No abstract

The importance of the tumor microenvironment in targeted anticancer therapies has been well recognized. Various protein factors participate in the cross-talk between tumor cells and non-malignant cells. Anterior gradient-2 (AGR2) is overexpressed in diverse human adenocarcinomas and it exists in both intracellular and extracellular spaces. Although intracellular AGR2 has been intensively investigated, the function of secreted AGR2, especially its exact mechanism of action is still poorly understood. Here we report that the secreted AGR2 promotes the angiogenesis and the invasion of vascular endothelial cells and fibroblasts by enhancing the activities of vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF2). Further study indicated that AGR2 directly binds to these extracellular signaling molecules, and enhances their homodimerization. The extracellular AGR2 activity can be blocked to reduce angiogenesis and inhibit tumor growth in vitro and in vivo by a monoclonal antibody targeting the AGR2 self-dimerization region, and combined treatment with bevacizumab produced maximum inhibition effect. In conclusion, our investigation reveals a mechanism that directly links the secreted AGR2 with extracellular signaling networks, and we propose that the secreted AGR2 is a blockable molecular target, which acts as a chaperon-like enhancer to VEGF and FGF2.

Ultrasonic welding is attracting increasing attentions in joining of dissimilar materials. The effect of welding energy on joint strength, failure behaviour and microstructure of Al-Cu ultrasonic welded joint has been experimentally investigated. The results showed that joint strength increased with welding energy initially and reached its maximum at 1000 J, then dropped significantly instead. Meanwhile, the failure mode changed from interfacial debonding to nugget pullout, and then back to cleavage failure. Various microstructures with different morphologies and properties were also observed at the interfacial region. At lower energy, the joint was only partly bonded by numbers of dispersed microbonds. A swirl-like structure appeared at the weld interface and led to a mechanical interlocking between the materials at higher energies (y1000 J). However, cavity defects and intermetallic compound (IMC) were more likely to form under excessively high energies. A 0?5 mm thick IMC layer with dominant phase of Al 4 Cu 9 was found in 2000 J joint.