title: Tumor-derived tissue factor activates coagulation and enhances thrombosis in a mouse xenograft model of human pancreatic cancer.
abstract: Cancer patients often have an activated clotting system and are at increased risk for venous thrombosis. In the present study, we analyzed tissue factor (TF) expression in 4 different human pancreatic tumor cell lines for the purpose of producing derivative tumors in vivo. We found that 2 of the lines expressed TF and released TF-positive microparticles (MPs) into the culture medium. The majority of TF protein in the culture medium was associated with MPs. Only TF-positive cell lines activated coagulation in nude mice, and this activation was abolished by an anti-human TF Ab. Of the 2 TF-positive lines, only one produced detectable levels of human MP TF activity in the plasma when grown orthotopically in nude mice. Surprisingly, < 5% of human TF protein in plasma from tumor-bearing mice was associated with MPs. Mice with TF-positive tumors and elevated levels of circulating TF-positive MPs had increased thrombosis in a saphenous vein model. In contrast, we observed no difference in thrombus weight between tumor-bearing and control mice in an inferior vena cava stenosis model. The results of the present study using a xenograft mouse model suggest that tumor TF activates coagulation, whereas TF on circulating MPs may trigger venous thrombosis.
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Jian-Guo
authors.initials: JG
authors.lastname: Wang
authors.forename: Julia E
authors.initials: JE
authors.lastname: Geddings
authors.forename: Maria M
authors.initials: MM
authors.lastname: Aleman
authors.forename: Jessica C
authors.initials: JC
authors.lastname: Cardenas
authors.forename: Pichika
authors.initials: P
authors.lastname: Chantrathammachart
authors.forename: Julie C
authors.initials: JC
authors.lastname: Williams
authors.forename: Daniel
authors.initials: D
authors.lastname: Kirchhofer
authors.forename: Vladimir Y
authors.initials: VY
authors.lastname: Bogdanov
authors.forename: Ronald R
authors.initials: RR
authors.lastname: Bach
authors.forename: Janusz
authors.initials: J
authors.lastname: Rak
authors.forename: Frank C
authors.initials: FC
authors.lastname: Church
authors.forename: Alisa S
authors.initials: AS
authors.lastname: Wolberg
authors.forename: Rafal
authors.initials: R
authors.lastname: Pawlinski
authors.forename: Nigel S
authors.initials: NS
authors.lastname: Key
authors.forename: Jen Jen
authors.initials: JJ
authors.lastname: Yeh
authors.forename: Nigel
authors.initials: N
authors.lastname: Mackman
mesh_terms: D000818:Animals; D001777:Blood Coagulation; D045744:Cell Line, Tumor; D055252:Cell-Derived Microparticles / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006487:Hemostasis; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000150:complications* / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D013925:Thromboplastin / Q000235:genetics / Q000378:metabolism*; D020246:Venous Thrombosis / Q000150:complications* / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D013925:Thromboplastin