Modulation of BDNF–TRKB Interactions on Schwann Cell-induced Oral Squamous Cell Carcinoma Dispersion In Vitro

Abstract

Background/Aim: Perineural invasion (PNI) is a significant pathological feature in head and neck cancer. The molecular mechanisms of PNI are poorly understood. Contrary to the previous belief that cancer cells invade nerves, recent studies have shown that Schwann cells (SC) can dedifferentiate, intercalate between cancer cells, and promote cancer dispersion. Communication between cells through brain-derived neurotrophic factor (BDNF) activation of its receptor tropomyosin receptor kinase B(TRKB) may contribute to these cellular events. We aimed to determine the effect of TRKB inhibitor ANA-12 on the direction of cell migration and degree of SC-induced oral cancer cell dispersion. Materials and Methods: Cell migration and dispersion assays were performed in vitro using murine SC and oral carcinoma cell lines. Assays were performed with and without ANA-12. Results: Although SCs preferentially migrated towards cancer cells in control medium, there was minimal SC-associated cancer cell dispersion. In contrast, treatment with ANA-12 reduced migration of SCs and cancer cells towards each other and initiated more SC-associated cancer cell dispersion. Conclusion: This pilot study shows that BDNF-TRKB signaling may have a role in regulating interactions between SC and oral cancer cells that affect cell migration, intercalation, and cancer cell dispersion. Further research into these interactions may provide important clues about the molecular and cellular mechanisms of PNI.

Schwann Cells in Digestive System Disorders

“…Glia are recognised as mediators of orofacial pain [ 91 , 92 ], and several studies suggest that SCs are involved in the increased nociception [ 58 , 59 ] and nerve invasion [ 60 , 61 ] observed in oral malignancies. One of the proposed mechanisms is the activation of SCs in response to tumour necrosis factor alpha (TNFα) secreted by OSCC cells.…”

Glia and Orofacial Pain: Progress and Future Directions

“…Emerging evidence highlights a critical role of Schwann cells in perineural invasion. Schwann cells are activated in the presence of pancreatic, colon, gastric, lung, skin, and oral cancer cells and promote cancer growth, invasion, and dispersion [11,52,[140][141][142][143][144][145][146][147][148][149]. Cancer-activated Schwann cells secrete neurotrophic factors, chemokines/cytokines, proteases, and adhesion molecules [52,143,146,147,149,150], many of which could directly excite and sensitize primary afferent neurons [151][152][153].…”

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

“…PNI is more likely a complex and dynamic process that relies on reciprocal signaling between the tumor and components of the nerve (e.g., Schwann cells and neurons). Recent evidence suggests that SCC can communicate with nerves long before physical contact between cell types occur [ 17 , 18 , 21 , 22 , 27 , 94 , 95 ]. Head and neck SCC may secrete neurotrophic factors into the local environment that are detected by Schwann cells and neurons.…”

“…Once detected, Schwann cells and neurons can secrete other neurotrophic factors that lead to downstream events, promoting cancer cell invasion and neurite outgrowth. The interactions of secreted neurotrophins with their high affinity receptors between cancer and nerve is a new area of interest in the pathogenesis of PNI [ 8 , 21 , 22 , 96 ].…”

“…Traditionally, cancer is thought to invade nerves by entering the path of least resistance in the perineural space [ 16 ]. However, recent studies suggest that PNI is more complex, involving reciprocal signaling between the tumor itself and the Schwann cells and neurons that compose the nerve [ 17 , 18 , 19 , 20 , 21 , 22 ]. In this narrative review, we discuss the clinical impact of PNI in oral cavity SCC and the molecular and cellular mechanisms contributing to PNI, including potential roles for Schwann cells.…”