title: PO-14 - Tumour expression of coagulation proteases of the aPC pathway - a role in the pathogenesis of gynaecological cancers?
abstract: BACKGROUND
  The close relationship between coagulation, thrombosis and cancer has long been established. Gynaecological cancers, in particular ovarian cancers, carry a high risk of thrombosis but coagulation activation is also thought to play a role in tumorigenesis and metastasis. In experimental animal models of metastasis, mice with a genetic procoagulant phenotype are prone to develop metastasis and anticoagulant therapy dramatically reduces pulmonary metastasis in these models. The aPC pathway is a key natural anticoagulant pathway, in addition to its role in venous thrombosis, dysregulation of this pathway is also thought to play a role in the pathogenesis of some cancers. No data exists in ovarian and endometrial cancers.
  
  
  OBJECTIVE
  The aim of this study is to determine the expression of key proteins of the activated protein C pathway in endometrial and ovarian malignant tumours compared to benign tumours and to assess their role in patient survival.
  
  
  METHODS
  RNA was extracted from 78 (54 malignant and 24 benign) fresh frozen ovarian and endometrial tumours samples. Tumour biopsies were mRNA expression of endothelial protein C receptor (EPCR), protein S (PS), protein C (PC), thrombomodulin (TM), Factor V (FV) and VIII (FVIII) and PAR-1 and PAR-2 was measured using TaqMan Low Density Arrays. mRNA fold change relative to benign expression was determined using the 2 -delta delta Ct method with 18s as internal standard. All patients gave full and informed consent and the study had the approval of the hospital ethics committee. Total cell protein was extracted from ovarian tumour tissue. Enzyme-linked immunosorbent assay (ELISA) was used to measure protein plasma expression
  
  
  RESULTS
  EPCR (P<0.001), protein S (P<0.0001) and Factor VIII (P<0.003) mRNA expression was significantly downregulated in malignant tumours compared with benign. Factor V and PAR-2 were significantly upregulated (P<0.001; P<0.004). Protein C was not consistently expressed. Reduced EPCR and TM protein expression was also observed in malignant tumours with increased plasma levels of Factor V. Reduced protein S and increased FV were associated with decreased survival. Plasma levels of Factor V were related to grade in the endometrial cancer group. PAR-2 mRNA expression was increased in ovarian tumours (P<0.001) however PAR-1 expression remained unchanged.
  
  
  CONCLUSIONS
  Our results show reduced expression of key proteins associated with activation of protein C combined with increased expression in FV in gynaecological malignancies. These changes may contribute to local thrombin production and tumour progression and metastasis. Further work is required to determine the precise mechanisms involved.
authors.affiliation: Coagulation Research Laboratory, Dept of Obstetrics and Gynaecology, Trinity College Dublin.
authors.forename: F
authors.initials: F
authors.lastname: Martin
authors.affiliation: Coagulation Research Laboratory, Dept of Obstetrics and Gynaecology, Trinity College Dublin.
authors.forename: J C
authors.initials: JC
authors.lastname: Long
authors.affiliation: Coagulation Research Laboratory, Dept of Obstetrics and Gynaecology, Trinity College Dublin; Dept of Histopathology, Trinity College Dublin.
authors.forename: S A
authors.initials: SA
authors.lastname: O'Toole
authors.affiliation: Dept of Histopathology, Trinity College Dublin.
authors.forename: J J
authors.initials: JJ
authors.lastname: O'Leary
authors.affiliation: Dept of Gynae-onocology, St. James's Hospital; Dublin, Ireland.
authors.forename: F
authors.initials: F
authors.lastname: Abu Saadeh
authors.affiliation: Dept of Gynae-onocology, St. James's Hospital; Dublin, Ireland.
authors.forename: N
authors.initials: N
authors.lastname: Gleeson
authors.affiliation: Coagulation Research Laboratory, Dept of Obstetrics and Gynaecology, Trinity College Dublin.
authors.forename: L A
authors.initials: LA
authors.lastname: Norris