Molecular and Cellular Mechanisms of Perineural Invasion in Oral Squamous Cell Carcinoma: Potential Targets for Therapeutic Intervention.

Abstract

Simple SummarySquamous cell carcinoma is the most common type of oral cavity cancer. It can spread along and invade nerves in a process called perineural invasion. Perineural invasion can increase the chances of tumor recurrence and reduce survival in patients with oral cancer. Understanding how oral cancer interacts with nerves to facilitate perineural invasion is an important area of research. Targeting key events that contribute to perineural invasion in oral cavity cancer may reduce tumor recurrence and improve survival. In this review, we describe the impact of perineural invasion in oral cancer and the mechanisms that contribute to perineural invasion. Highlighting the key events of perineural invasion is important for the identification and testing of novel therapies for oral cancer with perineural invasion.The most common oral cavity cancer is squamous cell carcinoma (SCC), of which perineural invasion (PNI) is a significant prognostic factor associated with decreased survival and an increased rate of locoregional recurrence. In the classical theory of PNI, cancer was believed to invade nerves directly through the path of least resistance in the perineural space; however, more recent evidence suggests that PNI requires reciprocal signaling interactions between tumor cells and nerve components, particularly Schwann cells. Specifically, head and neck SCC can express neurotrophins and neurotrophin receptors that may contribute to cancer migration towards nerves, PNI, and neuritogenesis towards cancer. Through reciprocal signaling, recent studies also suggest that Schwann cells may play an important role in promoting PNI by migrating toward cancer cells, intercalating, and dispersing cancer, and facilitating cancer migration toward nerves. The interactions of neurotrophins with their high affinity receptors is a new area of interest in the development of pharmaceutical therapies for many types of cancer. In this comprehensive review, we discuss diagnosis and treatment of oral cavity SCC, how PNI affects locoregional recurrence and survival, and the impact of adjuvant therapies on tumors with PNI. We also describe the molecular and cellular mechanisms associated with PNI, including the expression of neurotrophins and their receptors, and highlight potential targets for therapeutic intervention for PNI in oral SCC.