Blockade of RAGE-amphoterin signalling suppresses tumour growth and metastases

The receptor for advanced glycation end products (RAGE), a multi-ligand mem ber of the immunoglobulin superfamily of cell surface molecules(1-2), inter acts with distinct molecules implicated in homeostasis, development and inf lammation, and certain diseases such as diabetes and Alzheimer's disease(3- 8). Engagement of RAGE by a ligand triggers activation of key cell signalli ng pathways, such as p21(ras), MAP kinases, NF-kappa B and cdc42/rac, there by reprogramming cellular properties(9-11). RAGE is a central cell surface receptor for amphoterin, a polypeptide linked to outgrowth of cultured cort ical neurons derived from developing brain(3,12-15). Indeed, the co-localiz ation of RAGE and amphoterin at the leading edge of advancing neurites indi cated their potential contribution to cellular migration, and in pathologie s such as tumour invasion. Here we demonstrate that blockade of RAGE-amphot erin decreased growth and metastases of both implanted tumours and tumours developing spontaneously in susceptible mice. Inhibition of the RAGE-amphot erin interaction suppressed activation of p44/p42, p38 and SAP/JNK MAP kina ses; molecular effector mechanisms importantly linked to tumour proliferati on, invasion and expression of matrix metalloproteinases(16-23).