Faculty Collaboration Database

Chemical interactions between fibrosarcoma cancer cells and sensory neurons contribute to cancer pain. J Neurosci 2007 Sep 19;27(38):10289-98

Date

09/21/2007

Pubmed ID

17881535

Pubmed Central ID

PMC6672679

DOI

10.1523/JNEUROSCI.2851-07.2007

Scopus ID

2-s2.0-34548836298 (requires institutional sign-in at Scopus site)   58 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 alpha2delta1 and TRPV1 receptor. Pretreatment with gabapentin, an inhibitor of the alpha2delta1 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 alpha2delta1 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.

Author List

Khasabova IA, Stucky CL, Harding-Rose C, Eikmeier L, Beitz AJ, Coicou LG, Hanson AE, Simone DA, Seybold VS

Author

Cheryl L. Stucky PhD Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Coculture Techniques
Fibrosarcoma
Male
Mice
Mice, Inbred C3H
Neurons, Afferent
Pain
Pain Measurement
Tumor Cells, Cultured