Predictive value of microparticle-associated tissue factor activity for permeability glycoprotein-mediated multidrug resistance in cancer

Angelini,Antonio; Miscia,Sebastiano; Centurione,Maria  Antonietta; Di Pietro,Roberta; Centurione,Lucia

doi:10.3892/ol.2016.5105

Predictive value of microparticle-associated tissue factor activity for permeability glycoprotein-mediated multidrug resistance in cancer

Authors:
- Antonio Angelini
- Sebastiano Miscia
- Maria Antonietta Centurione
- Roberta Di Pietro
- Lucia Centurione
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Affiliations: Department of Medicine and Aging Science, School of Medicine and Health Science, ‘G. d'Annunzio’ University of Chieti‑Pescara, I‑66013 Chieti, Italy, Institute of Molecular Genetics, National Research Council ‑ Pavia, Chieti Unit, I‑66013 Chieti, Italy
Published online on: September 8, 2016 https://doi.org/10.3892/ol.2016.5105
Pages: 3273-3277
Copyright: © Angelini et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Multidrug resistance (MDR) protein 1, which is also known as permeability glycoprotein (Pgp), and tissue factor (TF) are recurrently overexpressed on the surface of cancer cells, likely in response to stimuli such as chemotherapy. Microparticles (MPs) released from cancer cells into the bloodstream express tumour markers on their surface that may be useful as predictive biomarkers for evaluating disease progression. The present study measured the level of TF/factor VII (FVII)‑dependent coagulation of MPs isolated from the plasma of cancer patients with various tumours, who were undergoing chemotherapy. Furthermore, Pgp expression on the surface of MPs was evaluated by immunohistochemistry. A total of 50 cancer patients, as well as 10 healthy volunteers, were enrolled in the present study. MP‑associated TF/FVII‑dependent coagulation pathways were evaluated as the effect of an anti‑FVII antibody on the time to thrombin generation, as compared with controls treated with saline. The significantly lengthened times of coagulation [obtained in 20/50 samples (36.5 ± 16%) after treatment with anti‑FVIIa when compared with controls] suggest the presence of TF activity is associated with circulating MPs. Furthermore, the 20 MP/TF‑positive samples were associated with Pgp overexpression on their surface. Conversely, in the remaining samples (n=30), treatment with the anti‑FVIIa antibody did not significantly lengthen the time to clotting (<10%), and Pgp overexpression was not detected. In addition, in the control samples from healthy individuals, Pgp expression at the plasma membrane and clotting in the presence of the anti‑FVII antibody were not observed, indicating the absence of MPs. The present study demonstrated that MPs in the blood of cancer patients promoted fibrin generation via TF/FVII‑dependent pathways, thus suggesting that the evaluation of MP‑TF activity may have a predictive value for Pgp‑mediated MDR in various cancer types. Although further studies are required, the measurement of plasma MP‑associated TF activity as a predictive biomarker may provide novel therapeutic perspectives to improve the prognosis and effectiveness of anti‑cancer drugs in patients who are at a high-risk of Pgp-mediated MDR.

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1	Ling V: Multidrug resistance: Molecular mechanism and clinical relevance. Cancer Chemother Pharmacol. 40:(Suppl). S3–S8. 1997. View Article : Google Scholar : PubMed/NCBI
2	Gottesman MM: Mechanisms of cancer drug resistance. Annu Rev Med. 53:615–627. 2002. View Article : Google Scholar : PubMed/NCBI
3	Sauna ZE, Smith MM, Müller M, Kerr KM and Ambudkar SV: The mechanism of action of multigrug-resistance-linked P-glycoprotein. J Bioenerg Biomembr. 33:481–491. 2001. View Article : Google Scholar : PubMed/NCBI
4	Gottesmann MM, Fojo T and Bates SE: Multidrug resistance in cancer: Role of ATP-dependent transporters. Nat Rev Cancer. 2:48–58. 2002. View Article : Google Scholar : PubMed/NCBI
5	Gillet JP and Gottesman MM: Mechanisms of multidrug resistance in cancer. Methods Mol Biol. 596:47–76. 2010. View Article : Google Scholar : PubMed/NCBI
6	Higgins CF: Multiple molecular mechanism for multidrug resistance transporters. Nature. 446:749–757. 2007. View Article : Google Scholar : PubMed/NCBI
7	Ward AB, Szewczyk P, Grimard V, Lee CW, Martinez L, Doshi R, Caya A, Villaluz M, Pardon E, Cregger C, et al: Structures of P-glycoprotein reveal its conformational flexibility and an epitope on the nucleotide-binding domain. Proc Natl Acad Sci USA. 110:13386–13391. 2013. View Article : Google Scholar : PubMed/NCBI
8	Lyman GH, Khorana AA, Kuderer NM, Lee AY, Arcelus JI, Balaban EP, Clarke JM, Flowers CR, Francis CW, Gates LE, et al: American Society of Clinical Oncology Practice: Venous thromboembolism prophilaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 31:2189–2204. 2013. View Article : Google Scholar : PubMed/NCBI
9	Sørensen HT, Mellemkjaer L, Olsen JH and Baron JA: Prognosis of cancers associated with venous thromboembolism. N Engl J Med. 343:1846–1850. 2000. View Article : Google Scholar : PubMed/NCBI
10	Heit JA, Silverstein MD, Mohr DN, Petterson TM, O'Fallon WM and Melton LJ III: Risk factors for deep vein thrombosis and pulmonary embolism: A population based case-control study. Arch Intern Med. 160:809–815. 2000. View Article : Google Scholar : PubMed/NCBI
11	Khorana AA, Francis CW, Culakova E, Kuderer NM and Lyman GH: Frequency, risk factors, and trends for venous thromboembolism among hospitalized cancer patients. Cancer. 110:2339–2346. 2007. View Article : Google Scholar : PubMed/NCBI
12	Beer JH, Haeberli A, Vogt A, Woodtli K, Henkel E, Furrer T and Fey MF: Coagulation markers predict survival in cancer patients. Thromb Haemost. 88:745–749. 2002.PubMed/NCBI
13	Callader NS, Varki N and Rao LV: Immunohistochemical identification of tissue factor in solid tumors. Cancer. 70:1194–1201. 1992. View Article : Google Scholar : PubMed/NCBI
14	Kataoka H, Uchino H, Asada Y, Hatakeyama K, Nabeshima K, Sumivoshi A and Koono M: Analysis of tissue factor and tissue factor pathway inhibitor expression in humanoid colorectal carcinoma cell lines and metastatic sublines to the liver. Int J Cancer. 72:878–884. 1997. View Article : Google Scholar : PubMed/NCBI
15	Uno K, Homma S, Satoh T, Nakanishi K, Abe D, Matsumoto K, Oki A, Tsunoda H, Yamaguchi I, Nagasawa T, et al: Tissue factor expression as a possible determinant of thromboembolism in ovarian cancer. Br J Cancer. 96:290–295. 2007. View Article : Google Scholar : PubMed/NCBI
16	Antoniou D, Pavlakou G, Stathopoulos GP, Karvdis I, Chondrou E, Papageorgiou C, Dariotaki F, Chaimala D and Veslemes M: Predictive value of D-dimer plasma levels in response and progressive disease in patients with lung cancer. Lung Cancer. 53:205–210. 2006. View Article : Google Scholar : PubMed/NCBI
17	Tomimaru Y, Yano M, Takachi K, Kishi K, Miyashiro I, Ohue M, Ohigashi H, Sasaki Y, Ishikawa O and Imaoka S: Correlation between pretreatment d-dimer levels and response to neoadjuvant chemotherapy in patients with advanced esophageal cancer. Dis Esophagus. 21:281–287. 2008. View Article : Google Scholar : PubMed/NCBI
18	Lwaleed BA and Cooper AJ: Tissue factor expression and multidrug resistance in cancer: Two aspects of a common cellular response to a hostile milieu. Med Hypotheses. 55:470–473. 2000. View Article : Google Scholar : PubMed/NCBI
19	Piccin A, Murphy WG and Smith OP: Circulating microparticles: Pathophysiology and clinical implications. Blood Rev. 21:157–171. 2007. View Article : Google Scholar : PubMed/NCBI
20	Hugel B, Martínez MC, Kunzelmann C and Freyssinet JM: Membrane microparticles: Two sides of the coin. Physiology (Bethesda). 20:22–27. 2005. View Article : Google Scholar : PubMed/NCBI
21	Haubold K, Rink M, Spath B, Friedrich M, Chun FK, Marx G, Amirkhosravi A, Francis JL, Bokemeyer C, Eifrig B and Langer F: Tissue factor procoagulant activity of plasma microparticles is increased in patients with early-stage prostate cancer. Thromb Haemost. 101:1147–1155. 2009.PubMed/NCBI
22	Hron G, Kollars M, Weber H, Sagaster V, Quehenberger P, Eichinger S, Kyrle PA and Welterman A: Tissue factor-positive microparticles: Cellular origin and association with coagulation activation in patients with colorectal cancer. Thromb Haemost. 97:119–123. 2007.PubMed/NCBI
23	Zwicker JI, Kos CA, Johnston KA, Liebman HA, Furie BC and Furie B: OC-06 tissue factor-bearing microparticles are associated with an increased risk of venous thromboembolic events in cancer patients. Thromb Res. 120:(Suppl). S1432007. View Article : Google Scholar
24	Zwicker JI, Liebman HA, Neuberg D, Lacroix R, Bauer KA, Furie BC and Furie B: Tumor-derived tissue factor-bearing microparticles are associated with venous thromboembolic events in malignancy. Clin Cancer Res. 15:6830–6840. 2009. View Article : Google Scholar : PubMed/NCBI
25	Manly DA, Wang J, Glover SL, Kasthuri R, Liebman HA, Key NS and Mackman N: Increased microparticle tissue factor activity in cancer patients with venous thromboembolism. Thromb Res. 125:511–512. 2010. View Article : Google Scholar : PubMed/NCBI
26	Lechner D and Weltermann A: Circulating tissue factor-exposing microparticules. Thromb Res. 122(Suppl 1): S42–S54. 2008.PubMed/NCBI
27	Thaler J, Ay C, Mackman N, Bertina RM, Kaider A, Marosi C, Key NS, Barcel DA, Scheithauer W, Kornek G, et al: Microparticle-associated tissue factor activity, venous thromboembolism and mortality in pancreatic, gastric, colorectal and brain cancer patients. J Thromb Haemost. 10:1363–1370. 2012. View Article : Google Scholar : PubMed/NCBI
28	Thaler J, Ay C, Mackman N, Metz-Schimmerl S, Stift J, Kaider A, Müllauer L, Gnant M, Scheithauer W and Pabinger I: Microparticle-associated tissue factor activity in patients with pancreatic cancer: Correlation with clinicopathological features. Eur J Clin Invest. 43:277–285. 2013. View Article : Google Scholar : PubMed/NCBI
29	Bharthuar A, Khorana AA, Hutson A, Wang JG, Key NS, Mackman N and Iyer R: Circulating microparticle tissue factor, thromboembolism and survival in pancreaticobiliary cancers. Thromb Res. 132:180–184. 2013. View Article : Google Scholar : PubMed/NCBI
30	Tesselaar ME, Romijn FP, Van Der Linden IK, Prins FA, Bertina RM and Osanto S: Microparticle-associated tissue factor activity: A link between cancer and thrombosis? J Thromb Haemost. 5:520–527. 2007. View Article : Google Scholar : PubMed/NCBI
31	Nitori N, Ino Y, Nakanishi Y, Yamada T, Honda K, Yanagihara K, Kosuge T, Kanai Y, Kitajima M and Hirohashi S: Prognostic significance of tissue factor in pancreatic ductal adenocarcinoma. Clin Cancer Res. 11:2531–2539. 2005. View Article : Google Scholar : PubMed/NCBI
32	Angelini A, Di Pietro R, Centurione L, Castellani ML, Conti P, Porreca E and Cuccurullo F: Inhibition of P-glycoprotein-mediated transport by S-adenosylmethionine and cynarin in multidrug-resistant human uterine sarcoma MES-SA/Dx5 cells. J Biol Regul Homeost Agents. 26:495–504. 2012.PubMed/NCBI
33	Angelini A, Centurione L, Sancilio S, Castellani ML, Conti P, Di Ilio C, Porreca E, Cuccurullo F and Di Pietro R: The effect of the plasticizer diethylhexyl phthalate on transport activity and expression of P-glycoprotein in parental and doxo-resistant human sarcoma cell lines. J Biol Regul Homeost Agents. 25:203–211. 2011.PubMed/NCBI