Cancer-induced bone pain: Mechanisms and models

•Non-painful primary tumors often yield severely painful bone metastases in cancer patients.•Tumor-derived growth factors stimulate neuronal sprouting of nociceptors in the bone microenvironment.•Acid-sensing ion channels are activated by acidic tumor-induced osteolysis and local tumor acidity.•Cytokines and chemokines released in the bone microenvironment lead to nociceptive signaling and sensitization in bone.•Oxidative stress produces an increase in glutamate signaling in bone through a glutamate–cystine antiporter on tumor cells. Cancerous cells can originate in a number of different tissues such as prostate, breast and lung, but often go undetected and are non-painful. Many types of cancers have a propensity to metastasize to the bone microenvironment first. Tumor burden within the bone causes excruciating breakthrough pain with properties of ongoing pain that is inadequately managed with current analgesics. Part of this failure is due to the poor understanding of the etiology of cancer pain. Animal models of cancer-induced bone pain (CIBP) have revealed that the neurochemistry of cancer has features distinctive from other chronic pain states. For example, preclinical models of metastatic cancer often result in the positive modulation of neurotrophins, such as NGF and BDNF, that can lead to nociceptive sensitization. Preclinical cancer models also demonstrate nociceptive neuronal expression of acid-sensing receptors, such as ASIC1 and TRPV1, which respond to cancer-induced acidity within the bone. CIBP is correlated with a significant increase in pro-inflammatory mediators acting peripherally and centrally, contributing to neuronal hypersensitive states. Finally, cancer cells generate high levels of oxidative molecules that are thought to increase extracellular glutamate concentrations, thus activating primary afferent neurons. Knowledge of the unique neuro-molecular profile of cancer pain will ultimately lead to the development of novel and superior therapeutics for CIBP.