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Disturbance in cerebral blood microcirculation and hypoxic-ischemic microenvironment are associated with the development of brain metastasis

Brain metastases (BM) constitute an increasing challenge in oncology due to their impact on neurological function, limited treatment options, and poor prognosis. BM occurs through extravasation of circulating tumor cells across the blood-brain barrier. However, the extravasation processes are still...

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Main Authors: Roesler, Jenny (Author) , Spitzer, Daniel (Author) , Jia, Xiaoxiong (Author) , Aasen, Synnøve Nymark (Author) , Sommer, Kathleen (Author) , Roller, Bastian (Author) , Olshausen, Niels (Author) , Hebach, Nils R (Author) , Albinger, Nawid (Author) , Ullrich, Evelyn (Author) , Zhu, Ling (Author) , Wang, Fan (Author) , Macas, Jadranka (Author) , Forster, Marie-Therese (Author) , Steinbach, Joachim P (Author) , Sevenich, Lisa (Author) , Devraj, Kavi (Author) , Thorsen, Frits (Author) , Karreman, Matthia A. (Author) , Plate, Karl H (Author) , Reiss, Yvonne (Author) , Harter, Patrick N (Author)
Format: Article (Journal)
Language:English
Published: November 2024
In: Neuro-Oncology
Year: 2024, Volume: 26, Issue: 11, Pages: 2084-2099
ISSN:1523-5866
DOI:10.1093/neuonc/noae094
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1093/neuonc/noae094
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Author Notes:Jenny Roesler, Daniel Spitzer, Xiaoxiong Jia, Synnøve Nymark Aasen, Kathleen Sommer, Bastian Roller, Niels Olshausen, Nils R. Hebach, Nawid Albinger, Evelyn Ullrich, Ling Zhu, Fan Wang, Jadranka Macas, Marie-Therese Forster, Joachim P. Steinbach, Lisa Sevenich, Kavi Devraj, Frits Thorsen, Matthia A. Karreman, Karl H. Plate, Yvonne Reiss, and Patrick N. Harter
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Summary:Brain metastases (BM) constitute an increasing challenge in oncology due to their impact on neurological function, limited treatment options, and poor prognosis. BM occurs through extravasation of circulating tumor cells across the blood-brain barrier. However, the extravasation processes are still poorly understood. We here propose a brain colonization process which mimics infarction-like microenvironmental reactions, that are dependent on Angiopoietin-2 (Ang-2) and vascular endothelial growth factor (VEGF).In this study, intracardiac BM models were used, and cerebral blood microcirculation was monitored by 2-photon microscopy through a cranial window. BM formation was observed using cranial magnetic resonance, bioluminescent imaging, and postmortem autopsy. Ang-2/VEGF targeting strategies and Ang-2 gain-of-function (GOF) mice were employed to interfere with BM formation. In addition, vascular and stromal factors as well as clinical outcomes were analyzed in BM patients.Blood vessel occlusions by cancer cells were detected, accompanied by significant disturbances of cerebral blood microcirculation, and focal stroke-like histological signs. Cerebral endothelial cells showed an elevated Ang-2 expression both in mouse and human BM. Ang-2 GOF resulted in an increased BM burden. Combined anti-Ang-2/anti-VEGF therapy led to a decrease in brain metastasis size and number. Ang-2 expression in tumor vessels of established human BM negatively correlated with survival.Our observations revealed a relationship between disturbance of cerebral blood microcirculation and brain metastasis formation. This suggests that vessel occlusion by tumor cells facilitates brain metastatic extravasation and seeding, while combined inhibition of microenvironmental effects of Ang-2 and VEGF prevents the outgrowth of macrometastases.
Item Description:Online veröffentlicht: 4. Juni 2024, Korrektur und Schriftsatz: 17. Juli 2024
Gesehen am 10.02.2025
Physical Description:Online Resource
ISSN:1523-5866
DOI:10.1093/neuonc/noae094

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