Halting the neural progression of cancer
Embargo Date
2027-09-29
OA Version
Citation
Abstract
Neuropilin (NRP) receptors have functions in axonal guidance and neuronal patterning. Class 3 semaphorin (SEMA3) molecules act as inhibitors of NRP receptors by preventing the activation of downstream signaling pathways involved in cytoskeletal organization and migration. Tumor-associated axonogenesis, defined as the growth of neuronal axons towards a tumor, is indicative of a more aggressive cancer phenotype. The aim of this thesis project was to investigate the role that axonogenesis and nerve-cancer interactions play in the progression of cancer and whether the SEMA3F/NRP2 axis could be targeted to inhibit this process. We hypothesized that the presence of SEMA3F would halt axonogenesis, thus slowing down the progression of tumorigenesis. Both in vivo and in vitro experiments were conducted to test this hypothesis. Immunohistochemistry (IHC) was used to examine neuronal density in tissue sections from mice implanted with melanomas that overexpressed SEMA3F compared to control tumors or in mice lacking Nrp2 compared to wildtype (WT) mice with both copies of the gene. In vitro, neurite outgrowth and repulsion assays were conducted in the presence of SEMA3F or SEMA3A. Our results indicated that nerves in the skin expressed NRP2 and grew towards the melanomas. There was less neuronal density in the melanomas that overexpressed SEMA3F than in control melanoma grafts. In addition, tissues from Nrp2-/- mice showed differential neural patterning than Nrp2+/+ mice, highlighting the importance of NRP2 in axonal guidance. In vitro, SEMA3F-induced repulsion was observed in PC12 and U87MG cells, which express NRP2. SEMA3A also successfully repelled SY5Y cells, which express NRP1. Neurite length was significantly inhibited by SEMA3F in PC12 and U87MG neurite outgrowth assays. Taken together, our results suggest that SEMA3F is a promising inhibitor of cancer induced neural growth and has therapeutic potential to slow down cancer progression that occurs due to tumor mediated innervation.
Description
2024