To test our hypothesis, we measured cathepsin S expression and activity in human and mouse oral cancers, immunolocalized cathepsin S in cancer cells and macrophages in human oral cancers, and used a series of mouse models, including a model in which the gene for PAR2 is selectively deleted on sensory neurons, to test whether cathepsin S mediated oral cancer pain. The gene discussed is CTSS; the disease is lip and oral cavity carcinoma.