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Blood, Vol. 92 No. 10 (November 15), 1998:
pp. 3694-3700
Protease-Activated Receptor 1 (PAR-1) Is Required and
Rate-Limiting for Thrombin-Enhanced Experimental Pulmonary
Metastasis
Mary Lynn Nierodzik,
Kui Chen,
Kenichi Takeshita,
Jian-Jun Li,
Yao-Qi Huang,
Xue-Sheng Feng,
Michael R. D'Andrea,
Patricia Andrade-Gordon, and
Simon Karpatkin
From the New York University Medical Center and Kaplan Cancer Center,
New York, NY; the Department of Veterans Affairs Medical Center, New
York, NY; and the R.W. Johnson Pharmaceutical Research Institute,
Spring House, PA.
Thrombin-treated tumor cells induce a metastatic phenotype in
experimental pulmonary murine metastasis. Thrombin binds to a unique
protease-activated receptor (PAR-1) that requires N-terminal proteolytic cleavage for activation by its tethered end. A 14-mer thrombin receptor activation peptide (TRAP) of the tethered end induces
the same cellular changes as thrombin. Four murine tumor cells (Lewis
lung, CT26 colon CA, B16F10 melanoma, and CCL163 fibroblasts) contain
PAR-1, as detected by reverse transcriptase-polymerase chain reaction
(RT-PCR). B16F10 cells did not contain the two other
thrombin receptors, PAR-3 and glycoprotein Ib. TRAP-treated B16F10
tumor cells enhance pulmonary metastasis 41- to 48-fold (n = 17).
Thrombin-treated B16F10 cells transfected with full-length murine PAR-1
sense cDNA (S6, S7, S14, and S22) enhanced their adhesion to
fibronectin 1.5- to 2.4-fold (n = 5, P < .04), whereas thrombin-treated wild-type cells do not. S6 (adhesion index, 1.5-fold) and S14 (index, 2.4-fold) when examined by RT-PCR and Northern analysis
showed minimal expression of PAR-1 for S6 over wild-type and
considerable expression for S14. Immunohistochemistry showed greater
expression of PAR-1 for S14 compared with wild-type or empty-plasmid
transfected cells. In vivo experiments with the thrombin-treated S14
transfectant showed a fivefold to sixfold increase in metastases
compared with empty-plasmid transfected thrombin-treated naive cells or
S6 cells (n = 20, P = .0001 to .02). Antisense
had no effect on thrombin-stimulated tumor mass. Thus, PAR-1 ligation
and expression enhances and regulates tumor metastasis.
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