Presence of activated (phosphorylated) STAT3 in radiation necrosis following stereotactic radiosurgery for brain metastases
Brain radiation necrosis (RN) is a subacute or late adverse event following radiotherapy, involving an exacerbated inflammatory response of the brain tissue. The risk of symptomatic RN associated with stereotactic radiosurgery (SRS) as part of the treatment of brain metastases (BMs) has been a subje...
| Authors: | , , , , , , , , |
|---|---|
| Format: | article |
| Publication Date: | 2023 |
| Country: | España |
| Institution: | Universidad de Navarra |
| Repository: | Dadun. Depósito Académico Digital de la Universidad de Navarra |
| Language: | English |
| OAI Identifier: | oai:dadun.unav.edu:10171/67861 |
| Online Access: | https://hdl.handle.net/10171/67861 |
| Access Level: | Open access |
| Keyword: | Animal model Brain metastases Phospho-STAT3 Radiation necrosis Stereotactic radiosurgery. |
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Presence of activated (phosphorylated) STAT3 in radiation necrosis following stereotactic radiosurgery for brain metastasesJablonska, P.A. (Paola Anna)|||/items/b6c857da-d099-4b5e-af72-9f51dcdeffdeGalán-Gallego, N. (Nuria)|||/items/5870b302-5fc8-4fb6-902d-4c680fae2558Barranco-Martínez, J. (Jennifer)|||/items/155d9a2b-1857-4fdb-8e84-aaee7355cfecLeon, S. (Sergio)|||/items/22c4e92f-d0b6-4b69-b271-728747ff716aRobledano, R. (Ramón)|||/items/82c1f8b5-8067-4fff-9323-1f0c54d02738Echeveste, J.I. (José I.)|||/items/37d13f4f-9c5d-4b46-84f1-6f449c18fb88Calvo-Alonso, A. (Alfonso)|||/items/25ff4764-dbe4-47b7-86b4-1f5d3523ff13Aristu-Mendioroz, J.J. (José Javier)|||/items/324b9db0-23f7-40e4-a8fa-7d27e66b099aSerrano-Tejero, D. (Diego)|||/items/1c12ec1a-108a-4bf8-a5bd-dc8c3b89fed4Animal modelBrain metastasesPhospho-STAT3Radiation necrosisStereotactic radiosurgery.Brain radiation necrosis (RN) is a subacute or late adverse event following radiotherapy, involving an exacerbated inflammatory response of the brain tissue. The risk of symptomatic RN associated with stereotactic radiosurgery (SRS) as part of the treatment of brain metastases (BMs) has been a subject of recent investigation. The activation of the signal transducer and activator of transcription 3 (STAT3) was shown in reactive astrocytes (RA) associated with BMs. Given that the pathophysiological mechanisms behind RN are not fully understood, we sought to investigate the role of STAT3 among other inflammatory markers in RN development. A mouse model of RN using clinical LINAC-based SRS was designed to induce brain necrosis with the administration of 50 Gy in a single fraction to the left hemisphere using a circular collimator of 5 mm diameter. Immunohistochemistry and multiplex staining for CD4, CD8, CD68, GFAP, and STAT3 were performed. For validation, eleven patients with BMs treated with SRS who developed symptomatic RN and required surgery were identified to perform staining for CD68, GFAP, and STAT3. In the mouse model, the RN and perinecrotic areas showed significantly higher staining for F4/80+ and GFAP+ cells, with a high infiltration of CD4 and CD8 T-lymphocytes, when compared to the non-irradiated cerebral hemisphere. A high number of GFAP+pSTAT3+ and F4/80+pSTAT3+ cells was found in the RN areas and the rest of the irradiated hemisphere. The analysis of human brain specimens showed that astrocytes and microglia were actively phosphorylating STAT3 in the areas of RN and gliosis. Phosphorylated STAT3 is highly expressed in the microglia and RA pertaining to the areas of brain RN. Targeting STAT3 via inhibition represents a promising strategy to ameliorate symptomatic RN in BM patients undergoing SRS.Dadun. Depósito Académico Digital Universidad de Navarra20232023-11-1520232023-01-0120232023-01-01journal articlehttp://purl.org/coar/resource_type/c_6501info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/10171/67861reponame:Dadun. Depósito Académico Digital de la Universidad de Navarrainstname:Universidad de NavarraInglésengopen accesshttp://purl.org/coar/access_right/c_abf2info:eu-repo/semantics/openAccessoai:dadun.unav.edu:10171/678612026-06-21T12:47:57Z |
| dc.title.none.fl_str_mv |
Presence of activated (phosphorylated) STAT3 in radiation necrosis following stereotactic radiosurgery for brain metastases |
| title |
Presence of activated (phosphorylated) STAT3 in radiation necrosis following stereotactic radiosurgery for brain metastases |
| spellingShingle |
Presence of activated (phosphorylated) STAT3 in radiation necrosis following stereotactic radiosurgery for brain metastases Jablonska, P.A. (Paola Anna)|||/items/b6c857da-d099-4b5e-af72-9f51dcdeffde Animal model Brain metastases Phospho-STAT3 Radiation necrosis Stereotactic radiosurgery. |
| title_short |
Presence of activated (phosphorylated) STAT3 in radiation necrosis following stereotactic radiosurgery for brain metastases |
| title_full |
Presence of activated (phosphorylated) STAT3 in radiation necrosis following stereotactic radiosurgery for brain metastases |
| title_fullStr |
Presence of activated (phosphorylated) STAT3 in radiation necrosis following stereotactic radiosurgery for brain metastases |
| title_full_unstemmed |
Presence of activated (phosphorylated) STAT3 in radiation necrosis following stereotactic radiosurgery for brain metastases |
| title_sort |
Presence of activated (phosphorylated) STAT3 in radiation necrosis following stereotactic radiosurgery for brain metastases |
| dc.creator.none.fl_str_mv |
Jablonska, P.A. (Paola Anna)|||/items/b6c857da-d099-4b5e-af72-9f51dcdeffde Galán-Gallego, N. (Nuria)|||/items/5870b302-5fc8-4fb6-902d-4c680fae2558 Barranco-Martínez, J. (Jennifer)|||/items/155d9a2b-1857-4fdb-8e84-aaee7355cfec Leon, S. (Sergio)|||/items/22c4e92f-d0b6-4b69-b271-728747ff716a Robledano, R. (Ramón)|||/items/82c1f8b5-8067-4fff-9323-1f0c54d02738 Echeveste, J.I. (José I.)|||/items/37d13f4f-9c5d-4b46-84f1-6f449c18fb88 Calvo-Alonso, A. (Alfonso)|||/items/25ff4764-dbe4-47b7-86b4-1f5d3523ff13 Aristu-Mendioroz, J.J. (José Javier)|||/items/324b9db0-23f7-40e4-a8fa-7d27e66b099a Serrano-Tejero, D. (Diego)|||/items/1c12ec1a-108a-4bf8-a5bd-dc8c3b89fed4 |
| author |
Jablonska, P.A. (Paola Anna)|||/items/b6c857da-d099-4b5e-af72-9f51dcdeffde |
| author_facet |
Jablonska, P.A. (Paola Anna)|||/items/b6c857da-d099-4b5e-af72-9f51dcdeffde Galán-Gallego, N. (Nuria)|||/items/5870b302-5fc8-4fb6-902d-4c680fae2558 Barranco-Martínez, J. (Jennifer)|||/items/155d9a2b-1857-4fdb-8e84-aaee7355cfec Leon, S. (Sergio)|||/items/22c4e92f-d0b6-4b69-b271-728747ff716a Robledano, R. (Ramón)|||/items/82c1f8b5-8067-4fff-9323-1f0c54d02738 Echeveste, J.I. (José I.)|||/items/37d13f4f-9c5d-4b46-84f1-6f449c18fb88 Calvo-Alonso, A. (Alfonso)|||/items/25ff4764-dbe4-47b7-86b4-1f5d3523ff13 Aristu-Mendioroz, J.J. (José Javier)|||/items/324b9db0-23f7-40e4-a8fa-7d27e66b099a Serrano-Tejero, D. (Diego)|||/items/1c12ec1a-108a-4bf8-a5bd-dc8c3b89fed4 |
| author_role |
author |
| author2 |
Galán-Gallego, N. (Nuria)|||/items/5870b302-5fc8-4fb6-902d-4c680fae2558 Barranco-Martínez, J. (Jennifer)|||/items/155d9a2b-1857-4fdb-8e84-aaee7355cfec Leon, S. (Sergio)|||/items/22c4e92f-d0b6-4b69-b271-728747ff716a Robledano, R. (Ramón)|||/items/82c1f8b5-8067-4fff-9323-1f0c54d02738 Echeveste, J.I. (José I.)|||/items/37d13f4f-9c5d-4b46-84f1-6f449c18fb88 Calvo-Alonso, A. (Alfonso)|||/items/25ff4764-dbe4-47b7-86b4-1f5d3523ff13 Aristu-Mendioroz, J.J. (José Javier)|||/items/324b9db0-23f7-40e4-a8fa-7d27e66b099a Serrano-Tejero, D. (Diego)|||/items/1c12ec1a-108a-4bf8-a5bd-dc8c3b89fed4 |
| author2_role |
author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Dadun. Depósito Académico Digital Universidad de Navarra |
| dc.subject.none.fl_str_mv |
Animal model Brain metastases Phospho-STAT3 Radiation necrosis Stereotactic radiosurgery. |
| topic |
Animal model Brain metastases Phospho-STAT3 Radiation necrosis Stereotactic radiosurgery. |
| description |
Brain radiation necrosis (RN) is a subacute or late adverse event following radiotherapy, involving an exacerbated inflammatory response of the brain tissue. The risk of symptomatic RN associated with stereotactic radiosurgery (SRS) as part of the treatment of brain metastases (BMs) has been a subject of recent investigation. The activation of the signal transducer and activator of transcription 3 (STAT3) was shown in reactive astrocytes (RA) associated with BMs. Given that the pathophysiological mechanisms behind RN are not fully understood, we sought to investigate the role of STAT3 among other inflammatory markers in RN development. A mouse model of RN using clinical LINAC-based SRS was designed to induce brain necrosis with the administration of 50 Gy in a single fraction to the left hemisphere using a circular collimator of 5 mm diameter. Immunohistochemistry and multiplex staining for CD4, CD8, CD68, GFAP, and STAT3 were performed. For validation, eleven patients with BMs treated with SRS who developed symptomatic RN and required surgery were identified to perform staining for CD68, GFAP, and STAT3. In the mouse model, the RN and perinecrotic areas showed significantly higher staining for F4/80+ and GFAP+ cells, with a high infiltration of CD4 and CD8 T-lymphocytes, when compared to the non-irradiated cerebral hemisphere. A high number of GFAP+pSTAT3+ and F4/80+pSTAT3+ cells was found in the RN areas and the rest of the irradiated hemisphere. The analysis of human brain specimens showed that astrocytes and microglia were actively phosphorylating STAT3 in the areas of RN and gliosis. Phosphorylated STAT3 is highly expressed in the microglia and RA pertaining to the areas of brain RN. Targeting STAT3 via inhibition represents a promising strategy to ameliorate symptomatic RN in BM patients undergoing SRS. |
| publishDate |
2023 |
| dc.date.none.fl_str_mv |
2023 2023-11-15 2023 2023-01-01 2023 2023-01-01 |
| dc.type.none.fl_str_mv |
journal article http://purl.org/coar/resource_type/c_6501 |
| dc.type.openaire.fl_str_mv |
info:eu-repo/semantics/article |
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article |
| dc.identifier.none.fl_str_mv |
https://hdl.handle.net/10171/67861 |
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https://hdl.handle.net/10171/67861 |
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Inglés eng |
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Inglés |
| language |
eng |
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open access http://purl.org/coar/access_right/c_abf2 |
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info:eu-repo/semantics/openAccess |
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open access http://purl.org/coar/access_right/c_abf2 |
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openAccess |
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application/pdf |
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reponame:Dadun. Depósito Académico Digital de la Universidad de Navarra instname:Universidad de Navarra |
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Universidad de Navarra |
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Dadun. Depósito Académico Digital de la Universidad de Navarra |
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Dadun. Depósito Académico Digital de la Universidad de Navarra |
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