CD44v4 Is a Major E-Selectin Ligand that Mediates Breast Cancer Cell Transendothelial Migration

BACKGROUND: Endothelial E-selectin has been shown to play a pivotal role in mediating cell-cell interactions between breast cancer cells and endothelial monolayers during tumor cell metastasis. However, the counterreceptor for E-selectin and its role in mediating breast cancer cell transendothelial migration remain unknown. METHODOLOGY/PRINCIPAL FINDINGS: By assessing migration of various breast cancer cells across TNF-alpha pre-activated human umbilical vein endothelial cells (HUVECs), we found that breast cancer cells migrated across HUVEC monolayers differentially and that transmigration was E-selectin dependent. Cell surface labeling with the E-selectin extracellular domain/Fc chimera (exE-selectin/Fc) showed that the transmigration capacity of breast cancer cells was correlated to both the expression level and localization pattern of E-selectin binding protein(s) on the tumor cell surface. The exE-selectin/Fc strongly bound to metastatic MDA-MB-231, MDA-MB-435 and MDA-MB-468 cells, but not non-metastatic MCF-7 and T47D cells. Binding of exE-selectin/Fc was abolished by removal of tumor cell surface sialyl lewis x (sLe(x)) moieties. Employing an exE-selectin/Fc affinity column, we further purified the counterreceptor of E-selectin from metastatic breast cancer cells. The N-terminal protein sequence and cDNA sequence identified this E-selectin ligand as a approximately 170 kD human CD44 variant 4 (CD44v4). Purified CD44v4 showed a high affinity for E-selectin via sLe(x) moieties and, as expected, MDA-MB-231 cell adhesion to and migration across HUVEC monolayers were significantly reduced by down-regulation of tumor cell CD44v4 via CD44v4-specific siRNA. CONCLUSIONS/SIGNIFICANCE: We demonstrated, for the first time, that breast cancer cell CD44v4 is a major E-selectin ligand in facilitating tumor cell migration across endothelial monolayers. This finding offers new insights into the molecular basis of E-selectin-dependent adhesive interactions that mediate breast cancer cell transendothelial metastasis

State of the Art on Alternative Fuels in Aviation. Executive summary

This paper summarises the findings from the SWAFEA preliminary state of the art study. It covers trends in aspects of future air transport, potential candidate fuels and associated feedstock along with sustainability and economical issues relevant for alternative fuels in aviation.

State of the Art on Alternative Fuels in Aviation. SWAFEA. Sustainable Way for Alternative Fuels and Energy in Aviation.

Currently, the aviation sector uses petroleum derived liquid fuels as the energy carrier of choice for flight. In light the present environmental, economical and political concerns as to the sustainability of this energy source, the question of which alternatives the aviation sector should pursue in the future has emerged. Among these concerns, the environmental impact of fossil fuel use on global warming and air quality is of major importance, while the impact of volatile oil prices and the need for a sustainable supply of fuel are strong drivers for the economies of fuel users. In this context, the European Commission’s Directorate General for Energy and Transport has initiated the SWAFEA study to investigate the feasibility and the impact of the use of alternative fuels in aviation. SWAFEA’s goal is to develop a comparative analysis of different energy/fuel options on the basis of an assessment of the available data. It also seeks to create a vision and possible roadmap for future deployments of alternative fuels and, in this regard, SWAFEA will provide policy makers with information and decision elements. This paper summarises the findings from the SWAFEA preliminary state of the art studyii. It covers trends in aspects of future air transport, potential candidate fuels and associated feedstock along with sustainability and economical issues relevant for alternative fuels in aviation