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 proinflammatory 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 proinflammatory 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 metastatic bone pain provides a novel therapy for pain management in breast cancer‐induced bone pain.