title: Carcinoma mucins trigger reciprocal activation of platelets and neutrophils in a murine model of Trousseau syndrome.
abstract: Trousseau syndrome is classically defined as migratory, heparin-sensitive but warfarin-resistant microthrombi in patients with occult, mucinous adenocarcinomas. Injecting carcinoma mucins into mice generates platelet-rich microthrombi dependent on P- and L-selectin but not thrombin. Heparin prevents mucin binding to P- and L-selectin and mucin-induced microthrombi. This model of Trousseau syndrome explains resistance to warfarin, which inhibits fluid-phase coagulation but not selectins. Here we found that carcinoma mucins do not generate microthrombi in mice lacking P-selectin glycoprotein ligand-1 (PSGL-1), the leukocyte ligand for P- and L-selectin. Furthermore, mucins did not activate platelets in blood from PSGL-1-deficient mice. Mucins induced microthrombi in radiation chimeras lacking endothelial P-selectin but not in chimeras lacking platelet P-selectin. Mucins caused leukocytes to release cathepsin G, but only if platelets were present. Mucins failed to generate microthrombi in cathepsin G-deficient mice. Mucins did not activate platelets in blood from mice lacking cathepsin G or protease-activated receptor-4 (PAR4), indicating that cathepsin G activates platelets through PAR4. Using knockout mice and blocking antibodies, we found that mucin-triggered cathepsin G release requires L-selectin and PSGL-1 on neutrophils, P-selectin on platelets, and Src family kinases in both cell types. Thus, carcinoma mucins promote thrombosis through adhesion-dependent, bidirectional signaling in neutrophils and platelets.
authors.affiliation: Department of Biochemistry & Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
authors.forename: Bojing
authors.initials: B
authors.lastname: Shao
authors.forename: Mark G
authors.initials: MG
authors.lastname: Wahrenbrock
authors.forename: Longbiao
authors.initials: L
authors.lastname: Yao
authors.forename: Tovo
authors.initials: T
authors.lastname: David
authors.forename: Shaun R
authors.initials: SR
authors.lastname: Coughlin
authors.forename: Lijun
authors.initials: L
authors.lastname: Xia
authors.forename: Ajit
authors.initials: A
authors.lastname: Varki
authors.forename: Rodger P
authors.initials: RP
authors.lastname: McEver
mesh_terms: D002288:Adenocarcinoma, Mucinous / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D000912:Antibodies, Neoplasm / Q000494:pharmacology; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D001792:Blood Platelets / Q000378:metabolism* / Q000473:pathology; D056649:Cathepsin G / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms; D004195:Disease Models, Animal; D006801:Humans; D019041:L-Selectin / Q000235:genetics / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009077:Mucins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018375:Neutrophil Activation; D009504:Neutrophils / Q000378:metabolism* / Q000473:pathology; D019007:P-Selectin / Q000235:genetics / Q000378:metabolism; D015539:Platelet Activation; D018179:Receptors, Thrombin / Q000235:genetics / Q000378:metabolism; D013577:Syndrome; D013927:Thrombosis / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D000912:Antibodies, Neoplasm; D057134:Antibodies, Neutralizing; D008562:Membrane Glycoproteins; D009077:Mucins; D009363:Neoplasm Proteins; D019007:P-Selectin; C084882:P-selectin ligand protein; D018179:Receptors, Thrombin; D019041:L-Selectin; D056649:Cathepsin G; C534096:Ctsg protein, mouse; C112908:protease-activated receptor 4