Brain Vascular Microenvironments in Cancer Metastasis

Abstract

Primary tumours, particularly from major solid organs, are able to disseminate into the blood and lymphatic system and spread to distant sites. These secondary metastases to other major organs are the most lethal aspect of cancer, accounting for the majority of cancer deaths. The brain is a frequent site of metastasis, and brain metastases are often fatal due to the critical role of the nervous system and the limited options for treatment, including surgery. This creates a need to further understand the complex cell and molecular biology associated with the establishment of brain metastasis, including the changes to the environment of the brain to enable the arrival and growth of tumour cells. Local changes in the vascular network, immune system and stromal components all have the potential to recruit and foster metastatic tumour cells. This review summarises our current understanding of brain vascular microenvironments, fluid circulation and drainage in the context of brain metastases, as well as commenting on current cutting-edge experimental approaches used to investigate changes in vascular environments and alterations in specialised subsets of blood and lymphatic vessel cells during cancer spread to the brain.

Keywords: blood vessels; brain; leptomeninges; lymphatic vessels; metastasis; microenvironment; stroma.

Figure 2

Characterised mechanisms of pre-metastatic niche formation in the brain. (A)—Primary tumours secrete soluble factors and extracellular vesicles (EVs) into circulation, which subsequently act on the vascular microenvironments of receptive distant organs to generate pre-metastatic niches. (B)—In mouse non-small cell lung cancer (NSCLC) tumours, extensive conditioning by TGF-β1 leads to EV production with increased levels of lnc-MMP2-2 [90]. (C)—Top: NSCLC EVs release lnc-MMP2-2 into endothelial cells of the blood–brain barrier, sequestering miR-1207-5p, a suppressor of EPB41L5. Elevated EPB41L5 causes decreased VE-cadherin and claudin-5 expression and increased N-cadherin expression, leading to EndoMT and increased vascular permeability [91,92,93,94]. NSCLC EVs also induce secretion of Dkk-1 by brain endothelial cells, contributing to suppression of pro-inflammatory microglia and increases in tumorigenic microglia, thus promoting an immunosuppressive microenvironment [96]. Bottom: Mouse breast cancer EVs containing high levels of miR-122 suppress glucose uptake by astrocytes by downregulating pyruvate kinase (PKM2) and glucose transport channel GLUT-1. This increases extracellular glucose in the pre-metastatic niche, thereby enhancing glucose availability for tumour cells [97].

Figure 3

Different modes of metastatic colonisation in brain parenchyma and leptomeninges. (A)—Metastatic colonisation of the brain adapted from Kienast et al. [98]: (1) Vascular arrest of cancer cells at narrowing capillaries, and extravasation into the perivascular space. (2) Cells obtain a perivascular position on the abluminal surface of the blood vessels in order to survive and proliferate. (3) Lung carcinoma cells induce marked angiogenesis, attracting an extensive vascular supply and proliferate quickly as a result. In contrast, melanoma cells proliferate along existing blood vessels via vascular co-option in a much slower fashion. (4) Melanoma cells form a growing tumour mass in close association with the existing blood vessels. (5) Tumour overgrowth may lead to vascular damage and bleeding. (B)—Leptomeningeal disease. Circulating tumour cells in the CSF of the subarachnoid space are thought to arise from non-adherent tumour cells and exhibit increased aerobic respiration, Krebs cycle and decreased ATP consumption compared to adherent leptomeningeal metastases. These tumour cells also show increased binding of iron through the LCN2/SLC22A17 signalling cascade. This allows them to outcompete monocytes for iron, resulting in decreased respiratory burst and phagocytosis [109,110].

Figure 1

(A)—Coronal cross-section of brain arterial supply (left), sagittal cross-section of brain arterial supply (middle), sagittal view of brain venous system (right). (B)—2D roadmap of blood and fluid circulation within the brain. The Aorta gives rise to the vertebral and carotid arteries, where at the circle of Willis, smaller parenchymal (anterior, middle and posterior cerebral arteries) and meningeal arteries branch off to supply different regions of the brain. Parenchymal arteries branch into arterioles and further into capillaries, all of which display blood–brain barrier (BBB) phenotypes. Capillaries coalesce into post capillary venules, which go on to form larger veins. Veins in the brain drain into the dural sinuses situated in the meninges, where molecules are sampled by the meningeal lymphatics before draining into the jugular veins. Importantly, blood vessels within the Dura are fenestrated, and thus lack the abundance of tight junctions typical of endothelial cells of the BBB. The cerebrospinal fluid (CSF) fluid flow, also referred to as the glymphatic system, begins with the production of CSF from fenestrated capillaries (no BBB) of the choroid plexus into the ventricles. CSF flows from the ventricles to the sub-arachnoid spaces, and further into Virchow–Robin and perivascular spaces which form between the basement membrane layers of endothelium and surrounding astrocytes. Virchow–Robin spaces are sites of fluid exchange between the interstitial fluid (ISF) of the parenchyma and the CSF space. The nasal lymphatic system receives drainage from the CSF space, and together with the meningeal lymphatics, drains into the cervical lymph nodes. Red arrows indicate arterial blood flow, blue indicates venous blood flow, green arrows indicate “glymphatic flow” which includes lymphatic fluid, CSF, and ISF. (C)—Coronal view of the surface of the cortex. The three meningeal layers are located between the parenchyma and skull, with the most superficial layer being the dura mater, followed by the arachnoid mater, sub-arachnoid space and finally, the pia mater. The dura mater contains a recently discovered network of lymphatic vessels and the sub-arachnoid space is host to a complex network of veins and arteries at the cortical–meningeal surface. The Neurovascular unit is comprised of select cells creating a tightly regulated system of molecular transport between the blood and the parenchyma (BBB). Endothelial cells are adhered to each other via tight junctions and are surrounded by endothelial basement membrane (BM). Pericytes and astrocytic foot processes further encapsulate the endothelial cells, anchored through an astrocytic basement membrane. (D)—Fluid flow within the choroid plexus. Ependymal cells of the choroid plexus create a blood–CSF barrier due to the presence of tight junctions. Passage of fluid extravasated from the fenestrated capillaries within the choroid plexus into the CSF space is regulated via transport through aquaporins such as AQP1.