Secretion of extracellular hsp90alpha via exosomes increases cancer cell motility: a role for plasminogen activation.
BACKGROUND
Metastasis is a multi-step process that is responsible for the majority of deaths in cancer patients. Current treatments are not effective in targeting metastasis. The molecular chaperone hsp90alpha is secreted from invasive cancer cells and activates MMP-2 to enhance invasiveness, required for the first step in metastasis.


METHODS
We analyzed the morphology and motility of invasive cancer cells that were treated with exogenous exosomes in the presence or absence of hsp90alpha. We performed mass spectrometry and immunoprecipitation to identify plasminogen as a potential client protein of extracellular hsp90alpha. Plasmin activation assays and migration assays were performed to test if plasminogen is activated by extracellular hsp90alpha and has a role in migration.


RESULTS
We found that hsp90alpha is secreted in exosomes in invasive cancer cells and it contributes to their invasive nature. We identified a novel interaction between hsp90alpha and tissue plasminogen activator that together with annexin II, also found in exosomes, activates plasmin. Extracellular hsp90alpha promotes plasmin activation as well as increases plasmin dependent cell motility.


CONCLUSIONS
Our data indicate that hsp90alpha is released by invasive cancer cells via exosomes and implicates hsp90alpha in activating plasmin, a second protease that acts in cancer cell invasion.
McCready
Jessica
J
Department of Physiology, Tufts University, 136 Harrison Ave, Boston, MA 02111, USA.
Sims
Jessica D
JD
Chan
Doug
D
Jay
Daniel G
DG
D045744:Cell Line, Tumor; D002465:Cell Movement; D048430:Cell Shape; D004789:Enzyme Activation; D055354:Exosomes / Q000201:enzymology / Q000378:metabolism*; D005341:Fibrinolysin / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D013058:Mass Spectrometry; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010958:Plasminogen / Q000378:metabolism*; D011485:Protein Binding; D034622:RNA Interference; D010959:Tissue Plasminogen Activator / Q000378:metabolism*
D018841:HSP90 Heat-Shock Proteins; C533585:HSP90AA2P protein, human; D010958:Plasminogen; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin