Plasma fibrinogen regularly extravasates and is clotted to crosslinked fibrin in the extravascular space in a wide variety of solid human and animal tumors, both autochthonous and transplantable. Tumor fibrin deposits are also degraded at a rapid rate. These fibrin deposits, and their degradation products, are likely to have significance for tumor growth. In experimental animals, fibrin gels alone induce angiogenesis in the absence of tumor cells, and fibrinogen/fibrin degradation products possess a variety of significant biological activities. Fibrin is also deposited in wounds where its degradation with healing accompanies angiogenesis and collagenous stroma formation. These studies suggest that tumors may behave in the body like wounds and, in fact, may induce new blood vessels and mature tumor stroma by activating the host's wound healing response. A multidisciplinary approach will be used to investigate this hypothesis. Accumulation and turnover of fibrinogen/fibrin will be compared in solid tumors, in defined skin wounds, and in ascites tumors where malignant cells grow in suspension without constraints imposed by connective tissue stroma. Fibrinogen/fibrin catabolites generated in tumors and wounds in vivo will be detected and compared either by following the fate of intravenously injected 125 I-fibrinogen or by immunoreactivity. In either case, tumor and wound extracts or ascites fluids will be subjected to SDS-PAGE or other electrophoretic steps (followed by autoradiography or immunoblotting), HPLC, etc. We will also define the sites, cells, and proteases responsible for fibrinogen/fibrin catabolite generation Agents that modulate clotting and fibrinolysis will be tested for their capacity to alter tumor growth rate, growth pattern (extent of desmoplasia), and metastases. Finally, fibrinogen extravasation and fibrin accumulation and turnover will be quantitated and compared in tumors other than transplantable carcinomas; e.g., sarcomas, lymphomas, melanomas, and metastases. Together, these experiments will shed new light on the pathogenesis of angiogenesis and tumor stroma formation. They may also elucidate mechanisms that determine the distinctly different growth patterns assumed by the same tumor cell lines when these grow in ascites or solid form.
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