Optic nerve activity promotes the growth of optic pathway gliomas: Shedding light on the glioma microenvironment

Abstract Neurons have recently emerged as essential cellular constituents of the tumor microenvironment, where their activity increases the growth of a diverse number of solid tumors. While the role of neurons in tumor progression has been previously demonstrated, the importance of neuronal activity to tumor initiation is less clear, particularly in the setting of cancer predisposition syndromes. In the Neurofibromatosis type 1 (NF1) cancer predisposition syndrome, in which tumors arise in close association with nerves, 15% of individuals develop low-grade neoplasms of the optic pathway (optic gliomas) during early childhood, raising the intriguing possibility that postnatal light-induced optic nerve activity drives tumor initiation. Here, we employ an authenticated murine model of Nf1 optic glioma to demonstrate that stimulation of optic nerve activity increases optic glioma growth, while decreasing optic nerve activity via light deprivation prevents tumor formation and maintenance. By manipulating environmental light to modulate optic pathway (retinal) neuron activity, we show that Nf1 optic glioma initiation depends on neuronal activity during a developmental period susceptible to tumorigenesis. Germline Nf1 mutation in retinal neurons results in aberrantly high optic nerve neuroligin-3 (Nlgn3) shedding in response to retinal neuronal activity. Moreover, genetic Nlgn3 loss or pharmacologic inhibition of Nlgn3 shedding blocks murine Nf1 optic gliomagenesis and progression. Collectively, these studies establish an obligate role for neuronal activity in the development of certain brain tumors, elucidate a therapeutic strategy to reduce optic glioma incidence or mitigate tumor progression, and underscore the role of Nf1 mutation-mediated dysregulation of neuronal signaling pathways in the NF1 cancer predisposition syndrome.

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Neuroophthalmological management of optic pathway gliomas

Neurosurgical FOCUS ◽

10.3171/foc-07/11/e1 ◽

2007 ◽

Vol 23 (5) ◽

pp. E1 ◽

Cited By ~ 44

Author(s):

Andrew G. Lee

Keyword(s):

Growth Rate ◽

Optic Nerve ◽

Major Complication ◽

Initial Step ◽

Neurofibromatosis Type ◽

Tumor Location ◽

Optic Pathway ◽

First Line ◽

Younger Patients ◽

Optic Pathway Gliomas

✓ The growth rate of optic pathway gliomas (OPGs) is unpredictable and quite variable, especially in children with neurofibromatosis Type 1 (NF1). Close neuroophthalmalogical clinical follow-up with serial imaging (magnetic resonance imaging of the brain with and without contrast enhancement) is the recommended initial step in management to establish the growth rate of the lesion in an individual patient. Typically, only symptomatic and/or radiographically growing tumors require treatment, and observation is the accepted first-line option. Although both chemotherapy and radiotherapy can stabilize growth or even decrease the size of tumors, chemotherapy, especially in younger patients, has fewer side effects than radiation therapy (such as secondary tumors, radiation necrosis, and Moyomoya disease) and is generally considered the first-line treatment for progressive lesions in younger patients. The tumor location defines prognosis in OPGs; optic nerve gliomas (ONG) have the lowest rate of complications and death, and optic chiasm and retrochiasmal gliomas the highest. Although the major complication of an OPG is visual loss, hypothalamic involvement can lead to death. Resection is an option for ONGs but is generally reserved for tumors confined to the optic nerve with poor or no vision, or for patients with severe, cosmetically unappealing proptosis, producing severe pain or exposure keratopathy in a blind eye. Resection is generally not an option for intrinsic chiasmal or retrochiasmal OPGs. Extrinsic (exophytic) components can be debulked surgically, and surgery can be performed for hydrocephalus (ventriculoperitoneal shunt placement). The approach to a patient with OPG must be individualized based on tumor location, radiographic or clinical progression, the presence of NF1, and a risk–benefit comparison for treatment.

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Tumor load rather than contrast enhancement is associated with the visual function of children and adolescents with optic pathway glioma – a retrospective Magnetic Resonance Imaging study

Journal of Neuro-Oncology ◽

10.1007/s11060-021-03941-1 ◽

2022 ◽

Author(s):

Anna Kilian ◽

Annette Aigner ◽

Michèle Simon ◽

Daniel J. Salchow ◽

Cornelia Potratz ◽

...

Keyword(s):

Optic Nerve ◽

Contrast Enhancement ◽

Mixed Model ◽

Linear Mixed Model ◽

Rank Correlation ◽

Imaging Study ◽

Optic Pathway Glioma ◽

Optic Pathway ◽

Tumor Load ◽

Optic Pathway Gliomas

Abstract Introduction Optic pathway gliomas are often asymptomatic tumors occurring in children with neurofibromatosis type 1 (NF1 + OPG) or sporadically (spOPG). Treatment is usually prompted by visual loss and/or tumor progression on MRI. The aim of this study was to investigate the relationship between visual acuity (VA), tumor growth, and contrast enhancement to provide more distinct indications for the administration of gadolinium-based contrast agents. Methods Tumor load was retrospectively measured and enhancement semi-quantitatively scored on 298 MRIs of 35 patients (63% NF1 + OPG). Spearman rank correlation between tumor load and enhancement was calculated and a linear mixed model used to examine the influence of tumor load and enhancement on corresponding VA tests (LogMAR). Results The optic nerve width in NF1 + OPGs was strongly associated with VA (regression coefficient 0.75; confidence interval 0.61—0.88), but weakly with enhancement (0.06; −0.04—0.15). In spOPGs, tumor volume and optic nerve width were more relevant (0.31; −0.19—0.81 and 0.39; 0.05—0.73) than enhancement (0.09; −0.09—0.27). Conclusions Tumor load measures may be more relevant for the surveillance of optic pathway gliomas than enhancement, given that VA is the relevant outcome parameter. Regular contrast administration should therefore be questioned in these patients.

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TAMI-69. NF1 MUTATION DRIVES NEURONAL ACTIVITY-DEPENDENT OPTIC GLIOMA INITIATION

Neuro-Oncology ◽

10.1093/neuonc/noab196.851 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi212-vi212

Author(s):

Yuan Pan ◽

Jared Hysinger ◽

Tara Barron ◽

Nicki Schindler ◽

Olivia Cobb ◽

...

Keyword(s):

Optic Nerve ◽

Tumor Progression ◽

Neuronal Activity ◽

Visual Experience ◽

Cancer Predisposition ◽

Optic Glioma ◽

Optic Pathway ◽

Nerve Activity ◽

Cancer Predisposition Syndrome

Abstract Neurons have recently emerged as essential cellular constituents of the tumor microenvironment, where their activity increases the growth of a diverse number of solid tumors. While the role of neurons in tumor progression has been previously demonstrated, the importance of neuronal activity to tumor initiation is less clear, particularly in the setting of cancer predisposition syndromes. In the Neurofibromatosis-1 (NF1) cancer predisposition syndrome, in which tumors arise in close association with nerves, 15% of individuals develop low-grade neoplasms of the optic pathway (optic pathway gliomas [OPGs]), during early childhood, raising the intriguing possibility that postnatal light-induced optic nerve activity drives tumor initiation. Here, we employ an authenticated murine model of Nf1-OPG to demonstrate that stimulation of optic nerve activity increases optic glioma growth, while decreasing visual experience via light deprivation prevents tumor formation and maintenance. We show that Nf1-OPG initiation depends on visual experience during a developmental period susceptible to tumorigenesis. Germline Nf1 mutation in retinal neurons results in aberrantly high optic nerve neuroligin-3 (Nlgn3) shedding in response to retinal neuronal activity. Moreover, genetic Nlgn3 loss or pharmacological inhibition of Nlgn3 shedding blocks murine Nf1 optic gliomagenesis and progression. Collectively, these studies establish an obligate role for neuronal activity in the development of certain brain tumors, elucidate a therapeutic strategy to reduce OPG incidence or mitigate tumor progression, and underscore the role of Nf1 mutation-mediated dysregulation of neuronal signaling pathways in the NF1 cancer predisposition syndrome.

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LGG-10. AN UNUSUAL PRESENTATION OF BILATERAL OPTIC NERVE GLIOMA IN CROUZON SYNDROME

Neuro-Oncology ◽

10.1093/neuonc/noab090.134 ◽

2021 ◽

Vol 23 (Supplement_1) ◽

pp. i33-i33

Author(s):

Brian Na ◽

Anthony C Wang ◽

Christopher Travis Watterson ◽

Julian A Martinez-Agosto ◽

Sulagna Saitta ◽

...

Keyword(s):

Visual Acuity ◽

Optic Nerve ◽

Optic Atrophy ◽

Low Grade ◽

Optic Pathway ◽

Crouzon Syndrome ◽

Optic Nerve Glioma ◽

Autosomal Dominant Disorder ◽

Low Grade Gliomas ◽

Optic Pathway Gliomas

Abstract Optic pathway gliomas (OPGs) are low grade gliomas intrinsic to the visual pathway, frequently associated with Neurofibromatosis Type 1 (NF-1). Bilateral OPGs without chiasmatic involvement are almost pathognomonic for NF-1. We report an unusual case of bilateral optic nerve glioma without chiasmatic involvement in a 17-month old male patient with craniosynostosis and Crouzon Syndrome, an autosomal dominant disorder caused by activating FGFR2 mutations associated with craniosynostosis and optic atrophy. The patient’s c.1032 G>A pathogenic variant in FGFR2 is a variant known to affect splicing and results in a protein that lacks part of an important domain involved in ligand binding. Although FGFR1 mutations have been implicated in low-grade glioma through MAPK activation, FGFR2 mutations have not yet been described in OPGs, although they have been described in epileptogenic low-grade gliomas and mixed neuronal-glial tumors. Our patient presented with worsening vision in the setting of known Crouzon Syndrome. An eye examination revealed bilateral primary optic atrophy. Brain and orbital MRIs demonstrated fusiform dilation and STIR hyperintensity of the intraorbital segments of the optic nerves bilaterally with normal pre-chiasmatic optic segments. There were no other radiographic or physical stigmata suggestive of NF-1. Next generation sequencing and copy number analysis from peripheral blood were negative for variants in NF1. RNA based studies for NF1 aberrations are pending. Although follow up MRI scans demonstrated stable size of his OPGs, the risk of further visual deficit was considered significant due to his pre-existing optic atrophy and poor baseline visual acuity. Therefore, he was started on vincristine and carboplatin chemotherapy according to A9952, and induction therapy has been well tolerated. To our knowledge, this is the first patient with Crouzon Syndrome who has developed bilateral optic pathway gliomas. Orbital MRIs should be considered for these patients with worsening visual acuity not explained by other causes.

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Neurosurgical experience of managing optic pathway gliomas

Child s Nervous System ◽

10.1007/s00381-021-05060-8 ◽

2021 ◽

Author(s):

Ciaran Scott Hill ◽

Mehdi Khan ◽

Kim Phipps ◽

Katherine Green ◽

Darren Hargrave ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Surgical Resection ◽

Visual Function ◽

Optic Pathway ◽

Who Grade ◽

Radiographic Findings ◽

Surgical Interventions ◽

Hypothalamic Dysfunction ◽

Cerebrospinal Fluid Diversion ◽

Optic Pathway Gliomas

Abstract Background Optic pathway gliomas (OPGs), also known as visual pathway gliomas, are debilitating tumors that account for 3–5% of all pediatric brain tumors. They are most commonly WHO grade 1 pilocytic astrocytomas and frequently occur in patients with neurofibromatosis type 1. The location of these tumors results in visual loss and blindness, endocrine and hypothalamic dysfunction, hydrocephalus, and premature death. Their involvement of the visual pathways and proximity to other eloquent brain structures typically precludes complete resection or optimal radiation dosing without incurring significant neurological injury. There are various surgical interventions that can be performed in relation to these lesions including biopsy, cerebrospinal fluid diversion, and partial or radical resection, but their role is a source of debate. This study catalogues our surgical experience and patient outcomes in order to support decision-making in this challenging pathology. Methods A retrospective review of all cases of OPGs treated in a single center from July 1990 to July 2020. Data was collected on patient demographics, radiographic findings, pathology, and management including surgical interventions. Outcome data included survival, visual function, endocrine, and hypothalamic dysfunction. Results One hundred twenty-one patients with OPG were identified, and 50 of these patients underwent a total of 104 surgical procedures. These included biopsy (31), subtotal or gross total resection (20 operations in 17 patients), cyst drainage (17), Ommaya reservoir insertion (9), or cerebrospinal fluid diversion (27). During the study period, there was 6% overall mortality, 18% hypothalamic dysfunction, 20% endocrine dysfunction, and 42% had some cognitive dysfunction. At diagnosis 75% of patients had good or moderate visual function in at least one eye, and overall, this improved to 83% at the end of the study period. In comparison the worst eye had good or moderate visual function in 56%, and this reduced to 53%. Baseline and final visual function were poorer in patients who had a surgical resection, but improvements in vision were still found—particularly in the best eye. Discussion/conclusion OPG are debilitating childhood tumor that have lifelong consequences in terms of visual function and endocrinopathies/hypothalamic dysfunction; this can result in substantial patient morbidity. Decisions regarding management and the role of surgery in this condition are challenging and include cerebrospinal fluid diversion, biopsy, and in highly select cases cystic decompression or surgical resection. In this paper, we review our own experience, outcomes, and surgical philosophy.

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