Are We Benign? What Can Wnt Signaling Pathway and Epithelial to Mesenchymal Transition Tell Us about Intracranial Meningioma Progression

Bukovac, Anja; Kafka, Anja; Raguž, Marina; Brlek, Petar; Dragičević, Katarina; Müller, Danko; Pećina‐Šlaus, Nives

doi:10.3390/cancers13071633

Cited by 11 publications

(9 citation statements)

References 70 publications

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“…Although nuclear expression was not found, higher expression levels of active β-catenin were significantly correlated with higher grades (ρ = 0.580, p = 0.004) and nuclear DVL1 expression (ρ = 0.456, p = 0.029). This is in alignment with our previous study [ 18 ], indicating β-catenin involvement in meningioma progression.…”

Section: Discussionsupporting

confidence: 93%

“…It has been shown that the activation of Wnt signaling can induce the malignant transformation of neural stem cells and thus contribute to the development of primary brain tumors [ 11 , 12 , 13 , 14 , 15 , 16 ]. The Wnt signaling pathway in meningiomas is known to be activated and plays a role in progression [ 17 , 18 ]. Activation occurs when Wnt ligands bind to membrane receptors called Frizzled.…”

Section: Introductionmentioning

confidence: 99%

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Decoding the Role of DVL1 in Intracranial Meningioma

Bukovac

Dragičević

Kafka

et al. 2021

IJMS

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In the search for molecular candidates for targeted meningioma therapies, increasing attention has been paid to the role of signaling pathways in the development and progression of intracranial meningiomas. Although it is well known that the Wnt signaling pathway is involved in meningioma progression, the role of its central mediator, DVL1, is still unclear. In order to investigate the influence of DVL1 gene alterations on the progression of human intracranial meningioma, we focused on its central PDZ domain, which is responsible for DVL interaction with the Fzd receptor and the phosphorylation of DVL mediated through the casein kinases CK1 and CK2. A genetic analysis of genomic instability revealed the existence of microsatellite instability in 9.09% and the loss of heterozygosity in 6.06% of the samples. The sequencing of the PDZ gene region showed repetitive deletions of two bases located in intron 7 and exon 8, and a duplication in intron 8 in most samples, with different outcomes on the biological function of the DVL1 protein. Immunohistochemistry revealed that the nuclear expression of DVL1 was significantly correlated with a higher expression of active β-catenin (p = 0.029) and a higher meningioma grade (p = 0.030), which leads to the conclusion that it could be used as biomarker for meningioma progression and the activation of the Wnt signaling pathway.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Decoding the Role of DVL1 in Intracranial Meningioma

Bukovac

Dragičević

Kafka

et al. 2021

IJMS

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“…Our previous studies on primary brain tumors revealed the importance of the molecular profile in tumorigenesis and progression of intracranial tumors [ 49 ], as well as the recognizable molecular behavior of astrocytomas of different grades [ 50 ]. Such results suggest the importance of upgrading diagnostic and prognostic classification that allows understanding the behavior of tumor cells that have adapted to survive in a highly competitive brain environment.…”

Section: Discussionmentioning

confidence: 99%

Integrative cBioPortal Analysis Revealed Molecular Mechanisms That Regulate EGFR-PI3K-AKT-mTOR Pathway in Diffuse Gliomas of the Brain

Brlek

Kafka

Bukovac

et al. 2021

Cancers

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Diffuse gliomas are a heterogeneous group of tumors with aggressive biological behavior and a lack of effective treatment methods. Despite new molecular findings, the differences between pathohistological types still require better understanding. In this in silico analysis, we investigated AKT1, AKT2, AKT3, CHUK, GSK3β, EGFR, PTEN, and PIK3AP1 as participants of EGFR-PI3K-AKT-mTOR signaling using data from the publicly available cBioPortal platform. Integrative large-scale analyses investigated changes in copy number aberrations (CNA), methylation, mRNA transcription and protein expression within 751 samples of diffuse astrocytomas, anaplastic astrocytomas and glioblastomas. The study showed a significant percentage of CNA in PTEN (76%), PIK3AP1 and CHUK (75% each), EGFR (74%), AKT2 (39%), AKT1 (32%), AKT3 (19%) and GSK3β (18%) in the total sample. Comprehensive statistical analyses show how genomics and epigenomics affect the expression of examined genes differently across various pathohistological types and grades, suggesting that genes AKT3, CHUK and PTEN behave like tumor suppressors, while AKT1, AKT2, EGFR, and PIK3AP1 show oncogenic behavior and are involved in enhanced activity of the EGFR-PI3K-AKT-mTOR signaling pathway. Our findings contribute to the knowledge of the molecular differences between pathohistological types and ultimately offer the possibility of new treatment targets and personalized therapies in patients with diffuse gliomas.

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“…In proteomic analysis the Wnt signaling cascade was identified as one of the significantly modulated pathways in meningioma and is involved in epithelialto-mesenchymal transition [16]. It is likely that brain invasion through epithelial-tomesenchymal transition may be modulated by altered expression of beta-catenin and E-cadherin in meningiomas as members of the Wnt pathway [17,18].…”

Section: Introductionmentioning

confidence: 99%

Brain Invasion in Meningioma—A Prognostic Potential Worth Exploring

Behling

Hempel

Schittenhelm

2021

Cancers

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Most meningiomas are slow growing tumors arising from the arachnoid cap cells and can be cured by surgical resection or radiation therapy in selected cases. However, recurrent and aggressive cases are also quite common and challenging to treat due to no established treatment alternatives. Assessment of the risk of recurrence is therefore of utmost importance and several prognostic clinical and molecular markers have been established. Additionally, the identification of invasive growth of meningioma cells into CNS tissue was demonstrated to lead to a higher risk of recurrence and was therefore integrated into the WHO classification of CNS tumors. However, the evidence for its prognostic impact has been questioned in subsequent studies and its exclusion from the next WHO classification proposed. We were recently able to show the prognostic impact of CNS invasion in a large comprehensive retrospective meningioma cohort including other established prognostic factors. In this review we discuss the growing experiences that have been gained on this matter, with a focus on the currently nonuniform histopathological assessment, imaging characteristics and intraoperative sampling as well as the overall outlook on the future role of this potential prognostic factor.

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Are We Benign? What Can Wnt Signaling Pathway and Epithelial to Mesenchymal Transition Tell Us about Intracranial Meningioma Progression

Cited by 11 publications

References 70 publications

Decoding the Role of DVL1 in Intracranial Meningioma

Decoding the Role of DVL1 in Intracranial Meningioma

Integrative cBioPortal Analysis Revealed Molecular Mechanisms That Regulate EGFR-PI3K-AKT-mTOR Pathway in Diffuse Gliomas of the Brain

Brain Invasion in Meningioma—A Prognostic Potential Worth Exploring

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