Blocking Neuron Migration and Cancer-It's All the RAGE

Abstract

Amphoterin, a protein found in the extracellular matrix, is required for proper cortical neuron growth in brain development. Amphoterin is a ligand for RAGE, a transmembrane protein found at the growing edge of neurites. Because activated RAGE is important for neurite migration, it is possible that RAGE signaling is also important for aberrant invasion and metastasis in brain cancer. Taguchi et al. find that blocking RAGE activation leads to the suppression of tumor growth and metastases in mice. Injection of C6 glioma cells expressing various forms of RAGE into mice showed that overexpression of full-length RAGE greatly increased tumor size compared with injection of mock-transfected cells. RAGE inhibition also led to decreased C6 glioma cell proliferation and treatment of C6 glioma cells with soluble RAGE or RAGE-specific antibody suppressed cellular invasion in vitro. Also, treatment of C6 glioma cells with the cytoplasmic tail-deleted RAGE or with soluble RAGE blocked p42/p44 MAPK, p38 MAPK, and Jun N-terminal kinase (JNK) activation, suggesting that the potential activation of three separate MAPK signal pathways is important for tumor invasion. A news & views article by Liotta and Clair discuss the implications of the results.Taguchi, A., Blood, D.C., del Toro, G., Canet, A., Lee, D.C., Qu, W., Tanji, N., Lu, Y., Lalla, E., Fu, C., Hofmann, M.A., Kislinger, T., Ingram, M., Lu, A., Tanaka, H., Hori, O., Ogawa, S., Stern, D.M., and Schmidt, A.M. (2000) Blockade of RAGE-amphoterin signalling suppresses tumour growth and metastases. Nature 405: 354-360. [Online Journal]Liotta, L.A., and Clair, T. (2000) Cancer: Checkpoint for invasion. Nature 405: 287-288. [Online Journal]