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Localized experimental bone metastasis drives osteolysis and sensory hypersensitivity at distant non-tumor-bearing sites

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Abstract

Patients with breast cancer metastasis to bone suffer from inadequate pain relief. Animal models provide increased understanding of cancer-induced bone and sensory alterations. The objective of this study was to investigate the measures of pain at distant non-tumor-bearing sites in animals with localized bone metastasis. Immunocompetent BALB/c mice are injected intra-tibially with murine mammary carcinoma cells (4T1) or saline, and the sensitivity to mechanical and thermal stimuli in the contralateral paw was examined. In addition to previously demonstrated development of osteolysis and hypersensitivity to mechanical and thermal stimuli in the cancer-injected tibia, these animals exhibited an increase in sensory hypersensitivity in the contralateral limb. No bone lesions were evident on radiographs of the contralateral limbs. Histomorphometry detected decreased bone volume per tissue volume and increased osteoclast number in the contralateral tibia and vertebral bones of cancer-bearing animals. Neuroplasticity was examined by immunofluorescence for calcitonin gene-related peptide (CGRP) in sensory neurons and glial fibrillary acidic protein (GFAP) in lumbar spinal cords. CGRP-immunoreactivity and GFAP-immunoreactivity were significantly elevated both ipsilateral and contralateral in tumor-bearing animals. The anti-inflammatory and osteolysis-targeting drug rapamycin reduced hypersensitivity to mechanical and cold stimuli, attenuated GFAP over-expression, and lowered osteoclast number. The osteoclast-targeting drug pamidronate reduced sensitivity to cold and protected against bone loss. Localized bone cancer drives hypersensitivity, bone remodeling, and sensory neuron plasticity at sites distant from the primary tumor area. Drugs targeting these mechanisms may be useful in the treatment of pain distant from the primary tumor site.

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Acknowledgments

We thank Dr. Peter Siegel for providing the 4T1 cells, Drs. Magali Millecamps, Osama Hussein, and Catherine Ferland-Legault for methodological and intellectual support, Drs. Monzur Murshed and Frank Rauch for advice on histomorphometry and McGill University undergraduate students Anita Ramachandran, Jingwen Chen, Katia Fox, and Robert Samberg for their help in performing the animal studies. This study was supported by the Cancer Research Society/Quebec Breast Cancer Foundation grant to LSS and SVK. DMA was supported by Ministry of Higher Education, Egypt. SVK holds Canada Research Chair in Osteoclast Biology.

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Authors and Affiliations

  1. Faculty of Dentistry, McGill University, Montreal, QC, Canada

    Dareen M. Abdelaziz, Laura S. Stone & Svetlana V. Komarova

  2. Alan Edwards Centre for Research on Pain, Montreal, QC, Canada

    Dareen M. Abdelaziz & Laura S. Stone

  3. Department of Anaesthesiology, Faculty of Medicine, McGill University, Montreal, Canada

    Laura S. Stone

  4. Department of Pharmacology & Therapeutics, Faculty of Medicine, McGill University, Montreal, Canada

    Laura S. Stone

  5. Integrated Program in Neuroscience, McGill University, Montreal, Canada

    Laura S. Stone

  6. Shriners Hospital for Children-Canada, 1529 Cedar Avenue, Room 300, Montreal, QC, H3G IA6, Canada

    Svetlana V. Komarova

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  1. Dareen M. Abdelaziz
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  2. Laura S. Stone
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  3. Svetlana V. Komarova
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Correspondence to Svetlana V. Komarova.

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Abdelaziz, D.M., Stone, L.S. & Komarova, S.V. Localized experimental bone metastasis drives osteolysis and sensory hypersensitivity at distant non-tumor-bearing sites. Breast Cancer Res Treat 153, 9–20 (2015). https://doi.org/10.1007/s10549-015-3517-x

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