Secretion of Heat Shock Protein-90 (Hsp90) by Normal Cells Under Stress or by Tumor Cells During Invasion: Why?

Until recently, heat shock protein 90 (Hsp90) has been mostly known as an intracellular ATP-dependent chaperone with more than 100 clients that often play a critical role in various branches of the intracellular signaling networks. Based on Hsp90's reported protecting role higher in cancer cells than that in normal cells, chemical inhibitors targeting Hsp90's ATPase function are currently in a number of clinical trials as anti-tumor drugs. However, emerging results of studies from the past few years have clearly unveiled a surprising need for cells to secrete Hsp90 to extracellular environment under either pathological conditions or stress. Outside the cells, Hsp90 has been shown to chaperone extracellular peptide antigens to antigen-presenting cells (APC), to act as a tumor-specific antigen, to stimulate cell growth and motility and to promote tumor invasion and metastasis. The mechanisms of Hsp90's extracellular action have also begun to be appreciated with its extracellular binding targets being identified. More intriguingly, unlike conventional growth factors, Hsp90α-induced cell migration is refractory to the anti-motility effect of TGF-β family cytokines, which otherwise has to be made ineffective in tumor cells by mutating key TGF-β signaling components. These latest observations have not only re-raised an old question of why Mother Nature keeps the amount of Hsp90 unusually abundant in all cells, but also hint reasons for why Hsp90, rather than conventional growth factors, is chosen to carry out those extracellular growth factor-like functions. In this review, we summarize the key findings of the studies and offer our humble interpretations. [ABSTRACT FROM AUTHOR]