well characterized in bone metastasis
We previously found that reciprocal amplification of CXCL10 and receptor activator of nuclear factor-kB ligand (RANKL) plays a crucial role in bone destruction in a mouse model of rheumatoid arthritis in which CXCL10 recruits CD4þ T cells and promotes them to produce RANKL, and RANKL induces CXCL10 expression and osteoclast differentiation from its precursors [18]
CXCL10 induced the chemotactic migration of several cancer cells capable of developing bone metastasis, including human MDA-MB-231 breast cancer cells and mouse B16F10 melanoma cells
Summary
The importance of the interaction between cancer cells and the surrounding environment in organ-specific metastasis has been well characterized in bone metastasis. The development and progression of osteolytic bone metastasis are thought to depend on a complex cycle of bone destruction and cancer outgrowth [3]. Increased bone resorption by activated osteoclasts releases growth factors such as transforming growth factor-b and insulin-like growth factors from the degraded bone matrix. These growth factors in turn enhance the growth of cancer cells and further stimulate them to produce the osteoclastogenic factors, resulting in a vicious cycle of bone destruction and cancer outgrowth [4, 5]
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