title: Thrombin Activity and Thrombin Receptor in Rat Glioblastoma Model: Possible Markers and Targets for Intervention?
abstract: High-grade gliomas constitute a group of aggressive CNS cancers that have high morbidity and mortality rates. Despite extensive research, current therapeutic approaches enable survival beyond 2 years in rare cases only. Thrombin and its main CNS target, protease-activated receptor-1, have been implicated in tumor progression and brain edema. Our aim was to study protease-activated receptor-1 (PAR-1) protein expression and thrombin-like activity levels in both in vitro and in vivo models of glioblastoma and correlate them with the volume of the surrounding edema. We measured the presence of PAR-1 protein using fluorescence immunohistochemistry and assessed thrombin activity in various glial and non-glial cell lines and in a CNS-1 glioma rat model using a thrombin-specific fluorescent assay. Thrombin activity was found to be highly elevated in various high-grade glioma cell lines as well as in non-glial malignant cell lines. In the CNS-1 glioma model, the level of PAR-1 fluorescence in the tumor was significantly elevated compared to adjacent regions of reactive gliosis or distant brain areas. The elevated level of thrombin activity observed in the high-grade glioma positively correlated with tumor-induced brain edema. In conclusion, thrombin is secreted from glioma cells and PAR-1 may be a new biological marker for high-grade gliomas.
authors.affiliation: Department of Neurosurgery, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel, zeevits@gmail.com.
authors.forename: Ze'ev
authors.initials: Z
authors.lastname: Itsekson-Hayosh
authors.forename: Efrat
authors.initials: E
authors.lastname: Shavit-Stein
authors.forename: David
authors.initials: D
authors.lastname: Last
authors.forename: David
authors.initials: D
authors.lastname: Goez
authors.forename: Dianne
authors.initials: D
authors.lastname: Daniels
authors.forename: Doron
authors.initials: D
authors.lastname: Bushi
authors.forename: Orna
authors.initials: O
authors.lastname: Gera
authors.forename: Zion
authors.initials: Z
authors.lastname: Zibly
authors.forename: Yael
authors.initials: Y
authors.lastname: Mardor
authors.forename: Joab
authors.initials: J
authors.lastname: Chapman
authors.forename: Sagi
authors.initials: S
authors.lastname: Harnof
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology; D008297:Male; D009457:Neuroglia / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D044463:Receptor, PAR-1 / Q000378:metabolism*; D013917:Thrombin / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D044463:Receptor, PAR-1; D013917:Thrombin