%0 Journal Article
%T Secretion of extracellular hsp90¦Á via exosomes increases cancer cell motility: a role for plasminogen activation
%A Jessica McCready
%A Jessica D Sims
%A Doug Chan
%A Daniel G Jay
%J BMC Cancer
%D 2010
%I BioMed Central
%R 10.1186/1471-2407-10-294
%X We analyzed the morphology and motility of invasive cancer cells that were treated with exogenous exosomes in the presence or absence of hsp90¦Á. We performed mass spectrometry and immunoprecipitation to identify plasminogen as a potential client protein of extracellular hsp90¦Á. Plasmin activation assays and migration assays were performed to test if plasminogen is activated by extracellular hsp90¦Á and has a role in migration.We found that hsp90¦Á is secreted in exosomes in invasive cancer cells and it contributes to their invasive nature. We identified a novel interaction between hsp90¦Á and tissue plasminogen activator that together with annexin II, also found in exosomes, activates plasmin. Extracellular hsp90¦Á promotes plasmin activation as well as increases plasmin dependent cell motility.Our data indicate that hsp90¦Á is released by invasive cancer cells via exosomes and implicates hsp90¦Á in activating plasmin, a second protease that acts in cancer cell invasion.Approximately 90% of cancer deaths are not from the primary tumor but due to metastasis to distant sites [1]. Current treatments do not target metastatic disease. Towards developing anti-metastasis drugs, a functional proteomic screen was performed to identify surface proteins required for tumor cell invasion, the first step in metastasis [2]. One of the proteins identified was the molecular chaperone heat shock protein 90¦Á (hsp90¦Á) [2]. Intracellular hsp90¦Á aids in the folding, assembly-disassembly and activation of a variety of client proteins including kinases, steroid hormone receptors and transcription factors [3]. We discovered that extracellular hsp90¦Á acts in tumor cell invasion through its activation of the pro-invasive protein matrix metalloproteinase-2 (MMP-2). Since the publication of this study, additional reports in the literature have demonstrated the importance of extracellular hsp90¦Á in both physiological and pathological states. Extracellular hsp90¦Á is required for both dermal fibroblast
%U http://www.biomedcentral.com/1471-2407/10/294