Secretion of Extracellular Hsp90alpha Via Exosomes Increases Cancer Cell Motility: a Role for Plasminogen Activation

Overview

Journal BMC Cancer

Publisher Biomed Central

Specialty Oncology

Date 2010 Jun 18

PMID 20553606

Citations 167

Authors

Jessica McCready

Jessica D Sims

Doug Chan

Daniel G Jay

Affiliations

Soon will be listed here.

Abstract

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.

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References

Stellas D, Karameris A, Patsavoudi E . Monoclonal antibody 4C5 immunostains human melanomas and inhibits melanoma cell invasion and metastasis. Clin Cancer Res. 2007; 13(6):1831-8. DOI: 10.1158/1078-0432.CCR-06-1585. View

Whitesell L, Lindquist S . HSP90 and the chaperoning of cancer. Nat Rev Cancer. 2005; 5(10):761-72. DOI: 10.1038/nrc1716. View

Thery C, Zitvogel L, Amigorena S . Exosomes: composition, biogenesis and function. Nat Rev Immunol. 2002; 2(8):569-79. DOI: 10.1038/nri855. View

Cheng C, Fan J, Fedesco M, Guan S, Li Y, Bandyopadhyay B . Transforming growth factor alpha (TGFalpha)-stimulated secretion of HSP90alpha: using the receptor LRP-1/CD91 to promote human skin cell migration against a TGFbeta-rich environment during wound healing. Mol Cell Biol. 2008; 28(10):3344-58. PMC: 2423165. DOI: 10.1128/MCB.01287-07. View

Clayton A, Turkes A, Navabi H, Mason M, Tabi Z . Induction of heat shock proteins in B-cell exosomes. J Cell Sci. 2005; 118(Pt 16):3631-8. DOI: 10.1242/jcs.02494. View

Sidera K, Gaitanou M, Stellas D, Matsas R, Patsavoudi E . A critical role for HSP90 in cancer cell invasion involves interaction with the extracellular domain of HER-2. J Biol Chem. 2007; 283(4):2031-41. DOI: 10.1074/jbc.M701803200. View

Lei H, Venkatakrishnan A, Yu S, Kazlauskas A . Protein kinase A-dependent translocation of Hsp90 alpha impairs endothelial nitric-oxide synthase activity in high glucose and diabetes. J Biol Chem. 2007; 282(13):9364-9371. DOI: 10.1074/jbc.M608985200. View

Al-Nedawi K, Meehan B, Micallef J, Lhotak V, May L, Guha A . Intercellular transfer of the oncogenic receptor EGFRvIII by microvesicles derived from tumour cells. Nat Cell Biol. 2008; 10(5):619-24. DOI: 10.1038/ncb1725. View

Lei H, Romeo G, Kazlauskas A . Heat shock protein 90alpha-dependent translocation of annexin II to the surface of endothelial cells modulates plasmin activity in the diabetic rat aorta. Circ Res. 2004; 94(7):902-9. DOI: 10.1161/01.RES.0000124979.46214.E3. View

10.

Mears R, Craven R, Hanrahan S, Totty N, Upton C, Young S . Proteomic analysis of melanoma-derived exosomes by two-dimensional polyacrylamide gel electrophoresis and mass spectrometry. Proteomics. 2004; 4(12):4019-31. DOI: 10.1002/pmic.200400876. View

11.

Savina A, Furlan M, Vidal M, Colombo M . Exosome release is regulated by a calcium-dependent mechanism in K562 cells. J Biol Chem. 2003; 278(22):20083-90. DOI: 10.1074/jbc.M301642200. View

12.

Hegmans J, Bard M, Hemmes A, Luider T, Kleijmeer M, Prins J . Proteomic analysis of exosomes secreted by human mesothelioma cells. Am J Pathol. 2004; 164(5):1807-15. PMC: 1615654. DOI: 10.1016/S0002-9440(10)63739-X. View

13.

Mai J, Waisman D, Sloane B . Cell surface complex of cathepsin B/annexin II tetramer in malignant progression. Biochim Biophys Acta. 2000; 1477(1-2):215-30. DOI: 10.1016/s0167-4838(99)00274-5. View

14.

Yu X, Harris S, Levine A . The regulation of exosome secretion: a novel function of the p53 protein. Cancer Res. 2006; 66(9):4795-801. DOI: 10.1158/0008-5472.CAN-05-4579. View

15.

Eustace B, Sakurai T, Stewart J, Yimlamai D, Unger C, Zehetmeier C . Functional proteomic screens reveal an essential extracellular role for hsp90 alpha in cancer cell invasiveness. Nat Cell Biol. 2004; 6(6):507-14. DOI: 10.1038/ncb1131. View

16.

Becker B, Multhoff G, Farkas B, Wild P, Landthaler M, Stolz W . Induction of Hsp90 protein expression in malignant melanomas and melanoma metastases. Exp Dermatol. 2004; 13(1):27-32. DOI: 10.1111/j.0906-6705.2004.00114.x. View

17.

Daquinag A, Fadri M, Jung S, Qin J, Kunz J . The yeast PH domain proteins Slm1 and Slm2 are targets of sphingolipid signaling during the response to heat stress. Mol Cell Biol. 2006; 27(2):633-50. PMC: 1800798. DOI: 10.1128/MCB.00461-06. View

18.

Stefansson S, Lawrence D . The serpin PAI-1 inhibits cell migration by blocking integrin alpha V beta 3 binding to vitronectin. Nature. 1996; 383(6599):441-3. DOI: 10.1038/383441a0. View

19.

Sidera K, Samiotaki M, Yfanti E, Panayotou G, Patsavoudi E . Involvement of cell surface HSP90 in cell migration reveals a novel role in the developing nervous system. J Biol Chem. 2004; 279(44):45379-88. DOI: 10.1074/jbc.M405486200. View

20.

Li W, Li Y, Guan S, Fan J, Cheng C, Bright A . Extracellular heat shock protein-90alpha: linking hypoxia to skin cell motility and wound healing. EMBO J. 2007; 26(5):1221-33. PMC: 1817627. DOI: 10.1038/sj.emboj.7601579. View