Insights into optic pathway glioma vision loss from mouse models of neurofibromatosis type 1

Abstract

Neurofibromatosis type 1 (NF1) is a common cancer predisposition syndrome caused by mutations in the NF1 gene. The NF1-encoded protein (neurofibromin) is an inhibitor of the oncoprotein RAS and controls cell growth and survival. Individuals with NF1 are prone to developing low-grade tumors of the optic nerves, chiasm, tracts, and radiations, termed optic pathway gliomas (OPGs), which can cause vision loss. A paucity of surgical tumor specimens and of patient-derived xenografts for investigative studies has limited our understanding of human NF1-associated OPG (NF1-OPG). However, mice genetically engineered to harbor Nf1 gene mutations develop optic gliomas that share many features of their human counterparts. These genetically engineered mouse (GEM) strains have provided important insights into the cellular and molecular determinants that underlie mouse Nf1 optic glioma development, maintenance, and associated vision loss, with relevance by extension to human NF1-OPG disease. Herein, we review our current understanding of NF1-OPG pathobiology and describe the mechanisms responsible for tumor initiation, growth, and associated vision loss in Nf1 GEM models. We also discuss how Nf1 GEM and other preclinical models can be deployed to identify and evaluate molecularly targeted therapies for OPG, particularly as they pertain to future strategies aimed at preventing or improving tumor-associated vision loss in children with NF1.

Severe Phenotype in Patients with Large Deletions of NF1

“…The most frequent central nervous system (CNS) tumors observed in NF1 are gliomas which concern about 20% of patients [65]. They are mainly low-grade gliomas of the optic pathways and are most often classified as pilocytic astrocytoma [66][67][68]. In our cohort, OPGs were present in 11% (9/80) of patients and were responsible for loss of visual acuity in three patients, with one presenting bilateral optic atrophy.…”

SIPA1 boosts migration and proliferation, and blocks apoptosis of glioma by activating the phosphorylation of the FAK signaling pathway

“…They can be utilized as specific biomarkers for guiding the screening, diagnosis and treatment, and predicting the prognosis of glioma (12). The development of targeted therapy based on these biomarkers is a promising approach to improving glioma patients' poor prognosis (13,14). identified that SIPA1 is located on the metastasis efficiency modifier locus mtes1.…”

Optic Pathway Glioma in Type 1 Neurofibromatosis: Review of Its Pathogenesis, Diagnostic Assessment, and Treatment Recommendations

“…The pathogenetic mechanisms at the basis of OPG development in NF1 are not completely understood, thus reducing the possibility to develop effective treatments. The main limitations for the study of the molecular pathways leading to OPG have been the paucity of biological samples, given the low rate of surgery, and the difficulty to obtain patient-derived xenograft-models or cell lines from these tumors [85]. However, over the last few years distinct strategies have been used to investigate gliomagenesis.…”

“…Furthermore, these engineered models of NF1 were crucial to confirming the role of RAS hyperactivation in the development of OPG, providing the biological rationale to test a series of compounds able to counteract the effectors downstream to RAS: the RAS-MEK-ERK and the PI3K-AKT-mTOR signaling pathways are up-regulated in tumor cells [91,92,93], whereas the adenylyl cyclase-mediated cyclic AMP is associated with decreased levels of cAMP [94]. However, some of the drugs acting on these pathways (including the mTOR inhibitor Rapamycin) are active in mice only during therapy, with recovery of tumor growth after treatment suspension [85].…”