Blood-brain barrier: peculiarities of structural and functional organization in patients with glioblastoma

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Abstract

The research of the blood-brain barrier began at the turn of the 18th–19th centuries. To date due to the large number of studies conducted, it is obvious that this system has an impossibly complex structure at the organ, tissue and molecular genetic levels. Scientific interest in the changes in the blood-brain barrier that occur during pathological neoplastic processes is increasing. As it turned out, the restructuring of this system is an important and integral stage in the pathogenesis of glioblastoma, a tumor of the central nervous system with the most unfavorable prognosis. Heterogeneous structure with the formation of areas of altered cellular composition, uneven and uncontrolled permeability, provided by a large number of transport vesicles and the destruction of tight contacts between endotheliocytes, active outflow of molecules from the parenchyma due to the continuous synthesis of new portions of ABC-carrier proteins, the creation of an immature vascular network under the influence of high expression of VEGF by tumor cells — the main characteristics of the hematopoietic barrier, formed in glioblastoma and supporting its survival. The further research of the features of the structure and mechanisms of functioning of the blood-brain barrier in glioblastoma is a new and promising task in modern neuro–oncology, the solution of which will not only expand the understanding of the biology of the most common and malignant brain tumor but will also improve the effectiveness of treatment of patients and improve the prognosis.

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About the authors

Sofia S. Sklyar

Polenov Russian Neurosurgical Institute — the Branch of Almazov National Medical Research Centre; B.P. Konstantinov Petersburg Nuclear Physics Institute of National Research Centre “Kurchatov Institute”

Author for correspondence.
Email: s.sklyar2017@yandex.ru

MD, PhD, Junior Research Associate, Laboratory of Neurooncology, Polenov Russian Neurosurgical Institute – the Branch of Almazov National Medical Research Centre; Junior Research Associate, Center for Preclinical and Clinical research, St. Petersburg B.P. Konstantinov Institute of Nuclear Physics

Russian Federation, Saint Petersburg; Saint Petersburg

Alexander P. Trashkov

B.P. Konstantinov Petersburg Nuclear Physics Institute of National Research Centre “Kurchatov Institute”; National Research Center “Kurchatov Institute”

Email: alexander.trashkov@gmail.com

Head, Center of Preclinical and Clinical Research, St. Petersburg B.P. Konstantinov Institute of Nuclear Physics; Head of the Neurocognitive Research Resource Center, National Research Center Kurchatov Institute

Russian Federation, Saint Petersburg; Moscow

Marina V. Matsko

Clinical Scientific-Practical Center of Oncology; Saint Petersburg State University; St. Petersburg Medico-Social Institute

Email: marinamatsko@mail.ru

MD, PhD, Dr. Sci. (Med.), Leading Research Associate, Clinical Scientific-Practical Center of Oncology; Assistant Professor, Department of Oncology, Saint Petersburg State University; Associate Professor, Department of Oncology, St. Petersburg Medico-Social Institute

Russian Federation, Saint Petersburg; Saint Petersburg; Saint Petersburg

Andrey L. Konevega

B.P. Konstantinov Petersburg Nuclear Physics Institute of National Research Centre “Kurchatov Institute”; National Research Center “Kurchatov Institute”

Email: konevega_al@pnpi.nrcki.ru

MD, PhD, Head, Department of Molecular and Radiation Biophysics, St. Petersburg B.P. Konstantinov Institute of Nuclear Physics; Head of the Department of Biomedical Technologies, National Research Center Kurchatov Institute

Russian Federation, Saint Petersburg; Moscow

Marina Yu. Kopaeva

National Research Center “Kurchatov Institute”

Email: m.kopaeva@mail.ru

Research Associate, Laboratory of Neuroscience National Research Center Kurchatov Institute

Russian Federation, Moscow

Anton B. Cherepov

National Research Center “Kurchatov Institute”

Email: ipmagus@mail.ru

Lead Engineer, Center for Neurocognitive Research

Russian Federation, Moscow

Nikolai V. Tsygan

Kirov Military Medical Academy; B.P. Konstantinov Petersburg Nuclear Physics Institute of National Research Centre “Kurchatov Institute”

Email: 77th77@gmail.com

MD, PhD, Dr. Sci. (Med.), Associate Professor, Department Neurology, Kirov Military Medical Academy; Leading Research Associate, St. Petersburg B.P. Konstantinov Institute of Nuclear Physics

Russian Federation, Saint Petersburg; Saint Petersburg

Bobir I. Safarov

Polenov Russian Neurosurgical Institute — the Branch of Almazov National Medical Research Centre

Email: safarovbob@mail.ru

MD, PhD, Head, 4th Department

Russian Federation, Saint Petersburg

Nikita E. Voinov

Polenov Russian Neurosurgical Institute — the Branch of Almazov National Medical Research Centre

Email: nik_voin@mail.ru

Neurosurgeon

Russian Federation, Saint Petersburg

Andrei G. Vasiliev

St. Petersburg State Pediatric Medical University

Email: avas7@mail.ru

MD, PhD, Dr. Sci. (Med.), Head, Pathophysiology Department

Russian Federation, Saint Petersburg

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Supplementary files

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2. Fig. 1. The structure and functioning of the blood-brain barrier in physiological conditions. A. Endotheliocytes are connected by tight contacts consisting of proteins claudin-5 and occludin. These compounds have an intracellular domain that regulates the cytoskeleton through ZO1. B. The main transport mechanisms in the endothelium (transcellular, paracellular, by SLC and receptor-mediated endocytosis, and the efflux pathway through ABC proteins are shown. The regulation of the expression of these carriers is controlled by astrocytes and pericytes via the WNT-catenin and SHH signaling pathways. C. Pericytes and astrocytes express Ang1, which is responsible for the formation of tight contacts between endotheliocytes. Pericytes control the expression of adhesive molecules on endotheliocytes (ICAM-1, VCAM-1). D. Fixation of pericytes on the basement membrane is ensured by their expression of PDGFRβ and synthesis by endotheliocytes of PDGFβ

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3. Fig. 2. The structure and functioning of BTB. A — the destruction of tight junctions (claudin-5 and occluding) leads to increased uncontrolled paracellular diffusion and disruption of the endotheliocyte cytoskeleton. Infiltrative growth of glioblastoma causes displacement and destruction of astrocyte processes. Reactive astrocytes express S1PR-3, which enhances infiltration by T-lymphocytes; B — endotheliocytes are characterized by the loss of many carriers and the presence of a large number of transport vesicles and ABC proteins; C — the distribution of pericytes is uneven with alternating zones of their absence and areas with a layered structure. Differentiating from stem tumor cells, pericytes express a large amount of CD248. The formation of new vessels in glioblastoma occurs through the synthesis of VEGF by tumor cells and endotheliocytes

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