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      The microenvironment of brain metastases from solid tumors

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          Abstract

          Brain metastasis (BrM) is an area of unmet medical need that poses unique therapeutic challenges and heralds a dismal prognosis. The intracranial tumor microenvironment (TME) presents several challenges, including the therapy-resistant blood–brain barrier, a unique immune milieu, distinct intercellular interactions, and specific metabolic conditions, that are responsible for treatment failures and poor clinical outcomes. There is a complex interplay between malignant cells that metastasize to the central nervous system (CNS) and the native TME. Cancer cells take advantage of vascular, neuronal, immune, and anatomical vulnerabilities to proliferate with mechanisms specific to the CNS. In this review, we discuss unique aspects of the TME in the context of brain metastases and pathways through which the TME may hold the key to the discovery of new and effective therapies for patients with BrM.

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          The blood-brain barrier.

          Richard Daneman, Alexandre Prat (2015)
          Blood vessels are critical to deliver oxygen and nutrients to all of the tissues and organs throughout the body. The blood vessels that vascularize the central nervous system (CNS) possess unique properties, termed the blood-brain barrier, which allow these vessels to tightly regulate the movement of ions, molecules, and cells between the blood and the brain. This precise control of CNS homeostasis allows for proper neuronal function and also protects the neural tissue from toxins and pathogens, and alterations of these barrier properties are an important component of pathology and progression of different neurological diseases. The physiological barrier is coordinated by a series of physical, transport, and metabolic properties possessed by the endothelial cells (ECs) that form the walls of the blood vessels, and these properties are regulated by interactions with different vascular, immune, and neural cells. Understanding how these different cell populations interact to regulate the barrier properties is essential for understanding how the brain functions during health and disease.
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            Astrocytes: biology and pathology

            Michael Sofroniew, Harry V. Vinters (2009)
            Astrocytes are specialized glial cells that outnumber neurons by over fivefold. They contiguously tile the entire central nervous system (CNS) and exert many essential complex functions in the healthy CNS. Astrocytes respond to all forms of CNS insults through a process referred to as reactive astrogliosis, which has become a pathological hallmark of CNS structural lesions. Substantial progress has been made recently in determining functions and mechanisms of reactive astrogliosis and in identifying roles of astrocytes in CNS disorders and pathologies. A vast molecular arsenal at the disposal of reactive astrocytes is being defined. Transgenic mouse models are dissecting specific aspects of reactive astrocytosis and glial scar formation in vivo. Astrocyte involvement in specific clinicopathological entities is being defined. It is now clear that reactive astrogliosis is not a simple all-or-none phenomenon but is a finely gradated continuum of changes that occur in context-dependent manners regulated by specific signaling events. These changes range from reversible alterations in gene expression and cell hypertrophy with preservation of cellular domains and tissue structure, to long-lasting scar formation with rearrangement of tissue structure. Increasing evidence points towards the potential of reactive astrogliosis to play either primary or contributing roles in CNS disorders via loss of normal astrocyte functions or gain of abnormal effects. This article reviews (1) astrocyte functions in healthy CNS, (2) mechanisms and functions of reactive astrogliosis and glial scar formation, and (3) ways in which reactive astrocytes may cause or contribute to specific CNS disorders and lesions.
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              Genes that mediate breast cancer metastasis to the brain.

              Paula Bos, Xiang Zhang, Cristina Nadal … (2009)
              The molecular basis for breast cancer metastasis to the brain is largely unknown. Brain relapse typically occurs years after the removal of a breast tumour, suggesting that disseminated cancer cells must acquire specialized functions to take over this organ. Here we show that breast cancer metastasis to the brain involves mediators of extravasation through non-fenestrated capillaries, complemented by specific enhancers of blood-brain barrier crossing and brain colonization. We isolated cells that preferentially infiltrate the brain from patients with advanced disease. Gene expression analysis of these cells and of clinical samples, coupled with functional analysis, identified the cyclooxygenase COX2 (also known as PTGS2), the epidermal growth factor receptor (EGFR) ligand HBEGF, and the alpha2,6-sialyltransferase ST6GALNAC5 as mediators of cancer cell passage through the blood-brain barrier. EGFR ligands and COX2 were previously linked to breast cancer infiltration of the lungs, but not the bones or liver, suggesting a sharing of these mediators in cerebral and pulmonary metastases. In contrast, ST6GALNAC5 specifically mediates brain metastasis. Normally restricted to the brain, the expression of ST6GALNAC5 in breast cancer cells enhances their adhesion to brain endothelial cells and their passage through the blood-brain barrier. This co-option of a brain sialyltransferase highlights the role of cell-surface glycosylation in organ-specific metastatic interactions.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Neurooncol Adv
                Journal ID (iso-abbrev): Neurooncol Adv
                Journal ID (publisher-id): noa
                Title: Neuro-oncology Advances
                Publisher: Oxford University Press (US )
                ISSN (Electronic): 2632-2498
                Publication date Collection: November 2021
                Publication date (Electronic): 27 November 2021
                Publication date PMC-release: 27 November 2021
                Volume: 3
                Issue: Suppl 5 , Neuro Oncology Advances Brain Metastases Supplement
                Pages: v121-v132
                Affiliations
                [1 ] Duke Brain and Spine Metastases Center, Duke University , Durham, North Carolina, USA
                [2 ] Department of Neurological Surgery, Keck School of Medicine, University of Southern California , Los Angeles, California, USA
                [3 ] Department of Neurological Surgery, Physiology and Neuroscience, USC Brain Tumor Center, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California , Los Angeles, California, USA
                [4 ] Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg , Heidelberg, Germany
                [5 ] Clinical Cooperation Unit Neurooncology, German Cancer Consortium, German Cancer Research Center , Heidelberg, Germany
                Author notes
                Corresponding Authors: Mustafa Khasraw, MD, Duke Brain and Spine Metastases Center, Duke University, 2301 Erwin Road, Durham, NC 27701, USA ( mustafa.khasraw@ 123456duke.edu );
                Josh Neman, PhD, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA ( yebrahim@ 123456usc.edu ).

                These authors contributed equally to this manuscript.

                Author information
                https://orcid.org/0000-0003-3249-9849
                Article
                Publisher ID: vdab121
                DOI: 10.1093/noajnl/vdab121
                PMC ID: 8633769
                PubMed ID: 34859239
                SO-VID: 87a4a383-0b76-43d3-9fd5-4b3c2714a175
                Copyright © © The Author(s) 2021. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date: 27 November 2021
                Page count
                Pages: 12
                Categories
                Subject: Supplement Articles
                Subject: AcademicSubjects/MED00300
                Subject: AcademicSubjects/MED00310

                Keywords: brain metastasis,immune suppression,microenvironment,neural niche,therapeutic targets
                Data availability:
                Keywords: brain metastasis, immune suppression, microenvironment, neural niche, therapeutic targets

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