Evidence for a Proangiogenic Activity of TNF-Related Apoptosis-Inducing Ligand

Abstract

Starting from the observation that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/Apo-2L protein is expressed in both malignant and inflammatory cells in some highly vascularized soft tissue sarcomas, the angiogenic potential of TRAIL was investigated in a series of in vitro assays. Recombinant soluble TRAIL induced endothelial cell migration and vessel tube formation to a degree comparable to vascular endothelial growth factor (VEGF), one of the best-characterized angiogenic factors. However, the proangiogenic activity of TRAIL was not mediated by endogenous expression of VEGF. Although TRAIL potentiated VEGF-induced extracellular signal-regulated kinase (ERK) phosphorylation and endothelial cell proliferation, the combination of TRAIL + VEGF did not show additive effects with respect to VEGF alone in inducing vessel tube formation. Thus, although TRAIL has gained attention as a potential anticancer therapeutic for its ability to induce apoptosis in a variety of cancer cells, our present data suggest that TRAIL might also play an unexpected role in promoting angiogenesis, which might have therapeutic implications.

TRAIL inhibits angiogenesis stimulated by VEGF expression in human glioblastoma cells

“…Thus, the apparent discrepancy of ours with other data demonstrating a mitogenic effect of TRAIL upon human endothelial cells (Secchiero et al, 2004) could be explained on the basis of the significantly lower (about 10-fold; 10 ng ml À1 ) concentrations used.…”

Death Receptors and Cognate Ligands in Cancer

“…Very recently, in vitro promotion of migration and invasion was reported for apoptosis-resistant cholangiocarcinoma cells and was explained to be a consequence of TRAIL-induced activation of NF-kappaB (Ishimura et al, 2006). Moreover, a proinflammatory, growth stimulating as well as proangiogenic activity of TRAIL was also demonstrated (Begue et al, 2006;Li et al, 2003;Morel et al, 2005;Secchiero et al, 2004). Similar to TRAIL, agonistic anti-TRAIL-R antibodies are also able to strongly induce nonapoptotic signaling at least in PDAC cells (our unpublished data).…”

Following a TRAIL: Update on a ligand and its five receptors

“…Some research suggests a role in the deletion of B-cells [65], and another study describes TRAIL as a negative regulator of erythropoesis [66], although no anaemia was observed in TRAIL -/-mice [47]. New evidence that TRAIL can exhibit potent proangiogenic properties, along with the anti-tumourigenicity heavily discussed, suggests a Jekyll and Hyde persona for TRAIL [67].…”