Chemical interactions between fibrosarcoma cancer cells and sensory neurons contribute to cancer pain

Iryna A. Khasabova, Cheryl L. Stucky, Catherine Harding-Rose, Laura Eikmeier, Alvin J. Beitz, Lia G. Coicou, Amy E. Hanson, Donald A. Simone, Virginia S. Seybold

Research output: Contribution to journalArticlepeer-review

48 Scopus citations

Abstract

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 α2δ1 and TRPV1 receptor. Pretreatment with gabapentin, an inhibitor of the α2δ1 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 α2δ1 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.

Original languageEnglish (US)
Pages (from-to)10289-10298
Number of pages10
JournalJournal of Neuroscience
Volume27
Issue number38
DOIs
StatePublished - Sep 19 2007

Keywords

  • Calcium
  • Capsaicin
  • Channel
  • Culture
  • Dorsal root ganglion
  • Receptor
  • TRPV

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