Nerve Degeneration and Regeneration Associated with NF1 Tumors

Abstract : Infiltrating peripheral nerve sheath tumors (PNST) are associated with significant neurological deficits and nerve damage. An initial aim of this project is to determine how tumor progression leads to loss of nerve function. A second aim is to determine if nerve damage caused by PNST is reversible and the potential for nerve regeneration after PNST eradication. Additional aims will test photodynamic therapy as modality for eradication of PNST without incurring substantial collateral damage to functioning nerve. We have completed all aims in a highly conclusive manner. Our work tested that hypothesis that tumor-induced nerve damage and loss of neurological function is reversible. Findings indicate that this is true only in the formative stages of tumor growth associated with low-level functional deficits. Tumor progression leads to increasing and permanent loss of nerve function. Function deficits persist even after tumor eradication. Results indicate that the tumor destroys the nerve, ablates supporting cells and replaces nerve structure with an impenetrable fibrotic mass. Even though afflicted neurons remain viable they fail to regrow axons into the fibrotic mass (even when devoid of tumor cells). The main conclusion of our findings is that tumor eradication does not induce or support nerve regeneration. Instead, a fibrotic mass remains that must be resolved for axonal regrowth to occur. We conclude that early stage tumors (that incur low to moderate nerve damage) can be effectively killed by PDT with a good prognosis for recovery of the nerve function that was not initially compromised by tumor growth. However, PDT is not indicated for the treatment of advance PNST with substantial loss of nerve function. Instead, the PNST must be surgically resected and a nerve graft implanted to bridge the gap and restore nerve continuity.