Abstract
PurposeMetastatic non-small cell lung (NSCLC) cancer represents one of the most common types of brain metastasis. The mechanisms involved in how circulating cancer cells transmigrate into brain parenchyma are not fully understood. The aim of this work was to investigate the role of fucosylated carbohydrate epitopes CD15 and sialyated CD15s in cancer adhesion to brain-derived endothelial cells and determine their influence in blood–brain barrier (BBB) disruptionMethodsThree distinct, independent methods were used to measure brain endothelial integrity and include voltohmmeter (EVOM™), impedance spectroscopy (CellZscope®) and electric cell-substrate impedance sensing system (ECIS™). Two fucosyltransferases (FUT4 and 7) responsible for CD15 and CD15s synthesis were modulated in four human cancer cell lines (three lung cancer and one glioma).ResultsOverexpression of CD15 or CD15s epitopes led to increase in adhesion of cancer cells to cerebral endothelial cells compared with wild-type and cells with silenced CD15 or CD15s (p < 0.01). This overexpression led to the disruption of cerebral endothelial cell monolayers (p < 0.01). Knockdown of FUT4 and FUT7 in metastatic cancer cells prevented disruption of an in vitro BBB model. Surprisingly, although the cells characterised as ‘non-metastatic’, they became ‘metastatic’ -like when cells were forced to over-express either FUT4 or FUT7.ConclusionsResults from these studies suggest that overexpression of CD15 and CD15s could potentiate the transmigration of circulating NSCLC cells into the brain. The clinical significance of these studies includes the possible use of these epitopes as biomarkers for metastasis.
Highlights
The majority of intracranial tumours are secondary metastases originating from primary non-central nervous system cancers. 20–40% of patients with systemic cancers develop secondary brain tumours [1, 2]
The central nervous system (CNS) is considered a site of refuge as cancers are protected from most systemic therapies by the blood–brain barrier (BBB)
Brain vascular endothelial cells are specific to the BBB with low pinocytosis and no fenestrations [6] and these cells may play a crucial role in the homing process of brain metastasis from breast cancer [7] and melanoma [8]
Summary
The majority of intracranial tumours are secondary metastases originating from primary non-central nervous system (non-CNS) cancers. 20–40% of patients with systemic cancers develop secondary brain tumours [1, 2]. Brain vascular endothelial cells are specific to the BBB with low pinocytosis and no fenestrations [6] and these cells may play a crucial role in the homing process of brain metastasis from breast cancer [7] and melanoma [8]. To gain a better understanding on the role of CD15 and CD15s in lung cancer metastasis to the brain, two fucosyltransferases, FUT4 and 7, responsible for their corresponding synthesis were genetically modulated in non-small cell lung cancer cells. The effect of these genetically modified cells on endothelial cell adhesion and on integrity of an in vitro BBB model was evaluated
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