Difference in the hypoxic immunosuppressive microenvironment of patients with neurofibromatosis type 2 schwannomas and sporadic schwannomas

Tamura, Ryota; Morimoto, Yukina; Sato, Mizuto; Kuranari, Yuki; Oishi, Yumiko; Kosugi, Kenzo; Yoshida, Kazunari; Toda, Masahiro

doi:10.1007/s11060-019-03388-5

Cited by 18 publications

(21 citation statements)

References 49 publications

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“…Mirdametinib (PD-0325901) is an orally delivered inhibitor of the dual specificity kinases (MEK1 and MEK2), which demonstrated tumor shrinkage and sustained inhibition of pERK. Furthermore, the recent study demonstrated that hypoxia was significantly associated with shorter progression-free survival in NF2 schwannomas [ 94 ]. HIF-1-targeted therapy might be considered for some NF2 schwannomas that are difficult to treat by surgical resection and stereotactic radiosurgery [ 94 ].…”

Section: Neurofibromatosis Typementioning

confidence: 99%

Current Understanding of Neurofibromatosis Type 1, 2, and Schwannomatosis

Tamura

2021

IJMS

Self Cite

140

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Neurofibromatosis (NF) is a neurocutaneous syndrome characterized by the development of tumors of the central or peripheral nervous system including the brain, spinal cord, organs, skin, and bones. There are three types of NF: NF1 accounting for 96% of all cases, NF2 in 3%, and schwannomatosis (SWN) in <1%. The NF1 gene is located on chromosome 17q11.2, which encodes for a tumor suppressor protein, neurofibromin, that functions as a negative regulator of Ras/MAPK and PI3K/mTOR signaling pathways. The NF2 gene is identified on chromosome 22q12, which encodes for merlin, a tumor suppressor protein related to ezrin-radixin-moesin that modulates the activity of PI3K/AKT, Raf/MEK/ERK, and mTOR signaling pathways. In contrast, molecular insights on the different forms of SWN remain unclear. Inactivating mutations in the tumor suppressor genes SMARCB1 and LZTR1 are considered responsible for a majority of cases. Recently, treatment strategies to target specific genetic or molecular events involved in their tumorigenesis are developed. This study discusses molecular pathways and related targeted therapies for NF1, NF2, and SWN and reviews recent clinical trials which involve NF patients.

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Section: Neurofibromatosis Typementioning

confidence: 99%

Current Understanding of Neurofibromatosis Type 1, 2, and Schwannomatosis

Tamura

2021

IJMS

Self Cite

140

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“…26,27 In VS, a higher infiltration of CD163 expressing M2 macrophages have been observed within fast-growing tumors compared with slow-growing tumors. 10 Macrophage colonystimulating factor (M-CSF) may play a role in inducing the macrophage M2 polarization and elevated expression of this cytokine has been observed as a feature of rapidly growing VS. 10,28 An association between CD163þ macrophage infiltration and shorter progression-free survival has also been demonstrated in NF2 associated VS. 29 In a study of VS patients who underwent initial subtotal resection (STR), higher TAM density in the resected tumor was associated with tumor recurrence and poorer postoperative facial nerve function. In apparent Table 1 A refresher of terminology relevant to the vestibular schwannoma microenvironment…”

Section: The Inflammatory Microenvironment In Vs: Evidence Emergesmentioning

confidence: 99%

“…54 Tamura et al demonstrated expression of Foxp3 þ regulatory T-cells (T reg ) in resected VS specimens and an association between increased Foxp3 þ T reg density and progressive tumor growth. 29,55 Another mechanism by which tumor cells evade immunosurveillance is through activation of immune checkpoint pathways, such as the PD-L1/PD1 (Programmed death-ligand 1 [PD-L1]/Programmed cell death protein 1 [PD1]) signaling axis. Programmed death-ligand 1 or PD-L1 (or B7 homolog 1) is a transmembrane protein upregulated in several tumors and is the target ligand for the T cell receptor PD-1.…”

Section: Immune Regulation and Evasion In Vsmentioning

confidence: 99%

“…58 While later studies have confirmed this expression and demonstrated an association of higher PD-L1 expression with both tumor progression and unfavorable facial nerve outcomes following STR, other authors have demonstrated low rates of PD-L1 expression in VS tumor cells. 29,30,57 Larger studies are therefore required to better understand the role of immune checkpoint pathways in VS progression and growth.…”

Section: Immune Regulation and Evasion In Vsmentioning

confidence: 99%

“…54 Tamura et al demonstrated expression of Foxp3 + regulatory T-cells (T reg ) in resected VS specimens and an association between increased Foxp3 + T reg density and progressive tumor growth. 29 55…”

Section: Immune Regulation and Evasion In Vsmentioning

confidence: 99%

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Beyond Antoni: A Surgeon's Guide to the Vestibular Schwannoma Microenvironment

Hannan

Lewis

O’Leary

et al. 2020

J Neurol Surg B Skull Base

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Introduction Vestibular schwannomas (VS) are histologically benign tumors arising from cranial nerve VIII. Far from a homogenous proliferation of Schwann cells, mounting evidence has highlighted the complex nature of the inflammatory microenvironment in these tumors. Methods A review of the literature pertaining to inflammation, inflammatory molecular pathways, and immune-related therapeutic targets in VS was performed. Relevant studies published up to June 2020 were identified based on a literature search in the PubMed and MEDLINE databases and the findings were synthesized into a concise narrative review of the topic. Results The VS microenvironment is characterized by a dense infiltrate of inflammatory cells, particularly macrophages. Significantly higher levels of immune cell infiltration are observed in growing versus static tumors, and there is a demonstrable interplay between inflammation and angiogenesis in growing VS. While further mechanistic studies are required to ascertain the exact role of inflammation in angiogenesis, tumor growth, and Schwann cell control, we are beginning to understand the key molecular pathways driving this inflammatory microenvironment, and how these processes can be monitored and targeted in vivo. Conclusion Observational research has revealed a complex and heterogeneous tumor microenvironment in VS. The functional landscape and roles of macrophages and other immune cells in the VS inflammatory infiltrate are, however, yet to be established. The antiangiogenic drug bevacizumab has shown the efficacy of targeted molecular therapies in VS and there is hope that agents targeting another major component of the VS microenvironment, inflammation, will also find a place in their future management.

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