title: Fibrinogen catabolism within the procoagulant VX-2 tumor of rabbit lung in vivo: Effluxing fibrin(ogen) fragments contain antiangiogenic activity.
abstract: Many types of solid tumors are known to be procoagulant environments. This is partly because a hyperpermeable vascular system within the tumor allows plasma hemostatic factors to accumulate in relatively high concentrations in the stroma, and many solid-tumor cells express tissue factor or a procoagulant factor. These circumstances appear to exist in the VX-2 lung tumor of the New Zealand White (NZW) rabbit, and they sustain a measurable turnover of stromal deposits of fibrin(ogen). We have measured the turnover of fibrinogen within tumors of the VX-2 tumor-burdened rabbit and analysed the catabolic products of fibrin(ogen) and the status of fibrinolysis in tumor-derived interpleural effusate. Using intravenously injected (125)I-labeled rabbit fibrinogen as a marker, we found that fibrinogen (approximate blood concentration 1740 microg/mL) passed from blood to VX-2 tumor stroma, saturating the tumor at a concentration of approximately 348 microg fibrinogen/g in approximately 12 hours. We measured fibrin(ogen) fragments, at a concentration of approximately 292 microg/mL, in interpleural effusates that we recovered from 13% of the VX-2-burdened rabbits. Unreduced fibrin(ogen) fragments consisted of 4 major components with a relative molecular mass of approximately 250,000 (assumed to be fragment X; approximately 9% of total fragments from densitometry of immunoblots), 200,000 (d-dimer; 41%), 110,000 (fragment D; 49%), and 50,000 to 55,000 (fragment E; 1%-2%) kD. Total fibrin(ogen) fragments immunopurified from effusates exhibited an antiangiogenic effect when subjected to a chick embryo chorioallantoic membrane procedure. Interpleural effusates were devoid of plasmin activity or active plasminogen activator inhibitor-1 but contained plasmin complexes and active urokinase-like plasminogen activator (uPA), alpha(2)-antiplasmin, and thrombin-activatable fibrinolysis inhibitor. We speculate that VX-2 cells release uPA to activate fibrinolysis within the tumor stroma. Catabolic products of hemostasis (eg, fibrinolytic fragments, angiostatin) flux from the stroma into the interpleural space, thereby providing a net antiangiogenic property to the effusate and ultimately to the lymphatic and circulatory systems.
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University Health Sciences Centre, 1200 Main Street W, Hamilton, Ontario, Canada L8N 3Z5.
authors.forename: Mark W C
authors.initials: MW
authors.lastname: Hatton
authors.forename: Suzanne M R
authors.initials: SM
authors.lastname: Southward
authors.forename: Kimberly J
authors.initials: KJ
authors.lastname: Legault
authors.forename: Bonnie L
authors.initials: BL
authors.lastname: Ross
authors.forename: Bryan J
authors.initials: BJ
authors.lastname: Clarke
authors.forename: Laszlo
authors.initials: L
authors.lastname: Bajzar
authors.forename: Morris A
authors.initials: MA
authors.lastname: Blajchman
authors.forename: Gurmit
authors.initials: G
authors.lastname: Singh
authors.forename: Mary
authors.initials: M
authors.lastname: Richardson
mesh_terms: D000818:Animals; D002642:Chick Embryo; D002645:Chickens; D002823:Chorion / Q000098:blood supply / Q000187:drug effects; D004195:Disease Models, Animal; D005338:Fibrin Fibrinogen Degradation Products / Q000378:metabolism* / Q000494:pharmacology; D005340:Fibrinogen / Q000378:metabolism*; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000139:chemically induced / Q000378:metabolism*; D010996:Pleural Effusion / Q000378:metabolism* / Q000473:pathology; D011817:Rabbits; D014412:Tumor Virus Infections / Q000378:metabolism* / Q000473:pathology
chemical_list: D005338:Fibrin Fibrinogen Degradation Products; D005340:Fibrinogen