An Overview of Optic Pathway Glioma With Neurofibromatosis Type 1: Pathogenesis, Risk Factors, and Therapeutic Strategies

Abstract

Optic pathway gliomas (OPGs) are most predominant pilocytic astrocytomas, which are typically diagnosed within the first decade of life. The majority of affected children with OPGs also present with neurofibromatosis type 1 (NF1), the most common tumor predisposition syndrome. OPGs in individuals with NF1 primarily affect the optic pathway and lead to visual disturbance. However, it is challenging to assess risk in asymptomatic patients without valid biomarkers. On the other hand, for symptomatic patients, there is still no effective treatment to prevent or recover vision loss. Therefore, this review summarizes current knowledge regarding the pathogenesis of NF1-associated OPGs (NF1-OPGs) from preclinical studies to seek potential prognostic markers and therapeutic targets. First, the loss of the NF1 gene activates 3 distinct Ras effector pathways, including the PI3K/AKT/mTOR pathway, the MEK/ERK pathway, and the cAMP pathway, which mediate glioma tumorigenesis. Meanwhile, non-neoplastic cells from the tumor microenvironment (microglia, T cells, neurons, etc.) also contribute to gliomagenesis via various soluble factors. Subsequently, we investigated potential genetic risk factors, molecularly targeted therapies, and neuroprotective strategies for tumor prevention and vision recovery. Last, potential directions and promising preclinical models of NF1-OPGs are presented for further research. On the whole, NF1-OPGs develop as a result of the interaction between glioma cells and the tumor microenvironment. Developing effective treatments require a better understanding of tumor molecular characteristics, as well as multistage interventions targeting both neoplastic cells and non-neoplastic cells.

Figure 1.

Ras signaling pathway. Deprivation of neurofibromin in NF1-related OPGs led to activate Ras and its 3 effector pathways. Nf1^−/− astrocytes displayed both upregulated MEK-ERK and PI3K-AKT manners, which individually contributed to activating mTOR activity and promoting tumor proliferation. Specifically, PI3K/AKT manner promoted the proliferation of o-GSCs and MEK/ERK pathway determined the progenitors multilineage differentiation. Besides, neurofibromin decreased the levels of cAMP in Nf1^−/− astrocytes to positively accelerate tumor development while downregulated cAMP levels attenuated Nf1^+/− RGC growth through PKCζ, which was related with visual dysfunction. This figure was created using the BioRender software.

Figure 2.

The risk factors of NF1-OPGs. *A series of clinical and preclinical trials have found some potential risk factors of NF1-OPGs, including age, sex, tumor location, germline gene mutations, co-existent gene mutations, and genomic alterations. Further investigation is needed to develop a scientific risk assessment algorithm to stratify patients based on their risk levels. This figure was created using the BioRender software.

Figure 3.

The complex communication between neoplastic and non-neoplastic cells. *O-GSCs expressed CX3CL1 to recruit microglia which elaborated molecules to support neoplastic cells proliferation, including Ccl5, CXCL12, and MGEA5, and, in turn, neoplastic cells also secreted molecules (“stromagens”) to recruit microglia. Activated by Ccl2 secreted from o-GSCs, T cells then produced Ccl4 to promotes microglia to excrete Ccl5. As immune system regulators, RGCs held upregulated expression of midkine to activate T cells and initiated optic gliomas progression by NLGN3 signaling axis. By contrast, in female GEMs, estrogen induced microglia to produce neurotoxins, like IL-1β and other inflammatory cytokines, resulting in vision deterioration. Besides, other cells within the tumor microenvironment, like endothelial cells and Müller cells, might also contribute to the development of OPGs. This figure was created using the BioRender software.