INFLAMMATORY SIGNALING AS A THERAPEUTIC TARGET FOR THE TREATMENT OF BREAST CANCER-INDUCED BONE PAIN.

Nicole Sayers , Symons-Liguori AM, Lozano-Ondoua AN, Vanderah T.

INFLAMMATORY SIGNALING AS A THERAPEUTIC TARGET FOR THE TREATMENT OF BREAST CANCER-INDUCED BONE PAIN.

       Many common cancers, including breast, prostate, lung and kidney, have a high propensity for bone metastasis; for breast cancer, 70% of malignancies will metastasize to bone, resulting in debilitating pain and bone destruction in 75-95% of patients.  Despite the prevalence of bone pain in cancer patients, the specific causes and therapeutic targets for managing bone pain are poorly understood.  Breast cancer metastasis to bone results in a pro-inflammatory shift in the bone-tumor microenvironment.  Here we hypothesize that breast cancer-induced bone metastasis elicits pain by the actions of pro-inflammatory mediators at their receptors on nociceptive neurons in the bone and periosteum.

      In the following work, we utilize an in vivo model of breast cancer-induced bone pain that results in both spontaneous and evoked pain behaviors.  Initial studies determined that the expression of pro-inflammatory cytokines (tumor necrosis factor-α, interleukin-6) and chemokines (chemokine C-C motif ligands 2 and 3) are enhanced in tumor-bearing bone, but not the contralateral bone or serum.  mRNA quantitation of bone marrow extrudate corroborated these findings.  The attenuation of bone-derived inflammatory mediators by cannabinoid-receptor 2 agonists, which produce inflammatory suppression of immune cells, was associated with decreases in evoked and spontaneous pain behaviors.

        Furthermore, we demonstrate in vitro that inflammatory mediators are constitutively produced by a murine breast cancer cell line.  Cannabinoid receptor-2 agonists attenuated not only the production of cytokines and chemokines by cancer cells, but also attenuated interleukin-6 or tumor necrosis factor α-induced proliferation.  The results of these data suggest that tumor-derived inflammatory mediators may drive bone cancer pain.  Targeting the inflammatory component of bone metastases provides a novel therapy for pain management in breast cancer-induced bone pain.

Funding Source:  NCI
Grant title:  Cannabinoid CB2 agonists for Treatment of Breast Cancer-Induced Bone Pain
Grant number:  R01-CA142115

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