Endothelial protein C receptor expressed by ovarian cancer cells as a possible biomarker of cancer onset

Ducros,Elodie; Mirshahi,Shahsoltan; Azzazene,Dalel; Camilleri-Broët,Sophie; Mery,Eliane; Al Farsi,Halema; Althawadi,Hamda; Besbess,Samaher; Chidiac,Jean; Pujade-Lauraine,Eric; Therwath,Amu; Soria,Jeannette; Mirshahi,Massoud

doi:10.3892/ijo.2012.1492

Endothelial protein C receptor expressed by ovarian cancer cells as a possible biomarker of cancer onset

Authors:
- Elodie Ducros
- Shahsoltan Mirshahi
- Dalel Azzazene
- Sophie Camilleri-Broët
- Eliane Mery
- Halema Al Farsi
- Hamda Althawadi
- Samaher Besbess
- Jean Chidiac
- Eric Pujade-Lauraine
- Amu Therwath
- Jeannette Soria
- Massoud Mirshahi
View Affiliations

Affiliations: National Institute for Medical Research (INSERM), Cordeliers Research Center (UMRS 872), University of Pierre and Marie Curie, Sorbonne University (UPMC) and University of Paris Descartes, Paris, France, Diagnostica Stago, Gennevilliers, France, Claudius Regaud Institute, Toulouse, France, Hôtel-Dieu Hospital, Paris, France
Published online on: May 18, 2012 https://doi.org/10.3892/ijo.2012.1492
Pages: 433-440
Copyright: © Ducros et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Coagulation disorders often accompany cancer onset and evolution, which, if not properly managed, could have grave consequences. Endothelial protein C is an important regulator of homeostasis and acts through its high affinity binding to its transmembrane receptor (EPCR). Soluble (sEPCR) which results from the proteolytic cleavage of the membrane bound form can trap activated endothelial protein C and deprive it of its anti-coagulant function. In this study, the expression of EPCR and its soluble form (sEPCR) released into plasma as a result of proteolytic cleavage were investigated in ovarian, breast, lung and colorectal cancer biopsies, as well as in ascitic cell clusters and peritoneal fluid from ovarian cancer samples. In parallel, breast, ovarian, lung and colorectal cancer cell lines were investigated for the expression of EPCR. The integrity of the EPCR gene sequence as well gene haplotypes were ascertained in the established cancer cell lines in order to understand their eventual regulatory functions. The results from the present study indicate that in cancer patients, the levels of sEPCR are significantly higher than the normal range compared to healthy volunteers. The increase in the levels of sEPCR parallels the increase in CA125, showing a close correlation. Therefore, the detection of sEPCR in cancer and during the post-treatment period could be taken into account as an additional marker that could re-inforce the one obtained using CA125 alone as a marker of cancer cell mass.

View Figures

View References

1	Dahlbäck B and Villoutreix BO: Molecular recognition in the protein C anticoagulant pathway. J Thromb Haemost. 1:1525–1534. 2003.
2	Li W, Zheng X, Gu J, Hunter J, Ferrell GL, Lupu F, Esmon NL and Esmon CT: Overexpressing endothelial cell protein C receptor alters the hemostatic balance and protects mice from endotoxin. J Thromb Haemost. 3:1351–1359. 2005. View Article : Google Scholar : PubMed/NCBI
3	Taylor FB Jr, Peer GT, Lockhart MS, Ferrell G and Esmon CT: Endothelial cell protein C receptor plays an important role in protein C activation in vivo. Blood. 97:1685–1688. 2001. View Article : Google Scholar : PubMed/NCBI
4	Fukudome K and Esmon CT: Identification, cloning, and regulation of a novel endothelial cell protein C/activated protein C receptor. J Biol Chem. 269:26486–26491. 1994.PubMed/NCBI
5	Xu J, Qu D, Esmon NL and Esmon CT: Metalloproteolytic release of endothelial cell protein C receptor. J Biol Chem. 275:6038–6044. 2000. View Article : Google Scholar : PubMed/NCBI
6	Fukudome K, Kurosawa S, Stearns-Kurosawa DJ, He X, Rezaie AR and Esmon CT: The endothelial cell protein C receptor. Cell surface expression and direct ligand binding by the soluble receptor. J Biol Chem. 271:17491–17498. 1996. View Article : Google Scholar : PubMed/NCBI
7	Menschikowski M, Hagelgans A, Eisenhofer G and Siegert G: Regulation of endothelial protein C receptor shedding by cytokines is mediated through differential activation of MAP kinase signaling pathways. Exp Cell Res. 315:2673–2682. 2009. View Article : Google Scholar
8	Guitton C, Gérard N, Sébille V, Bretonnière C, Zambon O, Villers D and Charreau B: Early rise in circulating endothelial protein C receptor correlates with poor outcome in severe sepsis. Intensive Care Med. 37:950–956. 2011. View Article : Google Scholar : PubMed/NCBI
9	Esmon CT: Possible involvement of cytokines in diffuse intravascular coagulation and thrombosis. Baillieres Best Pract Res Clin Haematol. 12:343–359. 1999. View Article : Google Scholar : PubMed/NCBI
10	Pintao MC, Roshani S, de Visser MC, Tieken C, Tanck MW, Wichers IM, Meijers JC, Rosendaal FR, Middeldorp S and Reitsma PH: High levels of protein C are determined by PROCR haplotype 3. J Thromb Haemost. 9:969–976. 2011. View Article : Google Scholar : PubMed/NCBI
11	Saposnik B, Reny JL, Gaussem P, Emmerich J, Aiach M and Gandrille S: A haplotype of the EPCR gene is associated with increased plasma levels of sEPCR and is a candidate risk factor for thrombosis. Blood. 103:1311–1318. 2004. View Article : Google Scholar : PubMed/NCBI
12	Qu D, Wang Y, Song Y, Esmon NL and Esmon CT: The Ser219 −>Gly dimorphism of the endothelial protein C receptor contributes to the higher soluble protein levels observed in individuals with the A3 haplotype. J Thromb Haemost. 4:229–235. 2006.
13	Tsuneyoshi N, Fukudome K, Horiguchi S, Ye X, Matsuzaki M, Toi M, Suzuki K and Kimoto M: Expression and anticoagulant function of the endothelial cell protein C receptor (EPCR) in cancer cell lines. Thromb Haemost. 85:356–361. 2001.PubMed/NCBI
14	Wang X, Wang E, Kavanagh JJ and Freedman RS: Ovarian cancer, the coagulation pathway, and inflammation. J Transl Med. 3:252005. View Article : Google Scholar : PubMed/NCBI
15	Scheffer GL, Flens MJ, Hageman S, Izquierdo MA, Shoemaker RH and Scheper RJ: Expression of the vascular endothelial cell protein C receptor in epithelial tumour cells. Eur J Cancer. 38:1535–1542. 2002.PubMed/NCBI
16	Beaulieu LM and Church FC: Activated protein C promotes breast cancer cell migration through interactions with EPCR and PAR-1. Exp Cell Res. 313:677–687. 2007. View Article : Google Scholar : PubMed/NCBI
17	Ducros E, Berthaut A, Mirshahi SS, Faussat AM, Soria J, Agarwal MK and Mirshahi M: Aldosterone modifies hemostasis via upregulation of the protein-C receptor in human vascular endothelium. Biochem Biophys Res Commun. 373:192–196. 2008. View Article : Google Scholar : PubMed/NCBI
18	Rafii A, Mirshahi P, Poupot M, Faussat AM, Simon A, Ducros E, Mery E, Couderc B, Lis R, Capdet J, Bergalet J, Querleu D, Dagonnet F, Fournié JJ, Marie JP, Pujade-Lauraine E, Favre G, Soria J and Mirshahi M: Oncologic trogocytosis of original stromal cells induces chemoresistance of ovarian tumours. PLoS One. 3:e38942008. View Article : Google Scholar : PubMed/NCBI
19	Cheng T, Liu D, Griffin JH, Fernández JA, Castellino F, Rosen ED, Fukudome K and Zlokovic BV: Activated protein C blocks p53-mediated apoptosis in ischemic human brain endothelium and is neuroprotective. Nat Med. 9:338–342. 2003. View Article : Google Scholar : PubMed/NCBI
20	Mosnier LO, Zlokovic BV and Griffin JH: The cytoprotective protein C pathway. Blood. 109:3161–3172. 2007. View Article : Google Scholar : PubMed/NCBI
21	Suzuki K and Hayashi T: Protein C and its inhibitor in malignancy. Semin Thromb Hemost. 33:667–672. 2007. View Article : Google Scholar : PubMed/NCBI
22	Uchiba M, Okajima K, Oike Y, Ito Y, Fukudome K, Isobe H and Suda T: Activated protein C induces endothelial cell proliferation by mitogen-activated protein kinase activation in vitro and angiogenesis in vivo. Circ Res. 95:34–41. 2004. View Article : Google Scholar : PubMed/NCBI
23	Kobayashi H, Moniwa N, Gotoh J, Sugimura M and Terao T: Role of activated protein C in facilitating basement membrane invasion by tumor cells. Cancer Res. 54:261–267. 1994.PubMed/NCBI
24	Uitte de Willige S, Van Marion V, Rosendaal FR, Vos HL, de Visser MC and Bertina RM: Haplotypes of the EPCR gene, plasma sEPCR levels and the risk of deep venous thrombosis. J Thromb Haemost. 2:1305–1310. 2004.PubMed/NCBI