Sarmiento Soto, M., Larkin, J.R., Martin, C. et al. (8 more authors) (2020) STAT3-mediated astrocyte reactivity associated with brain metastasis contributes to neurovascular dysfunction. Cancer Research, 80 (24). pp. 5642-5655. ISSN 0008-5472
Abstract
Astrocytes are thought to play a pivotal role in coupling neural activity and cerebral blood flow. However, it has been shown that astrocytes undergo morphological changes in response to brain metastasis, switching to a reactive phenotype which has the potential to significantly compromise cerebrovascular function and contribute to the neurological sequelae associated with brain metastasis. Given that signal transducer and activator of transcription 3 (STAT3) is a key regulator of astrocyte reactivity, we aimed here to determine the impact of STAT3-mediated astrocyte reactivity on neurovascular function in brain metastasis. Rat models of brain metastasis and ciliary neurotrophic factor (CNTF) were used to induce astrocyte reactivity. Multimodal imaging, electrophysiology, and immunohistochemistry were performed to determine the relationship between reactive astrocytes and changes in the cerebrovascular response to electrical and physiological stimuli. Subsequently, the STAT3 pathway in astrocytes was inhibited with WP1066 to determine the role of STAT3-mediated astrocyte reactivity, specifically, in brain metastasis. Astrocyte reactivity associated with brain metastases impaired cerebrovascular responses to stimuli at both the cellular and functional level and disrupted astrocyte-endothelial interactions in both animal models and human brain metastasis samples. Inhibition of STAT3-mediated astrocyte reactivity in rats with brain metastases restored cerebrovascular function, as shown by in vivo imaging, and limited cerebrovascular changes associated with tumor growth. Together these findings suggest that inhibiting STAT3-mediated astrocyte reactivity may confer significant improvements in neurological outcome for patients with brain metastases and could potentially be tested in other brain tumors.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2020, American Association for Cancer Research. This is an author-produced version of a paper accepted for publication in Cancer Research. Uploaded in accordance with the publisher's self-archiving policy. |
Keywords: | Brain metastasis; astrocytes; neurovascular unit; cerebral blood flow; STAT3 |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Science (Sheffield) > Department of Psychology (Sheffield) |
Funding Information: | Funder Grant number ROYAL SOCIETY UF080113 ROYAL SOCIETY UF130327 WELLCOME TRUST (THE) 093223/B/10/Z MEDICAL RESEARCH COUNCIL MR/M013553/1 |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 10 Nov 2020 16:19 |
Last Modified: | 08 Feb 2022 13:42 |
Status: | Published |
Publisher: | American Association for Cancer Research (AACR) |
Refereed: | Yes |
Identification Number: | 10.1158/0008-5472.can-20-2251 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:167851 |