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Research Article Free access | 10.1172/JCI925

Thrombomodulin modulates growth of tumor cells independent of its anticoagulant activity.

Y Zhang, H Weiler-Guettler, J Chen, O Wilhelm, Y Deng, F Qiu, K Nakagawa, M Klevesath, S Wilhelm, H Böhrer, M Nakagawa, H Graeff, E Martin, D M Stern, R D Rosenberg, R Ziegler, and P P Nawroth

Department of Medicine and Anesthesiology, University of Heidelberg, 69115 Heidelberg, Germany.

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Department of Medicine and Anesthesiology, University of Heidelberg, 69115 Heidelberg, Germany.

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Department of Medicine and Anesthesiology, University of Heidelberg, 69115 Heidelberg, Germany.

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Department of Medicine and Anesthesiology, University of Heidelberg, 69115 Heidelberg, Germany.

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Department of Medicine and Anesthesiology, University of Heidelberg, 69115 Heidelberg, Germany.

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Department of Medicine and Anesthesiology, University of Heidelberg, 69115 Heidelberg, Germany.

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Department of Medicine and Anesthesiology, University of Heidelberg, 69115 Heidelberg, Germany.

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Department of Medicine and Anesthesiology, University of Heidelberg, 69115 Heidelberg, Germany.

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Department of Medicine and Anesthesiology, University of Heidelberg, 69115 Heidelberg, Germany.

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Department of Medicine and Anesthesiology, University of Heidelberg, 69115 Heidelberg, Germany.

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Department of Medicine and Anesthesiology, University of Heidelberg, 69115 Heidelberg, Germany.

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Department of Medicine and Anesthesiology, University of Heidelberg, 69115 Heidelberg, Germany.

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Department of Medicine and Anesthesiology, University of Heidelberg, 69115 Heidelberg, Germany.

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Department of Medicine and Anesthesiology, University of Heidelberg, 69115 Heidelberg, Germany.

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Department of Medicine and Anesthesiology, University of Heidelberg, 69115 Heidelberg, Germany.

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Department of Medicine and Anesthesiology, University of Heidelberg, 69115 Heidelberg, Germany.

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Department of Medicine and Anesthesiology, University of Heidelberg, 69115 Heidelberg, Germany.

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Published April 1, 1998 - More info

Published in Volume 101, Issue 7 on April 1, 1998
J Clin Invest. 1998;101(7):1301–1309. https://doi.org/10.1172/JCI925.
© 1998 The American Society for Clinical Investigation
Published April 1, 1998 - Version history
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Abstract

Thrombomodulin (TM), recognized as an essential vessel wall cofactor of the antithrombotic mechanism, is also expressed by a wide range of tumor cells. Tumor cell lines subcloned from four patients with malignant melanoma displayed a negative correlation between TM expression and cell proliferation in vitro and in vivo. Overexpression of wild-type TM decreased cell proliferation in vitro and tumor growth in vivo. TM mutants with altered protein C activation capacity lead to a similar effect. In contrast, transfection of melanoma cells with mutant TM constructs, in which a portion of the cytoplasmic or lectin domain was deleted, abrogated the antiproliferative effect associated with overexpression of wild-type TM. Experiments performed with either peptide agonists/antagonists of the thrombin receptor, with hirudin, or with inhibitors of thrombin-TM interaction did not alter the growth inhibitory effect of TM overexpression. These data suggest that TM exerts an effect on cell proliferation independent of thrombin and the thrombin receptor, possibly related to the binding of novel ligands to determinants in the lectin domain which might trigger signal transduction pathways dependent on the cytoplasmic domain.

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