The goal of this research has been to evaluate the role of fibrin deposition and turnover in the biology of tumor growth, particularly with reference to tumor stroma formation. In the past year we have completed initial studies concerning the quantitation of fibrinogen influx and fibrin deposition and turnover in two well-characterized guinea pig carcinomas, line 1 and line 10 bile duct tumors. Earlier immunofluorescence studies revealed fibrin deposits in both tumors (line 1 much greater than line 10). In accord with these data, trace-labeled guinea pig fibrinogen (GPF) accumulated in both tumors in amounts that matched or exceeded plasma fibrinogen levels. However, line 1 tumor GPF content was four times that of line 10 tumors and 11 to 33 times that of normal subcutaneous tissue. The great bulk of accumulated GPF was in the form of cross linked (transglutaminated) fibrin. Because initial influx of fibrinogen into tumors and clotting were identical for both tumors, the large differences in GPF accumulation (line 1 greater than line 10) apparently reflect differences in fibrinolysis. Other studies have been concerned with the nature and importance of tumor-associated procoagulants to tumor fibrin deposition. Several tumor procoagulant activities have been identified in both the intrinsic and extrinsic coagulation pathways, as well as provision of a surface for prothrombinase generation, the penultimate step in the common coagulation pathway and one essential for clotting to proceed to completion. However, our studies in the past year have shown that tumor-associated procoagulants may be very much less important than had been thought earlier. We found that increased microvascular permeability alone is sufficient to induce equivalant extravascular coagulation in several normal tissues. The results indicate that saturating levels of procoagulant are present even in normal tissues in association with normal connective tissue cells. Therefore, the level of microvascular permeability becomes the rate limiting step in extravascular coagulation for solid tumors and also for a broad spectrum of inflammatory reactions. (A)
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