Lee TL, Chiu PH, Li WY, et al. - This is the first study using human peripheral nerves to define nerve-tumor interactions in oral squamous cell carcinoma (OSCC) and mechanisms of perineural invasion (PNI), a poor prognostic pathologic characteristic of OSCC. Using fresh human peripheral nerve, systematic investigation of nerve-tumor interactions was performed. The study sample consisted of 314 T1-2 OSCC patients. The transwell migration/invasion assay showed that human peripheral nerves significantly enhanced OSCC's migration/invasion capabilities relative to subcutaneous soft tissue. In addition, the enhanced migration was dose-dependent with increased length or number of peripheral nerve segments. Such results clearly demonstrated the existence of nerve-tumor interactions involving paracrine effects that result in OSCC becoming aggressive. Exploring key cell types and molecules involved in nerve-tumor interactions for future therapeutic targeting of PNI in OSCC needs further investigations.