Title: Tumor-derived Therapeutic Targets of Oral Cancer Pain: A Translational Approach
Zachary Conley (Presenter)
New York University
Nicole Scheff, New York University
Bradley Aouizerat, New York University
Brian Schmidt, New York University
Objectives: Oral cancer patients experience severe pain hypothesized to be due in part to secretion of pro-nociceptive mediators. We hypothesize that pro-nociceptive mediators secreted by human oral squamous cell carcinoma (oSCC) not only sensitize and activate primary afferent neurons but also attract immune cells to the cancer microenvironment.
Methods: To simultaneously study the immune cell chemoattractant and pain-producing effects of cancer-secreted mediators, we injected cell supernatant from different cancer cell lines into tongues of mice. Supernatant injection alone avoids the impact of tumor growth and perineural involvement. Tongue inflammatory infiltrate was quantified with flow cytometry and pain behavior was measured with an objective operant nociceptive assay (Dolognawmeter). We took a translational approach to identify tumor-derived therapeutic targets for oral cancer pain using publically available gene expression data (Affymetrix Human Genome U133 Plus 2.0 Array) on cell lines deposited in the Gene Expression Omnibus. An evaluation of genes that are consistently expressed within phenotypic groups of cells lines (e.g., oral cancer) and not in phenotypically contrasting cell lines (e.g., oral dysplasia) was performed.
We found that oral cancer cell lines, HSC3 and SCC9, drive both pain behavior and increased inflammatory infiltrate, whereas, melanoma cell line, SkMel28, only drives inflammation but without pain (all p<0.05). Lastly, oral dysplasia and normal keratinocytes cell line supernatant result in neither pain nor inflammation. These data suggest that oSCC-secreted mediators are unique from other malignant cancers and precancerous keratinocytes and may contain novel therapeutic targets to treat cancer pain. Pathway analysis based on differentially expressed genes from cell lines identified perturbed cytokine pathways (p<0.05) and provided a proof of concept that this strategy can be employed to identify proteins of interest.
Conclusions: Verification of genes identified via the transcriptome analyses in an oral cancer patient cohort is currently underway to identify novel therapeutic targets to treat oral cancer pain.