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The Journal of Neuroscience, September 19, 2007, 27(38):10289-10298; doi:10.1523/JNEUROSCI.2851-07.2007

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Neurobiology of Disease
Chemical Interactions between Fibrosarcoma Cancer Cells and Sensory Neurons Contribute to Cancer Pain

Iryna A. Khasabova,¹ Cheryl L. Stucky,⁶ Catherine Harding-Rose,¹ Laura Eikmeier,⁴ Alvin J. Beitz,⁵ Lia G. Coicou,² Amy E. Hanson,³ Donald A. Simone,¹ and Virginia S. Seybold²

Departments of ¹Diagnostic and Biological Sciences and ²Neuroscience and ³Pharmacology Graduate Program, University of Minnesota, Minneapolis, Minnesota 55455, ⁴Comparative and Molecular Biosciences Graduate Program and ⁵Department of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, Minnesota 55108, and ⁶Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin 53226

Correspondence should be addressed to Dr. Virginia S. Seybold, Department of Neuroscience, University of Minnesota, 6-145 Jackson Hall, 321 Church Street, Southeast, Minneapolis, MN 55455. Email: vseybold{at}umn.edu

In an experimental model of cancer pain, the hyperalgesia that occurs with osteolytic tumor growth is associated with the sensitization of nociceptors. We examined functional and molecular changes in small-diameter dorsal root ganglion (DRG) neurons to determine cellular mechanisms underlying this sensitization. The occurrence of a Ca²⁺ transient in response to either KCl (25 mM) or capsaicin (500 nM) increased in small neurons isolated from murine L3–L6 DRGs ipsilateral to fibrosarcoma cell tumors. The increased responses were associated with increased mRNA levels for the Ca²⁺ channel subunit 21 and TRPV1 receptor. Pretreatment with gabapentin, an inhibitor of the 21 subunit, blocked the increased response to KCl in vitro and the mechanical hyperalgesia in tumor-bearing mice in vivo. Similar increases in neuronal responsiveness occurred when DRG neurons from naive mice and fibrosarcoma cells were cocultured for 48 h. The CC chemokine ligand 2 (CCL2) may contribute to the tumor cell-induced sensitization because CCL2 immunoreactivity was present in tumors, high levels of CCL2 peptide were present in microperfusates from tumors, and treatment of DRG neurons in vitro with CCL2 increased the amount of mRNA for the 21 subunit. Together, our data provide strong evidence that the chemical mediator CCL2 is released from tumor cells and evokes phenotypic changes in sensory neurons, including increases in voltage-gated Ca²⁺ channels that likely underlie the mechanical hyperalgesia in the fibrosarcoma cancer model. More broadly, this study provides a novel in vitro model to resolve the cellular and molecular mechanisms by which tumor cells drive functional changes in nociceptors.

Key words: calcium; capsaicin; channel; culture; dorsal root ganglion; receptor; TRPV

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Received March 1, 2007; revised July 31, 2007; accepted Aug. 8, 2007.

Correspondence should be addressed to Dr. Virginia S. Seybold, Department of Neuroscience, University of Minnesota, 6-145 Jackson Hall, 321 Church Street, Southeast, Minneapolis, MN 55455. Email: vseybold{at}umn.edu

This article has been cited by other articles:

				F. A. White, H. Jung, and R. J. Miller Chemokines and the pathophysiology of neuropathic pain PNAS, December 18, 2007; 104(51): 20151 - 20158. [Abstract] [Full Text] [PDF]

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