CXCL10 Promotes Osteolytic Bone Metastasis by Enhancing Cancer Outgrowth and Osteoclastogenesis
Open Access
- 1 July 2012
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 72 (13), 3175-3186
- https://doi.org/10.1158/0008-5472.can-12-0481
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. Cancer Res; 72(13); 3175–86. ©2012 AACR.Other Versions
This publication has 34 references indexed in Scilit:
- Macrophage Binding to Receptor VCAM-1 Transmits Survival Signals in Breast Cancer Cells that Invade the LungsCancer Cell, 2011
- Histone deacetylase inhibitor MS-275 stimulates bone formation in part by enhancing Dhx36-mediated TNAP transcriptionJournal of Bone and Mineral Research, 2011
- Clinical development of anti-RANKL therapies for treatment and prevention of bone metastasisBone, 2011
- TNFα-exposed Bone Marrow-derived Mesenchymal Stem Cells Promote Locomotion of MDA-MB-231 Breast Cancer Cells through Transcriptional Activation of CXCR3 Ligand ChemokinesJournal of Biological Chemistry, 2010
- Organ-specific inhibition of metastatic colon carcinoma by CXCR3 antagonismBritish Journal of Cancer, 2009
- Trolox Prevents Osteoclastogenesis by Suppressing RANKL Expression and SignalingOnline Journal of Public Health Informatics, 2009
- Metastasis: from dissemination to organ-specific colonizationNature Reviews Cancer, 2009
- Natural Killer Cell Accumulation in Tumors Is Dependent on IFN-γ and CXCR3 LigandsCancer Research, 2008
- CXCR3 chemokine receptor immunoreactivity in primary cutaneous malignant melanoma: correlation with clinicopathological prognostic factorsJournal of Clinical Pathology, 2007
- Tumour-educated macrophages promote tumour progression and metastasisNature Reviews Cancer, 2004