Faculty Collaboration Database

Thrombomodulin is a determinant of metastasis through a mechanism linked to the thrombin binding domain but not the lectin-like domain. Blood 2011 Sep 08;118(10):2889-95

Date

07/27/2011

Pubmed ID

21788337

Pubmed Central ID

PMC3172805

DOI

10.1182/blood-2011-03-341222

Scopus ID

2-s2.0-80052668558 (requires institutional sign-in at Scopus site)   72 Citations

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.

Author List

Horowitz NA, Blevins EA, Miller WM, Perry AR, Talmage KE, Mullins ES, Flick MJ, Queiroz KC, Shi K, Spek CA, Conway EM, Monia BP, Weiler H, Degen JL, Palumbo JS

Author

Hartmut Weiler PhD Associate Professor in the Physiology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Carcinoma, Lewis Lung
Female
Hirudins
Humans
Lectins
Liver Neoplasms
Lung Neoplasms
Lymphatic Metastasis
Male
Melanoma, Experimental
Mice
Mice, Inbred C57BL
Mice, Transgenic
Mutation
Neoplastic Cells, Circulating
Oligonucleotides, Antisense
Platelet Count
Prothrombin
Recombinant Proteins
Sarcoma, Experimental
Thrombin
Thrombomodulin