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

Autor:	Roesler J; Goethe University, University Hospital, Institute of Neurology (Edinger Institute), Frankfurt, Germany., Spitzer D; Goethe University, University Hospital, Institute of Neurology (Edinger Institute), Frankfurt, Germany., Jia X; Tianjin Neurosurgical Institute, Tianjin Huanhu Hospital, Tianjin, China.; Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases, Tianjin Huanhu Hospital, Tianjin, China.; Goethe University, University Hospital, Institute of Neurology (Edinger Institute), Frankfurt, Germany.; Neurosurgery Department, Tianjin Huanhu Hospital, Tianjin, China., Aasen SN; Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway.; Department of Biomedicine, Kristian Gerhard Jebsen Brain Tumour Research Centre, University of Bergen, Bergen, Norway., Sommer K; Goethe University, University Hospital, Institute of Neurology (Edinger Institute), Frankfurt, Germany., Roller B; Goethe University, University Hospital, Dr. Senckenberg Institute for Neurooncology, Frankfurt, Germany.; Goethe University, University Hospital, Institute of Neurology (Edinger Institute), Frankfurt, Germany., Olshausen N; Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany., Hebach NR; Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany., Albinger N; Frankfurt Cancer Institute (FCI), Frankfurt, Germany.; Department of Pediatrics, Experimental Immunology and Cell Therapy, Goethe University, University Hospital, Frankfurt, Germany., Ullrich E; Frankfurt Cancer Institute (FCI), Frankfurt, Germany.; Department of Pediatrics, Experimental Immunology and Cell Therapy, Goethe University, University Hospital, Frankfurt, Germany., Zhu L; Goethe University, University Hospital, Institute of Neurology (Edinger Institute), Frankfurt, Germany., Wang F; Goethe University, University Hospital, Institute of Neurology (Edinger Institute), Frankfurt, Germany., Macas J; Goethe University, University Hospital, Institute of Neurology (Edinger Institute), Frankfurt, Germany., Forster MT; Department of Neurosurgery, Goethe University, University Hospital, Frankfurt, Germany., Steinbach JP; German Cancer Research Centre (DKFZ), Heidelberg, Germany.; German Cancer Consortium (DKTK) Partner Site Frankfurt/Mainz, Frankfurt, Germany.; Frankfurt Cancer Institute (FCI), Frankfurt, Germany.; Goethe University, University Hospital, Dr. Senckenberg Institute for Neurooncology, Frankfurt, Germany., Sevenich L; Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt am Main, Frankfurt, Germany.; German Cancer Research Centre (DKFZ), Heidelberg, Germany.; German Cancer Consortium (DKTK) Partner Site Frankfurt/Mainz, Frankfurt, Germany.; Frankfurt Cancer Institute (FCI), Frankfurt, Germany., Devraj K; Goethe University, University Hospital, Institute of Neurology (Edinger Institute), Frankfurt, Germany.; Department of Biological Sciences, Birla Institute of Technology and Science, Pilani, Hyderabad, India., Thorsen F; Department of Biomedicine, Molecular Imaging Center, University of Bergen, Bergen, Norway.; Department of Neurosurgery, Qilu Hospital of Shandong University and Brain Science Research Institute, Shandong University, Jinan, China.; Department of Neurosurgery, Haukeland University Hospital, Bergen, Norway., Karreman MA; Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.; Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany., Plate KH; German Cancer Research Centre (DKFZ), Heidelberg, Germany.; German Cancer Consortium (DKTK) Partner Site Frankfurt/Mainz, Frankfurt, Germany.; Frankfurt Cancer Institute (FCI), Frankfurt, Germany.; Goethe University, University Hospital, Institute of Neurology (Edinger Institute), Frankfurt, Germany., Reiss Y; German Cancer Research Centre (DKFZ), Heidelberg, Germany.; German Cancer Consortium (DKTK) Partner Site Frankfurt/Mainz, Frankfurt, Germany.; Frankfurt Cancer Institute (FCI), Frankfurt, Germany.; Goethe University, University Hospital, Institute of Neurology (Edinger Institute), Frankfurt, Germany., Harter PN; Center for Neuropathology and Prion Research, Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany.; German Cancer Research Centre (DKFZ), Heidelberg, Germany.; German Cancer Consortium (DKTK) Partner Site Frankfurt/Mainz, Frankfurt, Germany.; Frankfurt Cancer Institute (FCI), Frankfurt, Germany.; Goethe University, University Hospital, Institute of Neurology (Edinger Institute), Frankfurt, Germany.
Jazyk:	angličtina
Zdroj:	Neuro-oncology [Neuro Oncol] 2024 Nov 04; Vol. 26 (11), pp. 2084-2099.
DOI:	10.1093/neuonc/noae094
Abstrakt:	Background: 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). Methods: 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. Results: 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. Conclusions: 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. (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)
Databáze:	MEDLINE
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