title: Predictive value of microparticle-associated tissue factor activity for permeability glycoprotein-mediated multidrug resistance in cancer.
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.
authors.affiliation: Department of Medicine and Aging Science, School of Medicine and Health Science, 'G. d'Annunzio' University of Chieti-Pescara, I-66013 Chieti, Italy; Research Center on Aging and Translational Medicine (Ce.S.I Met), 'G. d'Annunzio' University of Chieti-Pescara, I-66013 Chieti, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Angelini
authors.affiliation: Department of Medicine and Aging Science, School of Medicine and Health Science, 'G. d'Annunzio' University of Chieti-Pescara, I-66013 Chieti, Italy; Research Center on Aging and Translational Medicine (Ce.S.I Met), 'G. d'Annunzio' University of Chieti-Pescara, I-66013 Chieti, Italy.
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Miscia
authors.affiliation: Institute of Molecular Genetics, National Research Council - Pavia, Chieti Unit, I-66013 Chieti, Italy.
authors.forename: Maria Antonietta
authors.initials: MA
authors.lastname: Centurione
authors.affiliation: Department of Medicine and Aging Science, School of Medicine and Health Science, 'G. d'Annunzio' University of Chieti-Pescara, I-66013 Chieti, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Di Pietro
authors.affiliation: Department of Medicine and Aging Science, School of Medicine and Health Science, 'G. d'Annunzio' University of Chieti-Pescara, I-66013 Chieti, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Centurione
keywords: P-glycoprotein; microparticles; multidrug resistance; tissue factor