Abstract
Fibrinogen enters wounds and solid tumors, where it is clotted to fibrin that may subsequently be replaced by collagenous stroma. If, as has been suggested, the pathogenesis of wound healing and tumor stroma generation is similar and dependent on fibrin deposition, then the types and amounts of fibrin deposited in wounds and tumors might also be expected to be similar. To test this hypothesis, the authors injected homologous tracer fibrinogen (125I-GPF) intravenously into guinea pigs and measured its influx and accumulation in skin wounds and syngeneic carcinomas. In support of their hypothesis, the urea-insoluble product deposited in both wounds and tumors was identified as cross-linked fibrin by gel electrophoresis. Accumulation of both total and urea-insoluble 125I-GPF was quantitatively similar in wounds and tumors. However, influx and initial clotting of 125I-GPF in tumors exceeded that in wounds; given equivalent accumulation, these data suggest that fibrin turnover is more rapid in tumors than in wounds. Fibrinogen influx and fibrin accumulation declined toward normal a few days after wounding but remained consistently elevated in tumors. Thus, the magnitude and the persistence of microvascular hyperpermeability, as well as fibrin turnover, are major points of difference that distinguish tumors from healing wounds.
Full text
PDF










Images in this article
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Ackerman N. B., Hechmer P. A. Studies on the capillary permeability of experimental liver metastases. Surg Gynecol Obstet. 1978 Jun;146(6):884–888. [PubMed] [Google Scholar]
- Budzynski A. Z., Marder V. J., Parker M. E., Shames P., Brizuela B. S., Olexa S. A. Antigenic markers on fragment DD, a unique plasmic derivative of human crosslinked fibrin. Blood. 1979 Oct;54(4):794–804. [PubMed] [Google Scholar]
- Churchill W. H., Jr, Rapp H. J., Kronman B. S., Borsos T. Detection of antigens of a new diethylnitrosamine-induced transplantable hepatoma by delayed hypersensitivity. J Natl Cancer Inst. 1968 Jul;41(1):13–29. [PubMed] [Google Scholar]
- DAY E. D., PLANINSEK J. A., PRESSMAN D. Localization in vivo of radio-iodinated anti-rat-fibrin antibodies and radio-iodinated rat fibrinogen in the Murphy rat lymphosarcoma and in other transplantable rat tumors. J Natl Cancer Inst. 1959 Feb;22(2):413–426. [PubMed] [Google Scholar]
- DEWEY W. C. Vascular-extravascular exchange of II31 plasma proteins in the rat. Am J Physiol. 1959 Aug;197:423–431. doi: 10.1152/ajplegacy.1959.197.2.423. [DOI] [PubMed] [Google Scholar]
- Dvorak H. F., Dickersin G. R., Dvorak A. M., Manseau E. J., Pyne K. Human breast carcinoma: fibrin deposits and desmoplasia. Inflammatory cell type and distribution. Microvasculature and infarction. J Natl Cancer Inst. 1981 Aug;67(2):335–345. [PubMed] [Google Scholar]
- Dvorak H. F., Dvorak A. M., Manseau E. J., Wiberg L., Churchill W. H. Fibrin gel investment associated with line 1 and line 10 solid tumor growth, angiogenesis, and fibroplasia in guinea pigs. Role of cellular immunity, myofibroblasts, microvascular damage, and infarction in line 1 tumor regression. J Natl Cancer Inst. 1979 Jun;62(6):1459–1472. [PubMed] [Google Scholar]
- Dvorak H. F., Form D. M., Manseau E. J., Smith B. D. Pathogenesis of desmoplasia. I. Immunofluorescence identification and localization of some structural proteins of line 1 and line 10 guinea pig tumors and of healing wounds. J Natl Cancer Inst. 1984 Nov;73(5):1195–1205. [PubMed] [Google Scholar]
- Dvorak H. F., Harvey V. S., McDonagh J. Quantitation of fibrinogen influx and fibrin deposition and turnover in line 1 and line 10 guinea pig carcinomas. Cancer Res. 1984 Aug;44(8):3348–3354. [PubMed] [Google Scholar]
- Dvorak H. F., Orenstein N. S., Carvalho A. C., Churchill W. H., Dvorak A. M., Galli S. J., Feder J., Bitzer A. M., Rypysc J., Giovinco P. Induction of a fibrin-gel investment: an early event in line 10 hepatocarcinoma growth mediated by tumor-secreted products. J Immunol. 1979 Jan;122(1):166–174. [PubMed] [Google Scholar]
- Dvorak H. F., Quay S. C., Orenstein N. S., Dvorak A. M., Hahn P., Bitzer A. M., Carvalho A. C. Tumor shedding and coagulation. Science. 1981 May 22;212(4497):923–924. doi: 10.1126/science.7195067. [DOI] [PubMed] [Google Scholar]
- Dvorak H. F., Senger D. R., Dvorak A. M. Fibrin as a component of the tumor stroma: origins and biological significance. Cancer Metastasis Rev. 1983;2(1):41–73. doi: 10.1007/BF00046905. [DOI] [PubMed] [Google Scholar]
- Dvorak H. F., Senger D. R., Dvorak A. M., Harvey V. S., McDonagh J. Regulation of extravascular coagulation by microvascular permeability. Science. 1985 Mar 1;227(4690):1059–1061. doi: 10.1126/science.3975602. [DOI] [PubMed] [Google Scholar]
- Dvorak H. F. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med. 1986 Dec 25;315(26):1650–1659. doi: 10.1056/NEJM198612253152606. [DOI] [PubMed] [Google Scholar]
- Dvorak H. F., Van DeWater L., Bitzer A. M., Dvorak A. M., Anderson D., Harvey V. S., Bach R., Davis G. L., DeWolf W., Carvalho A. C. Procoagulant activity associated with plasma membrane vesicles shed by cultured tumor cells. Cancer Res. 1983 Sep;43(9):4434–4442. [PubMed] [Google Scholar]
- Folkman J. Tumor angiogenesis. Adv Cancer Res. 1985;43:175–203. doi: 10.1016/s0065-230x(08)60946-x. [DOI] [PubMed] [Google Scholar]
- Form D. M., VanDeWater L., Dvorak H. F., Smith B. D. Pathogenesis of tumor desmoplasia. II. Collagens synthesized by line 1 and line 10 guinea pig carcinoma cells and by syngeneic fibroblasts in vitro. J Natl Cancer Inst. 1984 Nov;73(5):1207–1214. [PubMed] [Google Scholar]
- Francis C. W., Markham R. E., Jr, Marder V. J. Demonstration of in situ fibrin degradation in pathologic thrombi. Blood. 1984 May;63(5):1216–1224. [PubMed] [Google Scholar]
- Gaffney P. J., Brasher M., Lord K., Strachan C. J., Wilkinson A. R., Kakkar V. V., Scully M. F. Fibrin subunits in venous and arterial thromboembolism. Cardiovasc Res. 1976 Jul;10(4):421–426. doi: 10.1093/cvr/10.4.421. [DOI] [PubMed] [Google Scholar]
- HIRAMOTO R., BERNECKY J., JURANDOWSKI J., PRESSMAN D. Fibrin in human tumors. Cancer Res. 1960 Jun;20:592–593. [PubMed] [Google Scholar]
- Harris N. L., Dvorak A. M., Smith J., Dvorak H. F. Fibrin deposits in Hodgkin's disease. Am J Pathol. 1982 Jul;108(1):119–129. [PMC free article] [PubMed] [Google Scholar]
- Hermans J., McDonagh J. Fibrin: structure and interactions. Semin Thromb Hemost. 1982 Jan;8(1):11–24. doi: 10.1055/s-2007-1005039. [DOI] [PubMed] [Google Scholar]
- Herold G., Neier W. E., Straub P. W. Surface accumulation and reduced survival of I 125 -fibrinogen during wound healing. Helv Med Acta. 1973;37(1):57–61. [PubMed] [Google Scholar]
- Hubbard A. L., Cohn Z. A. The enzymatic iodination of the red cell membrane. J Cell Biol. 1972 Nov;55(2):390–405. doi: 10.1083/jcb.55.2.390. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Laemmli U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. doi: 10.1038/227680a0. [DOI] [PubMed] [Google Scholar]
- Leibovich S. J., Ross R. The role of the macrophage in wound repair. A study with hydrocortisone and antimacrophage serum. Am J Pathol. 1975 Jan;78(1):71–100. [PMC free article] [PubMed] [Google Scholar]
- O'Connor S. W., Bale W. F. Accessibility of circulating immunoglobulin G to the extravascular compartment of solid rat tumors. Cancer Res. 1984 Sep;44(9):3719–3723. [PubMed] [Google Scholar]
- O'MEARA R. A., JACKSON R. D. Cytological observations on carcinoma. Ir J Med Sci. 1958 Jul;(391):327–328. doi: 10.1007/BF02950396. [DOI] [PubMed] [Google Scholar]
- Peterson H. I., Appelgren L., Lundborg G., Rosengren B. Capillary permeability of two transplantable rat tumours as compared with various normal organs of the rat. Bibl Anat. 1973;12:511–518. [PubMed] [Google Scholar]
- Pineo G. F., Brain M. C., Gallus A. S., Hirsh J., Hatton M. W., Regoeczi E. Tumors, mucus production, and hypercoagulability. Ann N Y Acad Sci. 1974;230:262–270. doi: 10.1111/j.1749-6632.1974.tb14458.x. [DOI] [PubMed] [Google Scholar]
- SCHOEFL G. I. STUDIES ON INFLAMMATION. III. GROWING CAPILLARIES: THEIR STRUCTURE AND PERMEABILITY. Virchows Arch Pathol Anat Physiol Klin Med. 1963 Nov 8;337:97–141. [PubMed] [Google Scholar]
- Senger D. R., Galli S. J., Dvorak A. M., Perruzzi C. A., Harvey V. S., Dvorak H. F. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science. 1983 Feb 25;219(4587):983–985. doi: 10.1126/science.6823562. [DOI] [PubMed] [Google Scholar]
- Senger D. R., Perruzzi C. A., Feder J., Dvorak H. F. A highly conserved vascular permeability factor secreted by a variety of human and rodent tumor cell lines. Cancer Res. 1986 Nov;46(11):5629–5632. [PubMed] [Google Scholar]
- Song C. W., Levitt S. H. Quantitative study of vascularity in Walker carcinoma 256. Cancer Res. 1971 May;31(5):587–589. [PubMed] [Google Scholar]
- Spar I. L., Bale W. F., Marrack D., Dewey W. C., McCardle R. J., Harper P. V. 131-I-labeled antibodies to human fibrinogen. Diagnostic studies and therapeutic trials. Cancer. 1967 May;20(5):865–870. doi: 10.1002/1097-0142(1967)20:5<865::aid-cncr2820200546>3.0.co;2-5. [DOI] [PubMed] [Google Scholar]
- Tremblay G. Stromal aspects of breast carcinoma. Exp Mol Pathol. 1979 Aug;31(1):248–260. doi: 10.1016/0014-4800(79)90026-1. [DOI] [PubMed] [Google Scholar]
- VanDeWater L., Tracy P. B., Aronson D., Mann K. G., Dvorak H. F. Tumor cell generation of thrombin via functional prothrombinase assembly. Cancer Res. 1985 Nov;45(11 Pt 1):5521–5525. [PubMed] [Google Scholar]



