http://www.ncbi.nlm.nih.gov/pubmed/21868710
Am J Respir Cell Mol Biol. 2011 Aug 25. [Epub ahead of print]
Tissue Factor Pathway Inhibitor Attenuates the Progression of Malignant Pleural Mesothelioma in Nude Mice.
Williams L, Tucker TA, Koenig K, Allen T, Rao LV, Pendurthi U, Idell S.
Source
Texas Lung Injury Institute, The University of Texas Health Science Center at Tyler, Tyler, Texas, United States.
Abstract
Malignant pleural mesothelioma (MPM) is a rare cancer that is refractory to current treatments. It is characterized by robust transitional fibrin deposition that is in part promoted by tumor cells. MPM cells express tissue factor (TF) and its inhibitor; tissue factor pathway inhibitor (TFPI), but their contribution to the pathogenesis of MPM has been unclear. We found that REN MPM cells fail to express TFPI. Based on the tumor growth promoting properties of TF, we hypothesized that stable transfection of TFPI into REN MPM cells would decrease their aggressiveness. We tested our hypothesis using in vitro, in vivo and ex vivo analyses. TFPI knock-in decreased proliferation, invasion and TF activity of REN cells in vitro. REN TFPI knock-in cells, empty vector and naïve controls were next injected intrapleurally in nude mice. TFPI expression significantly decreased tissue invasion, inflammation, fibrin and collagen deposition associated with tumor tissues, pleural effusions, and tumor burden. In ex vivo analyses, REN cells were cultured from the harvested tumors. TFPI over-expression was maintained in cells propagated from the TFPI knock-in tumors and attenuated activation of Factor X and tumor cell invasiveness. These analyses demonstrate that TFPI reduces the aggressiveness of MPM in vitro, in vivo and ex vivo and that the effect involves inhibition of TF procoagulant activity. These observations suggest the possibility that the TF-TFPI interaction represents a novel therapeutic target for the treatment of MPM.
No comments:
Post a Comment