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

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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.

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Abbreviations

CXCL10:

C-X-C motif chemokine 10

CXCR3:

C-X-C motif chemokine receptor 3

rrCXCL10:

recombinant rat CXCL10 protein

GAPDH:

glyceraldehyde-3-phosphate dehydrogenase

CIBP:

cancer-induced bone pain

PWTs:

paw withdrawal thresholds

HPβCD:

2-Hydroxypropyl-β-cyclodextrin

MC:

minocycline

CD11b:

integrin alpha M chain, a special molecule in microglia

References

  1. Coleman RE (2006) Clinical features of metastatic bone disease and risk of skeletal morbidity. Clin Cancer Res 12(20 Pt 2):6243s–6249s. doi:10.1158/1078-0432.CCR-06-0931

    Article  PubMed  Google Scholar 

  2. Middlemiss T, Laird BJ, Fallon MT (2011) Mechanisms of cancer-induced bone pain. Clin Oncol 23(6):387–392. doi:10.1016/j.clon.2011.03.003

    Article  CAS  Google Scholar 

  3. Vadalouca A, Raptis E, Moka E, Zis P, Sykioti P, Siafaka I (2012) Pharmacological treatment of neuropathic cancer pain: a comprehensive review of the current literature. Pain Pract 12(3):219–251. doi:10.1111/j.1533-2500.2011.00485.x

    Article  PubMed  Google Scholar 

  4. Hu JH, Zheng XY, Yang JP, Wang LN, Ji FH (2012) Involvement of spinal monocyte chemoattractant protein-1 (MCP-1) in cancer-induced bone pain in rats. Neurosci Lett 517(1):60–63. doi:10.1016/j.neulet.2012.04.026

    Article  CAS  PubMed  Google Scholar 

  5. Hu JH, Yang JP, Liu L, Li CF, Wang LN, Ji FH, Cheng H (2012) Involvement of CX3CR1 in bone cancer pain through the activation of microglia p38 MAPK pathway in the spinal cord. Brain Res 1465:1–9. doi:10.1016/j.brainres.2012.05.020

    Article  CAS  PubMed  Google Scholar 

  6. Yin Q, Cheng W, Cheng MY, Fan SZ, Shen W (2010) Intrathecal injection of anti-CX3CR1 neutralizing antibody delayed and attenuated pain facilitation in rat tibial bone cancer pain model. Behav Pharmacol 21(7):595–601. doi:10.1097/FBP.0b013e32833e7e2a

    Article  CAS  PubMed  Google Scholar 

  7. Liu M, Guo S, Hibbert JM, Jain V, Singh N, Wilson NO, Stiles JK (2011) CXCL10/IP-10 in infectious diseases pathogenesis and potential therapeutic implications. Cytokine Growth Factor Rev 22(3):121–130. doi:10.1016/j.cytogfr.2011.06.001

    CAS  PubMed Central  PubMed  Google Scholar 

  8. Giuliani N, Bonomini S, Romagnani P, Lazzaretti M, Morandi F, Colla S, Tagliaferri S, Lasagni L, Annunziato F, Crugnola M, Rizzoli V (2006) CXCR3 and its binding chemokines in myeloma cells: expression of isoforms and potential relationships with myeloma cell proliferation and survival. Haematologica 91(11):1489–1497

    CAS  PubMed  Google Scholar 

  9. Neville LF, Mathiak G, Bagasra O (1997) The immunobiology of interferon-gamma inducible protein 10 kD (IP-10): a novel, pleiotropic member of the C-X-C chemokine superfamily. Cytokine Growth Factor Rev 8(3):207–219

    Article  CAS  PubMed  Google Scholar 

  10. Sato E, Fujimoto J, Tamaya T (2007) Expression of interferon-gamma-inducible protein 10 related to angiogenesis in uterine endometrial cancers. Oncology 73(3–4):246–251. doi:10.1159/000127422

    Article  CAS  PubMed  Google Scholar 

  11. Aksoy MO, Yang Y, Ji R, Reddy PJ, Shahabuddin S, Litvin J, Rogers TJ, Kelsen SG (2006) CXCR3 surface expression in human airway epithelial cells: cell cycle dependence and effect on cell proliferation. Am J Physiol Lung cell Mol Physiol 290(5):L909–L918. doi:10.1152/ajplung.00430.2005

    Article  CAS  PubMed  Google Scholar 

  12. Shin SY, Nam JS, Lim Y, Lee YH (2010) TNFalpha-exposed bone marrow-derived mesenchymal stem cells promote locomotion of MDA-MB-231 breast cancer cells through transcriptional activation of CXCR3 ligand chemokines. The J Biol Chem 285(40):30731–30740. doi:10.1074/jbc.M110.128124

    Article  CAS  Google Scholar 

  13. Muller M, Carter S, Hofer MJ, Campbell IL (2010) Review: The chemokine receptor CXCR3 and its ligands CXCL9, CXCL10 and CXCL11 in neuroimmunity—a tale of conflict and conundrum. Neuropathol Appl Neurobiol 36(5):368–387. doi:10.1111/j.1365-2990.2010.01089.x

    Article  CAS  PubMed  Google Scholar 

  14. Campanella GS, Tager AM, El Khoury JK, Thomas SY, Abrazinski TA, Manice LA, Colvin RA, Luster AD (2008) Chemokine receptor CXCR3 and its ligands CXCL9 and CXCL10 are required for the development of murine cerebral malaria. Proc Nat Acad Sci USA 105(12):4814–4819. doi:10.1073/pnas.0801544105

    Article  CAS  PubMed  Google Scholar 

  15. Strong JA, Xie W, Coyle DE, Zhang JM (2012) Microarray analysis of rat sensory ganglia after local inflammation implicates novel cytokines in pain. PloS one 7(7):e40779. doi:10.1371/journal.pone.0040779

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Fu ES, Zhang YP, Sagen J, Candiotti KA, Morton PD, Liebl DJ, Bethea JR, Brambilla R (2010) Transgenic inhibition of glial NF-kappa B reduces pain behavior and inflammation after peripheral nerve injury. Pain 148(3):509–518. doi:10.1016/j.pain.2010.01.001

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Cao F, Gao F, Xu AJ, Chen ZJ, Chen SS, Yang H, Yu HH, Mei W, Liu XJ, Xiao XP, Yang SB, Tian XB, Wang XR, Tian YK (2010) Regulation of spinal neuroimmune responses by prolonged morphine treatment in a rat model of cancer induced bone pain. Brain Res 1326:162–173. doi:10.1016/j.brainres.2010.02.039

    Article  CAS  PubMed  Google Scholar 

  18. Liu X, Bu H, Liu C, Gao F, Yang H, Tian X, Xu A, Chen Z, Cao F, Tian Y (2012) Inhibition of glial activation in rostral ventromedial medulla attenuates mechanical allodynia in a rat model of cancer-induced bone pain. J Huazhong Univ Sci Technolog Med Sci 32(2):291–298. doi:10.1007/s11596-012-0051-5

    Article  CAS  PubMed  Google Scholar 

  19. Steinmetz OM, Sadaghiani S, Panzer U, Krebs C, Meyer-Schwesinger C, Streichert T, Fehr S, Hamming I, van Goor H, Stahl RA, Wenzel U (2007) Antihypertensive therapy induces compartment-specific chemokine expression and a Th1 immune response in the clipped kidney of Goldblatt hypertensive rats. Am J Physiol Renal Physiol 292(2):F876–F887. doi:10.1152/ajprenal.00174.2006

    Article  CAS  PubMed  Google Scholar 

  20. Yaksh TL, Rudy TA (1976) Chronic catheterization of the spinal subarachnoid space. Physiol Behav 17(6):1031–1036

    Article  CAS  PubMed  Google Scholar 

  21. Walser TC, Rifat S, Ma X, Kundu N, Ward C, Goloubeva O, Johnson MG, Medina JC, Collins TL, Fulton AM (2006) Antagonism of CXCR3 inhibits lung metastasis in a murine model of metastatic breast cancer. Cancer Res 66(15):7701–7707. doi:10.1158/0008-5472.CAN-06-0709

    Article  CAS  PubMed  Google Scholar 

  22. Fox A, Medhurst S, Courade JP, Glatt M, Dawson J, Urban L, Bevan S, Gonzalez I (2004) Anti-hyperalgesic activity of the cox-2 inhibitor lumiracoxib in a model of bone cancer pain in the rat. Pain 107(1–2):33–40

    Article  CAS  PubMed  Google Scholar 

  23. Saika F, Kiguchi N, Kobayashi Y, Fukazawa Y, Kishioka S (2012) CC-chemokine ligand 4/macrophage inflammatory protein-1beta participates in the induction of neuropathic pain after peripheral nerve injury. Eur J Pain 16(9):1271–1280. doi:10.1002/j.1532-2149.2012.00146.x

    Article  CAS  PubMed  Google Scholar 

  24. Liou JT, Yuan HB, Mao CC, Lai YS, Day YJ (2012) Absence of C-C motif chemokine ligand 5 in mice leads to decreased local macrophage recruitment and behavioral hypersensitivity in a murine neuropathic pain model. Pain 153(6):1283–1291. doi:10.1016/j.pain.2012.03.008

    Article  CAS  PubMed  Google Scholar 

  25. Watkins LR, Maier SF (2002) Beyond neurons: evidence that immune and glial cells contribute to pathological pain states. Physiol Rev 82(4):981–1011. doi:10.1152/physrev.0 0011.2002

    CAS  PubMed  Google Scholar 

  26. Guillot X, Semerano L, Decker P, Falgarone G, Boissier MC (2012) Pain and immunity. Joint, bone, spine : revue du rhumatisme 79(3):228–236. doi:10.1016/j.jbspin.2011.10.008

    Article  Google Scholar 

  27. Schomberg D, Olson JK (2012) Immune responses of microglia in the spinal cord: contribution to pain states. Exp Neurol 234(2):262–270. doi:10.1016/j.expneurol.2011.12.021

    Article  CAS  PubMed  Google Scholar 

  28. Yao M, Chang XY, Chu YX, Yang JP, Wang LN, Cao HQ, Liu MJ, Xu QN (2011) Antiallodynic effects of propentofylline Elicited by interrupting spinal glial function in a rat model of bone cancer pain. J Neurosci Res 89(11):1877–1886. doi:10.1002/jnr.22711

    Article  CAS  PubMed  Google Scholar 

  29. Van Der Meer P, Goldberg SH, Fung KM, Sharer LR, Gonzalez-Scarano F, Lavi E (2001) Expression pattern of CXCR3, CXCR4, and CCR3 chemokine receptors in the developing human brain. J Neuropathol Exp Neurol 60(1):25–32

    Google Scholar 

  30. Rappert A, Bechmann I, Pivneva T, Mahlo J, Biber K, Nolte C, Kovac AD, Gerard C, Boddeke HW, Nitsch R, Kettenmann H (2004) CXCR3-dependent microglial recruitment is essential for dendrite loss after brain lesion. J Neurosci 24(39):8500–8509. doi:10.1523/JNEUROSCI.2451-04.2004

    Article  CAS  PubMed  Google Scholar 

  31. Vinet J, de Jong EK, Boddeke HW, Stanulovic V, Brouwer N, Granic I, Eisel UL, Liem RS, Biber K (2010) Expression of CXCL10 in cultured cortical neurons. J Neurochem 112(3):703–714. doi:10.1111/j.1471-4159.2009.06495.x

    Article  CAS  PubMed  Google Scholar 

  32. Kroeze KL, Boink MA, Sampat-Sardjoepersad SC, Waaijman T, Scheper RJ, Gibbs S (2012) Autocrine regulation of re-epithelialization after wounding by chemokine receptors CCR1, CCR10, CXCR1, CXCR2, and CXCR3. J Invest Dermatol 132(1):216–225. doi:10.1038/jid.2011.245

    Article  CAS  PubMed  Google Scholar 

  33. Park SJ, Burdick MD, Brix WK, Stoler MH, Askew DS, Strieter RM, Mehrad B (2010) Neutropenia enhances lung dendritic cell recruitment in response to Aspergillus via a cytokine-to-chemokine amplification loop. J Immunol 185(10):6190–6197. doi:10.4049/jimmunol.1002064

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Korkaya H, Liu S, Wicha MS (2011) Regulation of cancer stem cells by cytokine networks: attacking cancer’s inflammatory roots. Clinical Cancer Res 17(19):6125–6129. doi:10.1158/1078-0432.CCR-10-2743

    Article  CAS  Google Scholar 

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Acknowledgments

We are grateful to Amgen for kindly providing AMG487 to us. We also gratefully acknowledge the expertise of Ms. Amber Chen (Project Intern, Department of Neuroscience, Baylor College of Medicine, USA) in the proof-reading of the manuscript. This work was supported by grants from the Natural Science Foundation of China (Nos. 81070890, 30872441, 81371250, 81171259, 81100832 and 30901395), and also supported by 2010 Clinical Key Disciplines Construction Grant from the Ministry of Health of China.

Conflict of interest

The authors declare that they do not have financial relationships with any of the organizations that sponsored the research, and they do not have any other real or apparent conflict(s) of interest that may have a direct bearing on the subject matter of the article.

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Authors and Affiliations

  1. Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, 430030, Wuhan, People’s Republic of China

    Huilian Bu, Bin Shu, Feng Gao, Cheng Liu, Xuehai Guan, Changbin Ke, Fei Cao, Hongbing Xiang, Hui Yang, Xuebi Tian & Yuke Tian

  2. Department of Neuroscience, Baylor College of Medicine, Houston, TX, 77030, USA

    Fei Cao

  3. CNRC, Baylor College of Medicine, Houston, TX, 77030, USA

    Antentor Othrell Hinton Jr.

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  1. Huilian Bu
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Correspondence to Yuke Tian.

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Huilian Bu and Bin Shu contributed equally to this work.

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Bu, H., Shu, B., Gao, F. et al. Spinal IFN-γ-induced protein-10 (CXCL10) mediates metastatic breast cancer-induced bone pain by activation of microglia in rat models. Breast Cancer Res Treat 143, 255–263 (2014). https://doi.org/10.1007/s10549-013-2807-4

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