title: Thrombomodulin modulates growth of tumor cells independent of its anticoagulant activity.
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.
authors.affiliation: Department of Medicine and Anesthesiology, University of Heidelberg, 69115 Heidelberg, Germany.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: H
authors.initials: H
authors.lastname: Weiler-Guettler
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.forename: O
authors.initials: O
authors.lastname: Wilhelm
authors.forename: Y
authors.initials: Y
authors.lastname: Deng
authors.forename: F
authors.initials: F
authors.lastname: Qiu
authors.forename: K
authors.initials: K
authors.lastname: Nakagawa
authors.forename: M
authors.initials: M
authors.lastname: Klevesath
authors.forename: S
authors.initials: S
authors.lastname: Wilhelm
authors.forename: H
authors.initials: H
authors.lastname: Böhrer
authors.forename: M
authors.initials: M
authors.lastname: Nakagawa
authors.forename: H
authors.initials: H
authors.lastname: Graeff
authors.forename: E
authors.initials: E
authors.lastname: Martin
authors.forename: D M
authors.initials: DM
authors.lastname: Stern
authors.forename: R D
authors.initials: RD
authors.lastname: Rosenberg
authors.forename: R
authors.initials: R
authors.lastname: Ziegler
authors.forename: P P
authors.initials: PP
authors.lastname: Nawroth
mesh_terms: D000818:Animals; D002455:Cell Division; D006131:Growth Inhibitors / Q000502:physiology*; D006801:Humans; D008545:Melanoma / Q000473:pathology*; D051379:Mice; D011486:Protein C / Q000502:physiology; D018179:Receptors, Thrombin / Q000378:metabolism; D011994:Recombinant Proteins; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000378:metabolism; D018180:Thrombomodulin / Q000502:physiology*; D014407:Tumor Cells, Cultured
chemical_list: D006131:Growth Inhibitors; D011486:Protein C; D018179:Receptors, Thrombin; D011994:Recombinant Proteins; D018180:Thrombomodulin; D013917:Thrombin