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Fibrinogen catabolism within the procoagulant VX-2 tumor of rabbit lung in vivo: effluxing fibrin(ogen) fragments contain antiangiogenic activity

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 procoag...

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Bibliographic Details
Published in:The Journal of laboratory and clinical medicine 2004-04, Vol.143 (4), p.241-254
Main Authors: Hatton, Mark W.C, Southward, Suzanne M.R, Legault, Kimberly J, Ross, Bonnie L, Clarke, Bryan J, Bajzar, Laszlo, Blajchman, Morris A, Singh, Gurmit, Richardson, Mary
Format: Article
Language:English
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Summary: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 125I-labeled rabbit fibrinogen as a marker, we found that fibrinogen (approximate blood concentration 1740 μg/mL) passed from blood to VX-2 tumor stroma, saturating the tumor at a concentration of approximately 348 μg fibrinogen/g in approximately 12 hours. We measured fibrin(ogen) fragments, at a concentration of approximately 292 μg/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), α 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.
ISSN:0022-2143
1532-6543
DOI:10.1016/j.lab.2004.01.006