Schwannomas are the most common type of peripheral nerve tumor. Usually, schwannomas are benign, well‐circumscribed tumors clinging to peripheral nerves, consisting of a clonal population of Schwann cells (SCs), which often undergo cystic and degenerative changes. Most cases are sporadic, however, some are associated with neurofibromatosis type 2 (NF2), schwannomatosis (SCH) or the pathology called Carney's complex. The schwannoma affecting the auditory nerve, called vestibular schwannoma (VS), is the most common benign tumor of the cerebellopontine angle. The occurrence of VSs is frequent among patients with NF2, the autosomal dominant multiple syndromes resulting from mutations in the NF2 gene, coding for the protein merlin. The tumor suppressor merlin is a cytoskeleton-associated protein, which loss of function is the main cause for transformation of SCs into schwannomas. However, a large amount of VSs is sporadic and unilateral suggesting the presence of unknown pathogenic mechanisms beside NF2 gene mutation. Also, SCH is due to changes in NF2 gene, although recently other mutations in SMARCB1 and LZTR1 genes were found. Considerable overlap has been found between SCH and NF2, in terms of the occurrence of associated types of tumors, whereas both diseases are considered as separated clinical entities. Therefore, it is not excluded that mutations in other genes, may be responsible for the appearance of schwannomas presenting a characteristic clinical phenotype. The identification of such genes and/or cellular mechanisms has found limitations in the lack of in vitro cell models of human origin that may be useful to this purpose. In this thesis, human SCs were isolated, purified and characterized, for the first time, from the schwannomas, by using a positive immunomagnetic cell labelling technique, allowing the specific and high-purity enrichment of SCs in culture. The SCs from peripheral schwannoma were then immortalized using the LtAg-SV40, in order to obtain a continuous cell line for future studies addressed to better understand the schwannoma pathogenesis. Notably, the onset of schwannoma may be influenced by the exposure to environmental challenges, likely the electromagnetic fields (EMF), such as those generated by mobile phones or electronic devices. In fact, it was suggested that EMFs can induce cellular changes towards non-physiological behavior, that may be pathologically relevant to the development of schwannoma. Overall, in this work of thesis we focused our attention on the investigation of putative genes, pathways, and molecular targets responsible for the oncotrasformation of SCs, studying the possible factors, also environmental, that could induce the development of schwannomas. The data are promising but further confirmatory studies will be needed for a more direct cause–effect correlation between EMF and SCs oncotransformation and finally to arrive at definitive conclusions widely accepted by the international scientific community.

STUDY OF PHYSIO-PATHOLOGICAL MECHANISMS AT THE BASE OF SCHWANNOMA DEVELOPMENT / V. Melfi ; tutor: V. Magnaghi; coordinatore: G.D. Norata. - : . Dipartimento di Scienze Farmacologiche e Biomolecolari, 2022. ((35. ciclo, Anno Accademico 2022.

STUDY OF PHYSIO-PATHOLOGICAL MECHANISMS AT THE BASE OF SCHWANNOMA DEVELOPMENT

V. Melfi
2022

Abstract

Schwannomas are the most common type of peripheral nerve tumor. Usually, schwannomas are benign, well‐circumscribed tumors clinging to peripheral nerves, consisting of a clonal population of Schwann cells (SCs), which often undergo cystic and degenerative changes. Most cases are sporadic, however, some are associated with neurofibromatosis type 2 (NF2), schwannomatosis (SCH) or the pathology called Carney's complex. The schwannoma affecting the auditory nerve, called vestibular schwannoma (VS), is the most common benign tumor of the cerebellopontine angle. The occurrence of VSs is frequent among patients with NF2, the autosomal dominant multiple syndromes resulting from mutations in the NF2 gene, coding for the protein merlin. The tumor suppressor merlin is a cytoskeleton-associated protein, which loss of function is the main cause for transformation of SCs into schwannomas. However, a large amount of VSs is sporadic and unilateral suggesting the presence of unknown pathogenic mechanisms beside NF2 gene mutation. Also, SCH is due to changes in NF2 gene, although recently other mutations in SMARCB1 and LZTR1 genes were found. Considerable overlap has been found between SCH and NF2, in terms of the occurrence of associated types of tumors, whereas both diseases are considered as separated clinical entities. Therefore, it is not excluded that mutations in other genes, may be responsible for the appearance of schwannomas presenting a characteristic clinical phenotype. The identification of such genes and/or cellular mechanisms has found limitations in the lack of in vitro cell models of human origin that may be useful to this purpose. In this thesis, human SCs were isolated, purified and characterized, for the first time, from the schwannomas, by using a positive immunomagnetic cell labelling technique, allowing the specific and high-purity enrichment of SCs in culture. The SCs from peripheral schwannoma were then immortalized using the LtAg-SV40, in order to obtain a continuous cell line for future studies addressed to better understand the schwannoma pathogenesis. Notably, the onset of schwannoma may be influenced by the exposure to environmental challenges, likely the electromagnetic fields (EMF), such as those generated by mobile phones or electronic devices. In fact, it was suggested that EMFs can induce cellular changes towards non-physiological behavior, that may be pathologically relevant to the development of schwannoma. Overall, in this work of thesis we focused our attention on the investigation of putative genes, pathways, and molecular targets responsible for the oncotrasformation of SCs, studying the possible factors, also environmental, that could induce the development of schwannomas. The data are promising but further confirmatory studies will be needed for a more direct cause–effect correlation between EMF and SCs oncotransformation and finally to arrive at definitive conclusions widely accepted by the international scientific community.
MAGNAGHI, VALERIO
NORATA, GIUSEPPE DANILO
Settore BIO/09 - Fisiologia
STUDY OF PHYSIO-PATHOLOGICAL MECHANISMS AT THE BASE OF SCHWANNOMA DEVELOPMENT / V. Melfi ; tutor: V. Magnaghi; coordinatore: G.D. Norata. - : . Dipartimento di Scienze Farmacologiche e Biomolecolari, 2022. ((35. ciclo, Anno Accademico 2022.
Doctoral Thesis
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/947449
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