Inhibition of cancer invasion and metastasis by targeting the molecular chaperone heat-shock protein 90.

Heat-shock protein 90 (Hsp90) is a molecular chaperone required for the stability and function of numerous oncogenic signaling proteins that determine the hallmarks of cancer. Receptor tyrosine kinases (RTKs) and hypoxia-inducible factor-1 (HIF-1)-mediated pathways, commonly activated in aggressive cancer, potentiate each other and thus efficiently promote cancer invasion and metastasis. Hsp90 inhibitors, by interacting specifically with a single molecule, Hsp90, cause the destabilization and eventual degradation of multiple Hsp90 client proteins. These agents impede the cellular processes involved in cancer invasion and metastasis by simultaneously impairing multiple Hsp90-dependent signaling proteins including HIF-1alpha, most RTKs and their hub mediators Src, Raf-1 and Akt. Recently, a fraction of Hsp90 identified on the cell surface has been found to play a crucial role in cancer invasion and metastasis. The first-in-class Hsp90 inhibitor, 17-allylamino-17-demethoxy-geldanamycin, is currently in phase II clinical trials. The potential utility and problems of Hsp90 inhibitors in clinical settings are discussed. A fuller understanding of the roles of Hsp90 in cancer biology and accumulating clinical data on Hsp90 inhibitors will guide us toward the goal of optimizing the use of these agents in the clinic.