Fibrinogen influx and accumulation of cross-linked fibrin in mouse carcinomas

125I-radiolabeled guinea pig fibrinogen was used to measure the influx (20 min) and accumulation (18 h) of fibrinogen/fibrin in three transplantable carcinomas (Lewis lung, TA3/St mammary, and MOT ovarian) growing in the subcutaneous space of syngeneic mice. Fibrinogen influx and, to an even greater extent, fibrin accumulation were substantially increased in all three tumors, as compared with normal control tissues. A significantly larger fraction of tumor-associated than control tissue radioactivity was insoluble in 3 M urea, a property of cross-linked fibrin. Positive identification of cross-linked fibrin was made by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiography of tumor extracts. Tumor fibrin deposits were localized by immunoperoxidase staining of tissue sections. Fibrin accumulation was also significantly increased in premalignant hyperplastic alveolar nodules that had been transplanted to cleared mammary fat pads, as compared with normal mammary tissue, and was further increased in primary mammary carcinomas that arose from hyperplastic alveolar nodules. These findings generalize to the mouse the principles that tumor vessels are hyperpermeable to plasma proteins and that fibrin accumulates in transplantable and primary tumors. Further, they demonstrate that tumor fibrin is cross-linked and therefore analogous to the fibrin deposited in thrombi, wounds, and cellular immunity.