title: Tumor-derived matrix metalloproteinase-1 targets endothelial proteinase-activated receptor 1 promoting endothelial cell activation.
abstract: In the vascular system, circulating tumor cells interact with endothelial cells. Tumor-endothelial cross-talk transforms the intravascular milieu to a prothrombotic, proinflammatory, and cell-adhesive state called endothelial cell activation (ECA). In the present study, we analyze the potential of metastatic tumor-derived soluble factors to transform the vascular endothelium into a prothrombotic and proinflammatory activated state. Supernatant from cultured melanoma and colon cancer cells (A375, WM9, A7, and HT-29) induced an acute activation of macrovascular and microvascular endothelial cells (human umbilical vein endothelial cells and human dermal microvascular endothelial cells) as shown by intracellular calcium flux and secretion of von Willebrand factor and interleukin-8, all markers of acute ECA. This process was inhibited using specific proteinase-activated receptor 1 (PAR1) inhibitors (RWJ-58259 and SCH-79797), indicating a mediating role for endothelial thrombin receptors. Immunofluorescence, Western blot analysis, and collagenase activity assay of tumor cells and culture supernatant revealed the presence of matrix metalloproteinase-1 (MMP-1), a recently described activator of PAR1. Inhibition of MMP-1 in supernatant from cultured tumor cells significantly attenuated ECA. Additional studies using isolated human MMP-1 (5 nmol/L) proved the presence of a functional MMP-1/PAR1 axis in tumor-endothelial communication. These findings show a new pathway of tumor-endothelial cross-talk via an intravascular MMP1/PAR1 axis in microvascular and macrovascular endothelium. Inhibition of this cross-talk may be a powerful means to prevent tumor-induced ECA and thus thrombotic and inflammatory cell adhesion.
authors.affiliation: Department of Dermatology, Institute of Physiology II, Interdisziplinäres Zentrum für Klinische Forschung Münster, Von-Esmarch Strasse 58, 48149 Münster, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Goerge
authors.forename: Alexej
authors.initials: A
authors.lastname: Barg
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Schnaeker
authors.forename: Birgit
authors.initials: B
authors.lastname: Poppelmann
authors.forename: Victoria
authors.initials: V
authors.lastname: Shpacovitch
authors.forename: Anke
authors.initials: A
authors.lastname: Rattenholl
authors.forename: Christian
authors.initials: C
authors.lastname: Maaser
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Luger
authors.forename: Martin
authors.initials: M
authors.lastname: Steinhoff
authors.forename: Stefan W
authors.initials: SW
authors.lastname: Schneider
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D002118:Calcium / Q000378:metabolism; D002417:Cattle; D003110:Colonic Neoplasms / Q000098:blood supply / Q000201:enzymology / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D019073:HT29 Cells; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D008545:Melanoma / Q000098:blood supply / Q000201:enzymology / Q000378:metabolism*; D044463:Receptor, PAR-1 / Q000378:metabolism*; D010975:Platelet Aggregation Inhibitors
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D044463:Receptor, PAR-1; D020781:Matrix Metalloproteinase 1; D002118:Calcium; D010975:Platelet Aggregation Inhibitors