title: Promotion of experimental thrombus formation by the procoagulant activity of breast cancer cells.
abstract: The routine observation of tumor emboli in the peripheral blood of patients with carcinomas raises questions about the clinical relevance of these circulating tumor cells. Thrombosis is a common clinical manifestation of cancer, and circulating tumor cells may play a pathogenetic role in this process. The presence of coagulation-associated molecules on cancer cells has been described, but the mechanisms by which circulating tumor cells augment or alter coagulation remains unclear. In this study we utilized suspensions of a metastatic adenocarcinoma cell line, MDA-MB-231, and a non-metastatic breast epithelial cell line, MCF-10A, as models of circulating tumor cells to determine the thrombogenic activity of these blood-foreign cells. In human plasma, both metastatic MDA-MB-231 cells and non-metastatic MCF-10A cells significantly enhanced clotting kinetics. The effect of MDA-MB-231 and MCF-10A cells on clotting times was cell number-dependent and inhibited by a neutralizing antibody to tissue factor (TF) as well as inhibitors of activated factor X and thrombin. Using fluorescence microscopy, we found that both MDA-MB-231 and MCF-10A cells supported the binding of fluorescently labeled thrombin. Furthermore, in a model of thrombus formation under pressure-driven flow, MDA-MB-231 and MCF-10A cells significantly decreased the time to occlusion. Our findings indicate that the presence of breast epithelial cells in blood can stimulate coagulation in a TF-dependent manner, suggesting that tumor cells that enter the circulation may promote the formation of occlusive thrombi under shear flow conditions.
authors.affiliation: Department of Biomedical Engineering, School of Medicine, Oregon Health & Science University, 3303 SW Bond Ave, Portland, OR 97239, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Berny-Lang
authors.forename: J E
authors.initials: JE
authors.lastname: Aslan
authors.forename: G W
authors.initials: GW
authors.lastname: Tormoen
authors.forename: I A
authors.initials: IA
authors.lastname: Patel
authors.forename: P E
authors.initials: PE
authors.lastname: Bock
authors.forename: A
authors.initials: A
authors.lastname: Gruber
authors.forename: O J T
authors.initials: OJ
authors.lastname: McCarty
mesh_terms: D000230:Adenocarcinoma / Q000150:complications*; D001777:Blood Coagulation; D001943:Breast Neoplasms / Q000150:complications* / Q000556:secondary*; D002460:Cell Line; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D013927:Thrombosis / Q000209:etiology*