Blood-Brain Barrier Integrity and Breast Cancer Metastasis to the Brain

At secondary organ sites. The impairment of the BBB was observed recently in breast cancer patients who developed metastasis to the brain

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Reactive Astrocytes and Glia onmacroscopic growth step. The Fidler groupoxide pathway and modulated migration of HBMECs [42]. G. 1, pp. CNS:Central nervous system[12] O. [19] J. 1, no. Marchi, Q. P. 7, pp.
AGE-Hindawi Access to Research Pathology Research International Volume 2011, Article ID 920509, 12 pages doi:10.4061/2011/920509

Review Article Blood-Brain Barrier Integrity and Breast Cancer Metastasis to the Brain
Farheen Arshad,1 Lili Wang,1 Christopher Sy,1, 2 Shalom Avraham,1 and Hava Karsenty Avraham1

Division of Experimental Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Harvard Institutes of Medicine, 99 Brookline Avenue 3rd Floor, Boston, MA 02215, USA 2 Division of Graduate Medical Sciences, Boston University School of Medicine, Boston, MA 02118, USA Correspondence should be addressed to Hava Karsenty Avraham, Received 15 October 2010; Accepted 16 November 2010 Academic Editor: Rohit Bhargava Copyright (c) 2011 Farheen Arshad et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Brain metastasis, an important cause of cancer morbidity and mortality, occurs in at least 30% of patients with breast cancer. A key event of brain metastasis is the migration of cancer cells through the blood-brain barrier (BBB). Although preventing brain metastasis is immensely important for survival, very little is known about the early stage of transmigration and the molecular mechanisms of breast tumor cells penetrating the BBB. The brain endothelium plays an important role in brain metastasis, although the mechanisms are not clear. Brain Microvascular Endothelial Cells (BMECs) are the major cellular constituent of the BBB. BMECs are joined together by intercellular tight junctions (TJs) that are responsible for acquisition of highly selective permeability. Failure of the BBB is a critical event in the development and progression of several diseases that affect the CNS, including brain tumor metastasis development. Here, we have delineated the mechanisms of BBB impairment and breast cancer metastasis to the brain. Understanding the molecular mediators that cause changes in the BBB should lead to better strategies for effective treatment modalities targeted to inhibition of brain tumors.

1. Introduction
Breast cancer patients often develop metastatic lesions in the brain [1, 2]. The development of CNS metastasis in patients with solid malignancies represents a turning point in the disease process. The prevalence of CNS metastasis from breast cancer may be increasing due to improved systemic therapy for stage IV breast cancer. The standard treatment for multiple brain lesions remains whole-brain radiation for symptom control, with no improvement in survival. The therapy for a single brain metastasis remains either surgery or radiosurgery, with conflicting information as to the benefit of prior whole-brain radiation. To metastasize to the brain, breast cancer cells must attach to microvessel endothelial cells and then invade the blood-brain barrier (BBB), which constitutes the endothelium and the surrounding cells. The BBB is a unique anatomical structure that is mainly defined by tight junctions

and adherens junctions between the brain endothelial cells, that strictly regulate the flow of ions, nutrients, and cells into the brain [3, 4]. Compared with endothelial cells from other vascular beds, brain microvascular endothelial cells (BMECs) characteristically have very low permeability to solutes, high electrical resistance, complex tight junctions, and an array of transport systems that both supply the brain with nutrients and eliminates byproducts of brain metabolism. The low permeability is also important in protecting the brain from toxins circulating in the blood and restricting the migration of leukocytes and monocytes. The BMECs form an active permeability barrier and transport system known as the BBB, which is instrumental in the control of the brain fluid milieu. A widely supported hypothesis is that tumor cell adhesion to endothelium induces a retraction of the endothelium, which exposes the vascular basement membrane to the tumor cells. Numerous studies have shown that tumor cells recognize and bind to components in the vascular membrane, thereby

2 initiating extravasation and the beginning of new growth at secondary organ sites. The impairment of the BBB was observed recently in breast cancer patients who developed metastasis to the brain [5]. The BBB, a regulated interface between the peripheral circulation and the central nervous system (CNS), is comprised of the cerebral microvascular endothelium, which together with neurons, astrocytes, pericytes, and the extracellular matrix, constitute a \”neurovascular unit\” (Figure 1) [3, 4, 6]. The BBB is a highly selective diffusion barrier at the level of the cerebral microvascular endothelium, characterized by the presence of mainly tight cellcell junctions, adherens junctions and lack of fenestrations (Figure 2). The BBB regulates bidirectional control over the passage of a large diversity of regulatory proteins, nutrients and electrolytes, as well as potential neurotoxins [7, 8]. Increased BBB permeability can be either a consequence of the pathology or a precipitating event [7, 8]. Impairment of the BBB leads to an increase in permeability and formation of edema. Inflammatory mediators such as histamine, bradykinin, and Substance P cause increase in permeability of BBB in vivo, which results from the rapid formation of endothelial gaps [7, 8].

Pathology Research International the membrane [3]. ZO-1 links transmembrane proteins of the TJ to the actin cytoskeleton. The primary cytoskeletal protein, actin, has known binding sites on all ZO proteins and on claudins and occludin. Actin filaments serve both structural and dynamic roles in the cell. ZO-1 binds to actin filaments and to the C-terminus of occludin and claudins, which couples the structural and dynamic properties of perijunctional actin to the paracellular barrier. The numerous pathways by which specific TJ proteins are regulated and the specific effects of certain pathologies on tight junction (TJ) proteins strongly suggest that therapies targeted to components of the TJ complex and its modulators for the treatment and prevention of breast metastasis to the brain and development of brain tumors are a promising avenue that needs to be explored.

3. Genes That Mediate Breast Cancer Metastasis to the Brain
The molecular mediators that influence metastasis in distant sites appear to vary by organ (Figure 4). In malignancies of the breast, cancer cells enter a prolonged period of latency before they gain competence to colonize and produce organspecific metastases [10-12]. During this period of time, disseminated cancer cells may acquire distinct sets of metastasis functions depending on the target organ [13, 14]. Despite the various infiltration and colonization functions, the general process of metastasis can be broken down into local invasion, intravasation, survival in the circulation, extravasation and colonization [15] (Figure 5). After intravasation the cancer cells need to survive in the circulation, travel to specific target organs and extravasate into a microenvironment where they can colonize as secondary tumors [15]. Searches for genetic determinants of metastasis have led to identification of gene signatures that selectively mediate breast cancer cell metastasis to bones, the lungs, and the brain [13-15]. Based on previous work on genomic analysis of breast cancer metastasis to bone and lung, the Massagu group identified e three tumor metastasis genes that mediate extravasation through the BBB and cancer cell colonization in the brain [15]. The barriers to metastasis are distinct in organs. To colonize the brain parenchyma, invading tumor cells must penetrate the blood-brain barrier (BBB). Brain capillary walls are more difficult to penetrate due to a tight layer of endothelial cells, tight junctions, and astrocyte foot processes [10, 16]. Functional validation of these genes provided clues as to how cancer cells can penetrate the BBB and initiate tumor growth in brain vasculature. A brain metastasis signature (BrMS) consisting of 17 genes was created using genomic profiling and univariate analysis. The cycloxygenase-2 (COX2), the epidermal growth factor receptor (EGFR) ligand HB-EGF, and the 2, 6-sialyltransferase (ST6GALNAC5) were identified as mediators in cancer cell extravasation and infiltration through the BBB. The expression of COX-2 and EGFR ligand HB-EGF enhances the extravasation of cancer cells across the capillaries in an in vivo animal model system. The ST6GALNAC5 expression is restricted to the brain both in mice and humans [17]. The knockdown of ST6GALNAC5 reduced the cell passage

2. Tight Junctions and Blood-Brain Barrier Integrity
Most forms of brain injury are associated with BBB disruption, resulting in secondary damage to neural cells. The interendothelial space of the cerebral microvasculature is characterized by the presence of a junctional complex that includes adherens junctions (AJs), tight junctions (TJs) and Gap junctions [8] (see Figure 3). Whereas gap junctions mediate intercellular communication, both AJs and TJs act to restrict the permeability across the endothelium. AJs are ubiquitous in the vasculature and mediate the adhesion of endothelial cells to each other, contact inhibition during vascular growth and remodeling, initiation of cell polarity and partly the regulation of paracellular permeability. The primary component of AJs is VE-cadherin. The TJs are the main components that confer the low paracellular permeability and high electrical resistance. TJs are elaborate structures that span the apical region of the intercellular cleft of endothelial barrier tissues. TJs function both as a \”zipper\” and a \”fence\” that limit paracellular permeability and are composed of transmembrane proteins as primary seals linked via accessory proteins to the actin cytoskeleton. The TJs are composed of a complex of belt-like zonula occludin, which is localized close to the lumen of the capillary. Electrical resistance in vivo across the barrier can increase to approximately 1200 ohm*cm2 or higher due to the TJs. The proteins of the TJs include the junctional adhesion molecules (JAM) (JAM-1, JAM-2 and JAM-3), occludin, the claudins, and zonula occludin proteins (ZO-1 and ZO-2). Interestingly, brain microvascular endothelial cells do not express ZO-3 [8]. The ZO proteins are involved in the coordination and clustering of protein complexes to the cell membrane and in the establishment of specialized domains within

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The \”neurovascular unit\” Neurons * 5-HT * ACh * NE * GABA * Peptides

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