Tumorigenesis in neurofibromatosis type 1: role of the microenvironment

Abstract

Neurofibromatosis Type 1 (NF1) is one of the most common inherited neurological disorders and predisposes patients to develop benign and malignant tumors. Neurofibromas are NF1-associated benign tumors but can cause substantial discomfort and disfigurement. Numerous studies have shown that neurofibromas arise from the Schwann cell lineage but both preclinical mouse models and clinical trials have demonstrated that the neurofibroma tumor microenvironment contributes significantly to tumorigenesis. This offers the opportunity for targeting new therapeutic vulnerabilities to treat neurofibromas. However, a translational gap exists between deciphering the contribution of the neurofibroma tumor microenvironment and clinically applying this knowledge to treat neurofibromas. Here, we discuss the key cellular and molecular components in the neurofibroma tumor microenvironment that can potentially be targeted therapeutically to advance neurofibroma treatment.

Fig. 1. Clinical manifestations of neurofibroma.

a Multiple cutaneous neurofibromas on the trunk. b Plexiform neurofibroma on the right foot of an individual with Neurofibromatosis Type 1.

Fig. 2. Components of neurofibroma tumor microenvironment.

Schematic diagram showing key components in the tumor microenvironment that impact the development of neurofibroma. Illustration created with BioRender.com.

Fig. 3. Signaling pathways regulating the functions of NFAFs.

Schematic diagram showing key signaling pathways that may contribute to NFAF functions. Dashed arrows indicate that those pathways remain to be further characterized for their role in regulating NFAF functions. Illustration created with BioRender.com. (TGF-β transforming growth factor-β, TGF-βR transforming growth factor-β receptor, ECM extracellular matrix, FGF-2 fibroblast growth factor 2, PDGF platelet-derived growth factor, YAP Yes-associated protein, NF1 neurofibromin).

Fig. 4. Proposed interactions between Schwann cells and fibroblasts in neurofibroma.

Schematic diagram showing the direct and indirect interactions between Schwann cells and fibroblasts. Key factors mediating those interactions are listed. Illustration created with BioRender.com. ECM extracellular matrix, TGF-β transforming growth factor-β, FGF-2 fibroblast growth factor 2, PDGF platelet-derived growth factor, MK midkine, SCF stem cell factor, CSF1 colony-stimulating factor 1.