Tissue Factor Pathway Inhibitor Attenuates the Progression of Malignant Pleural Mesothelioma in Nude Mice

LaTerrica Williams, Torry A. Tucker, Kathy Koenig, Timothy Allen, L. Vijaya Mohan Rao, Usha Pendurthi, Steven Idell

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Malignant pleural mesothelioma (MPM) is a rare cancer that is refractory to current treatments. It is characterized by a robust deposition of transitional fibrin that is in part promoted by tumor cells.MPMcells express tissue factor (TF) and the 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 the 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 the proliferation, invasion, and TF activity of REN cells in vitro. REN TFPI knock-in cells, empty vector, and naive control cells were next injected intrapleurally into nude mice. The expression of TFPI significantly decreased tissue invasion, inflammation, and the deposition of fibrin and collagen associated with tumor tissue, pleural effusions, and tumor burden. In ex vivo analyses, REN cells were cultured from harvested tumors. The overexpression of TFPI was maintained in cells propagated from TFPI knock-in tumors, and attenuated the activation of Factor X and the invasiveness of tumor cells. These analyses demonstrate that TFPI reduces the aggressiveness of MPM in vitro and in vivo, and that its effect involves the inhibition of TF procoagulant activity. These observations suggest that the interactions of TF and TFPI represent a novel therapeutic target in the treatment of MPM.

Original languageEnglish (US)
Pages (from-to)173-179
Number of pages7
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Volume46
Issue number2
DOIs
StatePublished - Feb 1 2012
Externally publishedYes

Fingerprint

Nude Mice
Tumors
Thromboplastin
Neoplasms
Fibrin
Cells
Malignant Mesothelioma
lipoprotein-associated coagulation inhibitor
Tissue
Factor X
Pleural Effusion
Tumor Burden
Refractory materials
Transfection
Cultured Cells
Collagen
Chemical activation
Inflammation
Growth

Keywords

  • Invasion
  • Malignant pleural mesothelioma
  • Proliferation
  • Tissue factor pathway inhibitor
  • Tumorigenesis

ASJC Scopus subject areas

  • Cell Biology
  • Pulmonary and Respiratory Medicine
  • Molecular Biology
  • Clinical Biochemistry

Cite this

Tissue Factor Pathway Inhibitor Attenuates the Progression of Malignant Pleural Mesothelioma in Nude Mice. / Williams, LaTerrica; Tucker, Torry A.; Koenig, Kathy; Allen, Timothy; Rao, L. Vijaya Mohan; Pendurthi, Usha; Idell, Steven.

In: American Journal of Respiratory Cell and Molecular Biology, Vol. 46, No. 2, 01.02.2012, p. 173-179.

Research output: Contribution to journalArticle

Williams, LaTerrica ; Tucker, Torry A. ; Koenig, Kathy ; Allen, Timothy ; Rao, L. Vijaya Mohan ; Pendurthi, Usha ; Idell, Steven. / Tissue Factor Pathway Inhibitor Attenuates the Progression of Malignant Pleural Mesothelioma in Nude Mice. In: American Journal of Respiratory Cell and Molecular Biology. 2012 ; Vol. 46, No. 2. pp. 173-179.
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