Tumour
necrosis factor (TNF) is a multi-functional
cytokine with profound and diverse effects on physiology and pathology. Identifying the molecular determinants underlying the functions and pathogenic effects of TNF is key to understanding its mechanisms of action and identifying new therapeutic opportunities based on this important molecule. Previously, we showed that some evolutionarily conserved
peptides derived from TNF could induce cell death (e.g. apoptosis and/or
necrosis), a feature of immune defence mechanisms shared by many vertebrates. In this study, we demonstrated that
necrosis-inducing
peptide P16 kills human
glioblastoma cancer cells and primary human
hepatoma or
renal cancer cells isolated from patients who had not responded to standard treatments. Importantly, we show that the
necrosis-inducing
peptide P1516 significantly improves survival by inhibiting tumour
metastasis in a 4T1
breast cancer syngeneic graft mouse model. Because the lymphatic system is an important metastatic route in many
cancers, we also tested the effect of TNF-derived
peptides on monolayers of primary human lymphatic endothelial cells (hDLEC) and found that they increased junctional permeability by inducing cytoskeletal reorganization, gap junction formation and cell death. Transmission electron microscopy imaging evidence, structural analysis and in-vitro
liposome leakage experiments strongly suggest that this killing is due to the cytolytic nature of these
peptides. P1516 provides another example of a pro-cytotoxic TNF
peptide that probably functions as a cryptic necrotic factor released by TNF degradation. Its ability to inhibit tumour
metastasis and improve survival may form the basis of a novel approach to
cancer therapy.