Spinal IFN-γ-induced protein-10 (CXCL10) mediates metastatic breast cancer-induced bone pain by activation of microglia in rat models.

Abstract

Cancer-induced bone pain (CIBP) is a common clinical problem in breast cancer patients with bone metastasis. Recent studies shows chemokines are novel targets for treatment of CIBP. In this study, we intra-tibial inoculated with Walker 256 rat mammary gland carcinoma cells into rat bone to established metastatic breast cancer. Then we measured the expression of CXCL10 in the spinal cord of metastatic bone cancer rats, investigated the role of CXCL10 in the development of CIBP, and the underlying mechanism. Results revealed that after intra-tibial inoculation with Walker 256 cells, rats showed up-regulation of CXCL10 and its receptor CXCR3 in the spinal cord. Interestingly, intrathecally injection of recombinant CXCL10 protein induced mechanical allodynia in naïve rats. Blocking the function of CXCL10/CXCR3 pathway via anti-CXCL10 antibody or CXCR3 antagonist prevented the development of CIBP and microglial activation. Moreover, CXCL10-induced mechanical allodynia was rescued by minocycline treatment during the late-stage of CIBP, days 10-14. The regulation of CXCL10 expression involved microglial activation in a manner of autocrine positive feedback. These results suggest that CXCL10 may be a necessary algogenic molecule, especially in the development of CIBP. Its function was partly mediated via spinal microglial activation. This study provides a novel insight into the biological function of chemokine CXCL10 in the molecular mechanism underlying cancer pain. It also provides new target for clinical treatment of metastatic breast cancer-induced bone pain in future.

• Authors: Huilian Bu, Bin Shu, Feng Gao, Cheng Liu, Xuehai Guan, Changbin Ke, Fei Cao, Antentor Othrell Hinton Jr, Hongbing Xiang, Hui Yang, Xuebi Tian, Yuke Tian
• Journal: Breast cancer research and treatment (Breast Cancer Res Treat) Vol. 143 Issue 2 Pg. 255-63 (Jan 2014) ISSN: 1573-7217 [Electronic] Netherlands
• PMID: 24337539 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Bacterial Agents
• Chemokine CXCL10
• Cxcl10 protein, rat
• Cxcr3 protein, rat
• Receptors, CXCR3
• Interferon-gamma
• Minocycline

Topics

• Animals
• Anti-Bacterial Agents (therapeutic use)
• Bone Neoplasms (secondary)
• Carcinoma 256, Walker (drug therapy, pathology)
• Chemokine CXCL10 (antagonists & inhibitors, cerebrospinal fluid, pharmacology)
• Disease Models, Animal
• Female
• Gene Expression Regulation, Neoplastic
• Hyperalgesia (drug therapy)
• Interferon-gamma
• Mammary Neoplasms, Experimental (pathology)
• Microglia (cytology, metabolism)
• Minocycline (therapeutic use)
• Musculoskeletal Pain (drug therapy)
• Pain Threshold
• Rats
• Rats, Sprague-Dawley
• Receptors, CXCR3 (analysis, antagonists & inhibitors)
• Spinal Cord (cytology)