Abstract
BackgroundArrest of metastasising lung cancer cells to the brain microvasculature maybe mediated by interactions between ligands on circulating tumour cells and endothelial E-selectin adhesion molecules; a process likely to be regulated by the endothelial glycocalyx. Using human cerebral microvascular endothelial cells and non-small cell lung cancer (NSCLC) cell lines, we describe how factors secreted by NSCLC cells i.e. cystatin C, cathepsin L, insulin-like growth factor-binding protein 7 (IGFBP7), vascular endothelial growth factor (VEGF) and tumour necrosis factor-alpha (TNF-α), damage the glycocalyx and enhance initial contacts between lung tumour and cerebral endothelial cells.MethodsEndothelial cells were treated with tumour secreted-proteins or lung tumour conditioned medium (CM). Surface levels of E-selectin were quantified by ELISA. Adhesion of A549 and SK-MES-1 cells was examined under flow conditions (1 dyne/cm2). Alterations in the endothelial glycocalyx were quantified by binding of fluorescein isothiocyanate-linked wheat germ agglutinin (WGA-FITC).ResultsA549 and SK-MES-1 CM and secreted-proteins significantly enhanced endothelial surface E-selectin levels after 30 min and 4 h and tumour cell adhesion after 30 min, 4 and 24 h. Both coincided with significant glycocalyx degradation; A549 and SK-MES-1 CM removing 55 ± 12 % and 58 ± 18.7 % of WGA-FITC binding, respectively. Inhibition of E-selectin binding by monoclonal anti-E-selectin antibody completely attenuated tumour cell adhesion.ConclusionThese data suggest that metastasising lung cancer cells facilitate their own adhesion to the brain endothelium by secreting factors that damage the endothelial glycocalyx, resulting in exposure of the previously shielded adhesion molecules and engagement of the E-selectin-mediated adhesion axis.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-015-0223-9) contains supplementary material, which is available to authorized users.
Highlights
Brain metastases arising from primary lung cancer contribute significantly to the morbidity and mortality of the disease
Lung cancer cells secrete a range of factors with a potential role in mediating brain metastasis Initially, mass spectrometry (MS) was used to screen the secretome of A549 and SK-MES-1 cells for the presence of metastasisrelated proteins
In health the length of glycocalyx components often exceeds that of the endothelial adhesion molecules, we investigated whether factors secreted from lung tumour cells could induce the rapid loss of cerebral endothelial glycocalyx; exposing the previously shielded adhesion molecules and facilitating adhesion
Summary
Brain metastases arising from primary lung cancer contribute significantly to the morbidity and mortality of the disease These tumours present a challenging clinical scenario since they are generally resistant to conventional chemotherapy due to the inability of these drugs to cross the blood–brain barrier (BBB) [1]. In order to form metastases, tumour cells must successfully complete a sequence of key, inter-related steps initiated by extensive proliferation of the primary tumour cells and their invasion of the surrounding extracellular matrix (ECM). These malignant cells dissociate from the primary site, intravasate the circulation and form tumour microemboli, which eventually arrest along the microvasculature of a target organ. Using human cerebral microvascular endothelial cells and non-small cell lung cancer (NSCLC) cell lines, we describe how factors secreted by NSCLC cells i.e. cystatin C, cathepsin L, insulin-like growth factor-binding protein 7 (IGFBP7), vascular endothelial growth factor (VEGF) and tumour necrosis factor-alpha (TNF-α), damage the glycocalyx and enhance initial contacts between lung tumour and cerebral endothelial cells
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
