Secretion of extracellular hsp90α via exosomes increases cancer cell motility: a role for plasminogen activation

We analyzed the morphology and motility of invasive cancer cells that were treated with exogenous exosomes in the presence or absence of hsp90α. We performed mass spectrometry and immunoprecipitation to identify plasminogen as a potential client protein of extracellular hsp90α. Plasmin activation assays and migration assays were performed to test if plasminogen is activated by extracellular hsp90α and has a role in migration.We found that hsp90α is secreted in exosomes in invasive cancer cells and it contributes to their invasive nature. We identified a novel interaction between hsp90α and tissue plasminogen activator that together with annexin II, also found in exosomes, activates plasmin. Extracellular hsp90α promotes plasmin activation as well as increases plasmin dependent cell motility.Our data indicate that hsp90α is released by invasive cancer cells via exosomes and implicates hsp90α 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 90α (hsp90α) [2]. Intracellular hsp90α 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 hsp90α 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 hsp90α in both physiological and pathological states. Extracellular hsp90α is required for both dermal fibroblast