Microfluidic reveals generation of platelet-strings on tumor-activated endothelium.
Neoplastic diseases are often associated with thromboembolic events, however the precise mechanism underlying this observation is a matter of ongoing investigation. It is known that matrixmetalloproteinase-1 (MMP-1) canonically activates the thrombin receptor (PAR-1) and we recently reported that highly metastatic tumor cells of melanoma and colon cancer are secreting matrixmetalloproteinase-1. This tumor-derived MMP1 was shown to be a major activator of endothelial PAR-1, thus leading to endothelial cell activation. As tumor-induced thrombosis is a characteristic of metastazing tumors, we investigated whether tumor-derived supernatant (TUSN) from melanoma and colon cancer may induce adhesion of circulating platelets, an initial step in thrombus formation. A time-course study revealed that TU-SN induces a rapid secretion of von Willebrand factor (VWF) within minutes. Using a novel microfluidic device we analyzed platelet-endothelial interactions in a closed circuit. Immunofluorescence imaging showed that TU-SN rapidly induces platelet-string formation via secreted VWF. We demonstrated that tumor-derived supernatant is a potent agonist inducing platelet adhesion under flow conditions.
Goerge
Tobias
T
University of Münster, Department of Dermatology, Münster, Germany. Tobias.Goerge@ukmuenster.de
Kleinerüschkamp
Felix
F
Barg
Alexej
A
Schnaeker
Eva-Maria
EM
Huck
Volker
V
Schneider
Matthias F
MF
Steinhoff
Martin
M
Schneider
Stefan W
SW
D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000150:complications / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000473:pathology*; D006801:Humans; D020781:Matrix Metalloproteinase 1; D008545:Melanoma / Q000150:complications / Q000378:metabolism; D044085:Microfluidics / Q000379:methods*; D009369:Neoplasms / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D010973:Platelet Adhesiveness / Q000187:drug effects*; D044463:Receptor, PAR-1; D013923:Thromboembolism / Q000209:etiology*; D014841:von Willebrand Factor / Q000378:metabolism*
D017077:Culture Media, Conditioned; D044463:Receptor, PAR-1; D014841:von Willebrand Factor; D020781:Matrix Metalloproteinase 1