Summary
A volume of data that has accumulated for over a century has suggested that fibrin may facilitate the persistence and progression of malignancy. Techniques that have been developed recently have shown that fibrin is indeed a component of the connective tissue stroma in human malignancy but in only a few tumor types. However, therapeutic intervention studies with drugs that limit thrombin activity or enhance fibrinolysis have shown favorable clinical effects in at least one such tumor type. These favorable findings affirm the concept that cause-and-effect relationships do, in fact, exist between thrombin generation with fibrin formation and tumor progression, and suggest that a rational basis exists for the design of future drug intervention trials that target reactions relevant to specific tumor types. These findings also provide a basis for the design of experiments capable of defining further the role of fibrin in the integrity of these tumor types. Because fibrinogen is found much more commonly than fibrin in the connective tissue of a variety of human malignancies, attention might reassumably be directed to determining the possible contribution of this molecule as well as of fibrin to tumor progression.
Similar content being viewed by others
References
ZacharskiLR: Anticoagulation in the treatment of cancer in man. In: DonatiMB, DavidsonJ, GarattiniS (ed) Malignancy and the hemostatic system. Raven Press, New York, pp 113–128, 1981
RicklesFR, EdwardsRL: Activation of blood coagulation in patients with cancer: Trousseau's syndrome revisited. Blood 62: 14–31, 1983
DonatiMB, PoggiA, SemeraroN: Coagulation and malignancy. In: PollerL (ed) Recent advances in blood coagulation. Livingston, New York, pp 375–391, 1981
ZacharskiLR, HendersonWG, RicklesFR, FormanWG, CornellCJ, HarrowerHW, JohnsonRO: Rationale and experimental design for the VA Cooperative study of anticoagulation (warfarin) in the treatment of cancer. Cancer 44: 732–741, 1979
RicklesFR, HancockWW, EdwardsRL, ZacharskiLR: Antimetastatic agents. I. The role of cellular procoagulants in the pathogenesis of fibrin deposition in cancer and the use of anticoagulants and/or antiplatelet drugs in cancer treatment. Sem Thrombos Hemostas 14: 88–94, 1988
DvorakHF: Tumors: Wounds that do not heal. New Engl J Med 315: 1650–1659, 1986
DvorakHF: Thrombosis and cancer. Human Pathol 18: 275–284, 1987
DvorakHF, HarveyVS, BuchinskiB, EstrellaP, McDonaghJ, DvorakAM: Fibrin gels induce angiogenesis: a new assay with implications for tumor stroma generation and wound healing. Fed Proc 46: 970, 1987
BrownLF, AschB, HarveyVS, BuchinskiB, DvorakHF: Fibrinogen influx and accumulations of cross-linked fibrin in mouse carcinomas. Cancer Res 48: 1920–1925, 1988
DvorakHF, SengerDR, DvorakAM: Fibrin as a componant of the tumor stroma: origins and biological significance. Cancer Metast Rev 2: 41–73, 1983
ZacharskiLR, MemoliVA, CostantiniV, WojtukiewiczMZ, OrnsteinDL: Clotting factors in tumor tissue: Implications for cancer therapy. Blood Coag Fibrinolys 1: 71–78, 1990
ZacharskiLR, HowellAL, MemoliVA: The coagulation biology of cancer. Fibrinolysis 6 (Suppl): 39–42, 1992
CardinaliM, UchinoR, ChungSI: Interaction of fibrinogen with murine melanoma cells: covalent association with cell membranes and protection against recognition by lumpholkine-activated killer cells. Cancer Res 50: 8010–8016, 1990
GunjiY, GorelikE: Role of fibrin coagulation in protection of murine tumor cells from destruction by immune cells. Cancer Res 48: 5216–5221, 1988
ZacharskiLR, HendersonWG, RicklesFR, FormanWG, VanEeckhoutJP, CornellCJ, ForcierRJ, MartinJF: Rationale and experimental design for the VA Cooperative Study of RA-233 in the treatment of cancer. Am J Clin Oncol 5: 593–609, 1982
KarpatkinS, PearlsteinE: Role of platelets in tumor cell metastasis. Ann Int Med 95: 636–641, 1981
ZacharskiLR, HendersonWG, RicklesFR, FormanWB, CornellCJ, ForcierRJ, HeadleyE, KimS-H: Effect of sodium warfarin on survival in small cell carcinoma of the lung. J Am Med Assoc 245: 831–835, 1981
ZacharskiLR, HendersonWG, RicklesFR, FormanWB, CornellCJ, ForcierRJ, EdwardsRL, HeadleyE: Effect of warfarin anticoagulation on survival in carcinoma of the lung, colon, head and neck, and prostate. Final report of the VA Cooperative Study 75. Cancer 53: 2046–2052, 1984
ChahinianAP, PropertKJ, WareJH, ZimmerB, PerryMC, HirshV, SkarinA, KopelS: A randomized trial of anticoagulation with warfarin and of alternating chemotherapy in extensive small-cell lung cancer by the Cancer and Leukemia Group B. J Clin Oncol 7: 993–1002, 1989
CalvoPA, HarguindeySS, AparicioLA, DyC, GilA, RochaE: Urokinase and combination chemotherapy for treatment of small cell carcinoma of the lung. Cancer Treat Sympos 2: 105–108, 1985
CalvoFA, SantosM, HidalgoOF: Urokinase-combination chemotherapy in small cell lung cancer: A phase II study. Proc ASCO 9: 237, 1991
LebeauB, ChastangCL, BrechotJM: Subcutaneous heparin treatment increases complete response rate and overall survival in small cell lung cancer (SCLC). Lung Cancer 7 (Suppl): 129, 1991
DonatiMB, DavidsonJF, GarattiniS: Malignancy and the hemostatic system. Raven Press, N.Y., 1981
SalsaliM, ClifftonEE: Superior vena caval obstruction with lung cancer. Ann Thoracic Surg 6: 437–442, 1968
AstedtB, GlifbergI, MattssonW, TropeC: Arrest of growth of ovarian tumor by tranexamic acid. J Am Med Assn 238: 154–155, 1977
KudrykB, RohozaA, AhadiM, ChinJ, WiebeME: Specificity of a monoclonal antibody for the NH2-terminal region of fibrin. Mol Immunol 21: 89–94, 1984
KudrykB, GrossmanZD, McAfeeJG, RosebroughSF: Monoclonal antibodies as probes for fibrin(ogen) proteolysis. In: ChatalJF (ed) CRC Press, Boca Raton, Florida, pp 365–398, 1989
ZacharskiLR, MemoliVA, RousseauSM, KisielW: Coagulation-cancer interactionin situ in small cell carcinoma of the lung. Cancer 60: 2675–2681, 1987
ZacharskiLR, MemoliVA, RousseauSM: Thrombin-specific sites of fibrinogen in small cell carcinoma of the lung. Cancer 62: 299–302, 1988
WojtukiewiczMZ, ZacharskiLR, MemoliVA, KisielW, KudrykBJ, RousseauSM, StumpDC: Abnormal regulation of coagulation/fibrinolysis in small cell carcinoma of the lung. Cancer 65: 481–485, 1990
ZacharskiLR, MemoliVA, RousseauSM: Cancer-coagulation interactionin situ in renal cell carcinoma. Blood 68: 394–399, 1986
WojtukiewiczMZ, ZacharskiLR, MemoliVA, KisielW, KudrykBJ, RousseauSM, StumpDC: Fibrinogen-fibrin transformationin situ in renal cell carcinoma. Anticancer Res 10: 579–582, 1990
WojtukiewiczMZ, ZacharskiLR, MemoliVA, KisielW, KudrykBJ, RouseauSA, StumpDC: Malignant melanoma: Interaction with coagulation and fibrinolysis pathwaysin situ. Am J Clin Pathol 93: 516–521, 1990
OrnsteinD, ZacharskiLR, MemoliVA, KisielW, KudrykBJ, HuntJ, RousseauSM, StumpDC: Coexistant macrophage procoagulant and tumor cell plasminogen activator in adenocarcinoma and squamous cell carcinoma of the lung. Cancer 68: 1061–67, 1991
CostantiniV, ZacharskiLR, MemoliVA, KisielW, KudrykBJ, HuntJ, RousseauSM, StumpDC: Fibrinogen deposition without thrombin generation in primary human breast cancer tissue. Cancer Res 51: 349–353, 1991
CostantiniV, ZacharskiLR, MemoliVA, KisielW, KudrykBJ, HuntJ, RousseauSM, StumpDC: Occurence of components of fibrinolysis pathwaysin situ in neoplastic and non-neoplastic human breast tissue. Cancer Res 51: 354–358, 1991
WojtukiewiczMZ, ZacharskiLR, MemoliVA, KisielW, KudrykBJ, RousseauSM, StumpDC: Indirect activation of blood coagulation in colon cancer. Thrombosis and Haemostasis 62: 1062–1066, 1989
Wojtukiewicz MZ, Zacharski LR, Memoli VA, Moritz TE, Kisiel W, Kudryk BJ, Rousseau SM, Stump DC: Fibrin formation on vessel walls in hyperplastic and malignant prostate tissue. Cancer 67: 1991
WojtukiewiczMZ, ZacharskiLR, MemoliVA, KisielW, KudrykBJ, RousseauSM, StumpDC: Absence of components of coagulation and fibrinolysis pathwaysin situ in mesothelioma. Thrombos Res 55: 279–284, 1989
CostantiniV, ZacharskiLR, MemoliVA, KisielW, KudrykBJ, RousseauSM, StumpDC: Fibrinogen deposition and macrophage-associated fibrin formation in malignant and non-malignant lymphoid tissue. J Lab Clin Med 119: 124–131, 1992
ZacharskiLR, DunwiddieC, NuttEM, HuntJ, MemoliVA: Cellular localization of activated factor X by a Xa-specific probe. Thromb Haemost 65: 545–548, 1991
Werling RW, Zacharski LR, Kisiel W, Bajaj SP, Memoli VA, Rousseau SM: Distribution of tissue factor pathway inhibitor (TFPI, EPI, LACI) in normal and pathologic human tissues. Blood 78: 72a, 1991
ZacharskiLR, DunwiddieC, NuttEM, HuntJ, MemoliVA: Cellular localization of activated factor X by a Xa-specific probe. Thromb Haemost 65: 545–548, 1991
FingertHJ, ChenZ, MigrakiN, GajewakiWH, BambergMP, KradinRL: Rapid growth of human cancer cells in a mouse model with fibrin clot subrenal capsule assay. Cancer Res 47: 3824–3829, 1987
BogdenAE, CobbWR, LepageDJ, HaskellPM, GulkinTA, WardA, KeltonDE, EsberHJ: Chemotherapy responsiveness of human tumors as first transplant generation xenografts in the normal mouse: six day subrenal capsule assay. Cancer 48: 10–20, 1981
OlanderJV, BremerME, MarasaJC, FederJ: Fibrin-enhanced endothelial cell organization. J Cell Physiol 125: 1–9, 1985
BlombackB, OkadaM, ForslindB, LarssonU: Fibrin gels as biological filters and interfaces. Biorheology 21: 93–104, 1984
ColvinRB, GardnerPI, RoblinRO, VerderberEL, LaniganJM, MosessonMW: Cell surface fibrinogen-fibrin receptors on cultured human fibroblasts. Lab Invest 41: 464–473, 1979
AzzaroneB, Frouty-BoyeD, Macieira-CoelhoA: Relationship between fibrin clot retraction and tumorigenesis in C3H/1071/2 cells. Int J Cancer 28: 799–803, 1981
CuratoloL, AzzaroneB, Fally-CrepinC, MorascaL, Macieira-CoelhoA: Comparison of fibrin clot retraction with other transformation parameters after hybridization of normal and established cell lines. Int J Cancer 31: 249–255, 1983
HopperKE, GeczyCL, DaviesWA: A mechanism of migration inhibition in delayed-type hypersensitivity reactions. I Fibrin deposition on the surface of elicited peritoneal macrophagesin vivo. J Immunol 126: 1052–7, 1981
SultanAM, DunnCJ, WilloughbyDA: Leukocyte migration inhibition activity of nonimmune acute inflammatory pleural exudate. Inflammation 3: 305–317, 1979
CianoPS, ColvinRB, DvorakAM, McDonaghJ, DvorakHF: Macrophage migration in fibrin gel matrices. Lab Invest 54: 62–70, 1986
ChereshDA, SmithJW, CooperHM, QuarantaV: A novel vitronectin receptor integrin (alpha V beta X) is responsible for distinct adhesive properties of carcinoma cells. Cell 57: 59–69, 1989
ChereshDA, SiroRC: Biosynthetic and functional properties of an Arg-Gly-Asp-directed receptor involved in human melanoma cell attachment to vitronection, fibrinogen, and von Willebrand factor. J Biol Chem 262: 17703–17711, 1987
YlanneJ, HormiaM, JarvinenM, VartioT, VirtanenI: Platelet glycoprotein IIG IIIa complex in cultured cells. Localization in focal adhesion sites in spreading HEL cells. Blood 72: 1478–1486, 1988
SosmanJA, KohlerPC, HankJ, MooreKH, BechhoferR, StorerB, SondelPM: Repetitive weekly cycles of recombinant human interleukin-2: responses of renal carcinoma with acceptable toxicity. J Natl Cancer Inst 80: 60–63, 1988
WestWH, TauerKW, YannelliJR, MarshallGD, OrrDW, ThurmenGB, OldhamRK: Constant-infusion recombinant interleukin-2 in adoptive immunotherapy of advanced cancer. N Engl J Med 316: 898–905, 1987
GreenbergCS, BirckbichlerPJ, RiceRH: Transglutaminases: multifunctional cross-linking enzymes that stabilize tissues. FASEB J 5: 3071–7, 1991
MurthySNP, LorandL: Cross-linked Ax.8 chain hybrids serve as unique markers for fibrinogen polymerized by tissue transglutaminase. Proc Natl Acad Sci 87: 9679–9682, 1990
AlaouiSE, LegasteloisS, RochAM, ChantepieJ, QuashG: Transglutaminase activity and NE (γ-glutamyl) lysine isopeptide levels during cell growth: an enzymic and immunological study. Int J Cancer 48: 221–226, 1991
RochAM, DuchetM, LointierP, QuashG: Polyamine biosynthesis, degradation and sequestration in tumors, polyps and histologically normal mucosa from the human colon. In: PerinA, ScalabrinoG, SessaA, FerioliME (ed) Perspectives in polyamine research. Wichtig, Milan, 129–132, 1988
ReidMB, GrayC, FearJD, BirdCC: Immunohistological demonstration of factors XIIIa and XIIIs in reactive and neoplastic fibroblastic and fibrohistiocytic lesions. Histopathol 10: 1171–1178, 1986
RochAM, NoelP, AlaoiniSE, CharlotC, QuashG: Differential expression of isopeptide bonds NE (γ-glutamyl) lysine in benign and malignant human breast lesions: an immunohistochemical study. Int J Cancer 48: 215–220, 1991
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Costantini, V., Zacharski, L.R. The role of fibrin in tumor metastasis. Cancer Metast Rev 11, 283–290 (1992). https://doi.org/10.1007/BF01307183
Issue Date:
DOI: https://doi.org/10.1007/BF01307183