Tumor-derived matrix metalloproteinase-1 targets endothelial proteinase-activated receptor 1 promoting endothelial cell activation

• Published in: Cancer research (Chicago, Ill.) Vol. 66; no. 15; pp. 7766 - 7774
• Main Authors: GOERGE, Tobias, BARG, Alexej, SCHNAEKER, Eva-Maria, POPPELMANN, Birgit, SHPACOVITCH, Victoria, RATTENHOLL, Anke, MAASER, Christian, LUGER, Thomas A, STEINHOFF, Martin, SCHNEIDER, Stefan W
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.08.2006
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Caco-2 Cells; Calcium - metabolism; Cattle; Colonic Neoplasms - blood supply; Colonic Neoplasms - enzymology; Colonic Neoplasms - metabolism; Endothelial Cells - cytology; Endothelial Cells - metabolism; HT29 Cells; Humans; Matrix Metalloproteinase 1 - metabolism; Matrix Metalloproteinase Inhibitors; Medical sciences; Melanoma - blood supply; Melanoma - enzymology; Melanoma - metabolism; Pharmacology. Drug treatments; Receptor, PAR-1 - antagonists & inhibitors; Receptor, PAR-1 - metabolism; Tumors; Peptidases; Endothelial cell; Target; Targeting; Enzyme; Hydrolases; Metalloendopeptidases; Malignant tumor; Interstitial collagenase; Endothelium; Biological receptor
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-05-3897

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.