title: Thrombomodulin is a determinant of metastasis through a mechanism linked to the thrombin binding domain but not the lectin-like domain.
abstract: Thrombomodulin (TM) is a predominantly endothelial transmembrane glycoprotein that modulates hemostatic function through a domain that controls thrombin-mediated proteolysis and an N-terminal lectin-like domain that controls inflammatory processes. To test the hypothesis that TM is a determinant of malignancy and dissect the importance of these functional domains in cancer biology, metastatic potential was evaluated in TM(Pro) mice expressing a mutant form of TM with reduced thrombin affinity and TM(LeD) mice lacking the N-terminal lectin-like domain. Studies of TM(Pro) mice revealed that TM is a powerful determinant of hematogenous metastasis. TM(Pro) mice exhibited a strongly prometastatic phenotype relative to control mice that was found to result from increased survival of tumor cells newly localized to the lung rather than any alteration in tumor growth. The impact of the TM(Pro) mutation on metastasis was dependent on both tumor cell-associated tissue factor and thrombin procoagulant function. In contrast, expression of a mutant form of TM lacking the lectin-like domain had no significant impact on metastasis. These studies directly demonstrate for the first time that TM-mediated regulation of tumor cell-driven procoagulant function strongly influences metastatic potential and suggest that endothelial cell-associated modulators of hemostasis may represent novel therapeutic targets in limiting tumor dissemination.
authors.affiliation: Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Netanel A
authors.initials: NA
authors.lastname: Horowitz
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Blevins
authors.forename: Whitney M
authors.initials: WM
authors.lastname: Miller
authors.forename: Ashley R
authors.initials: AR
authors.lastname: Perry
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Talmage
authors.forename: Eric S
authors.initials: ES
authors.lastname: Mullins
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Flick
authors.forename: Karla C S
authors.initials: KC
authors.lastname: Queiroz
authors.forename: Kun
authors.initials: K
authors.lastname: Shi
authors.forename: C Arnold
authors.initials: CA
authors.lastname: Spek
authors.forename: Edward M
authors.initials: EM
authors.lastname: Conway
authors.forename: Brett P
authors.initials: BP
authors.lastname: Monia
authors.forename: Hartmut
authors.initials: H
authors.lastname: Weiler
authors.forename: Jay L
authors.initials: JL
authors.lastname: Degen
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Palumbo
mesh_terms: D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000378:metabolism / Q000473:pathology; D005260:Female; D006629:Hirudins / Q000378:metabolism; D006801:Humans; D037102:Lectins / Q000378:metabolism*; D008113:Liver Neoplasms / Q000378:metabolism / Q000556:secondary*; D008175:Lung Neoplasms / Q000378:metabolism / Q000556:secondary*; D008207:Lymphatic Metastasis; D008297:Male; D008546:Melanoma, Experimental / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D009360:Neoplastic Cells, Circulating; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010976:Platelet Count; D011516:Prothrombin / Q000037:antagonists & inhibitors / Q000235:genetics; D011994:Recombinant Proteins / Q000378:metabolism; D012513:Sarcoma, Experimental / Q000378:metabolism / Q000473:pathology; D013917:Thrombin / Q000378:metabolism*; D018180:Thrombomodulin / Q000502:physiology*
chemical_list: D006629:Hirudins; D037102:Lectins; D016376:Oligonucleotides, Antisense; D011994:Recombinant Proteins; D018180:Thrombomodulin; D011516:Prothrombin; D013917:Thrombin