The Role of Hemostasis and Fibrinolysis in the Metastatic Spread of Cancer

Markus, Gabor

doi:10.1055/s-2007-1004408

Cited by 100 publications

(59 citation statements)

References 34 publications

(39 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The serine proteases tissue plasminogen activator (t-PA)' (1) and urinary plasminogen activator (u-PA) (2) convert the zymogen plasminogen into the serine protease plasmin and thereby have been implied in various physiological and pathological processes including fibrinolysis (3), cellular migration (4), neuronal outgrowth (5), ovulation (6), activation of latent collagenase (7), and tumor metastasis (8). Whereas plasminogen activators (PAs) possess greatly restricted substrate specificity, plasmin cleaves a wide range of proteins.…”

Section: Introductionmentioning

confidence: 99%

Plasminogen activator inhibitor is associated with the extracellular matrix of cultured bovine smooth muscle cells.

Knudsen¹,

Harpel²,

Nachman³

1987

J. Clin. Invest.

152

View full text Add to dashboard Cite

The extracellular matrix secreted by cultured bovine smooth muscle cells (BSMC) contains an endothelial type plasminogen activator (PA) inhibitor. When PA is incubated with the matrix, a high molecular weight complex containing a truncated PA inhibitor is released into the supernatant. The inhibitor also dissociates from the matrix by treatment with glycine, pH 2.7, in its intact, functionally active, 45-kD form, whereas treatment of the matrix with thrombin results in the release of a cleaved, inactive, 41 kD PA inhibitor. Bowes melanoma cells but not smooth muscle cells cultured on BSMC matrices decrease available matrix associated PA inhibitor. PA inhibitor incorporated into the extracellular matrix may serve an important role in the regulation of plasminogen activator mediated matrix degradation.

show abstract

Section: Introductionmentioning

confidence: 99%

Plasminogen activator inhibitor is associated with the extracellular matrix of cultured bovine smooth muscle cells.

Knudsen¹,

Harpel²,

Nachman³

1987

J. Clin. Invest.

152

View full text Add to dashboard Cite

show abstract

“…The smaller molecules of LMWH, however, have relatively selective inhibitory activity against factor Xa compared with thrombin, the clinical significance of which is currently unknown. [42,43] Heparin is an antithrombin [44] Histamine promotes tumour growth in experimental models [39] Heparin binds to and inactivates histamine [45] Chemokines (e.g. IL-8, melanoma growth stimulating factor) stimulate growth and metastasis [45] Heparin inhibits chemokine activity [46] Viruses (e.g.…”

Section: Potential Mechanisms Of the Anticancer Activity Of Heparinmentioning

confidence: 99%

The Use of Heparin for Treating Human Malignancies

Ornstein

Zacharski

1999

Pathophysiol Haemos Thromb

View full text Add to dashboard Cite

There is a substantial amount of data implicating coagulation mechanisms in the pathogenesis of malignancy. Studies in some experimental animal models have shown that the anticoagulant heparin limits tumour growth and metastasis and prolongs survival. Experience with the effects of heparin on human malignancy is limited primarily to settings in which it was given either to prevent or to treat thrombosis in patients who also had cancer. However, these studies have shown noteworthy apparent improvement in cancer outcome with heparin, especially with low-molecular-weight heparin. There are several possible mechanisms by which heparin could potentially alter the natural history of cancer progression because of its ability to modify the cellular and molecular environment of tumour cells. This experience provides the rationale for definitive clinical trials of heparin in patients with cancer and also for further experimentation to define the mechanisms of antineoplastic activity by this familiar class of drugs.

show abstract

mentioning

confidence: 99%

“…For example, in sublines derived from transplanted tumors, such as the B16 melanoma and the Lewis lung carcinoma, comparison was made between PA production and metastatic capacity (6,9,14,40,54). Comparison was also made between PA levels of spontaneously arising human tumors of the colon, breast, and prostate and PA produced by their invasive and metastatic derivatives (5,22,26,27,36 ., Clifton, N.J.) ion-exchange chromatography. Poly(A)-containing RNA was prepared from the urokinase-rich HEp-3 human epidermoid carcinoma propagated in nude mice and was enriched for uPA about threefold on two successive sucrose gradients before use for cDNA synthesis.…”

mentioning

confidence: 99%

Expression of human recombinant plasminogen activators enhances invasion and experimental metastasis of H-ras-transformed NIH 3T3 cells.

Axelrod¹,

Reich²,

Miskin³

1989

Mol. Cell. Biol.

117

View full text Add to dashboard Cite

The gene transfer technique was used to examine the role of plasminogen activator (PA) Tumor cell invasion and metastasis are complex processes affected by a multiplicity of factors whose molecular nature is scarcely defined (13,24,44). Hydrolytic enzymes, including proteinases, were long ago implicated in tumor metastasis to account in part for the ability of tumor cells to detach from the primary lesion, to penetrate through basement membrane surrounding blood vessels, and finally to implant themselves into a remote organ (for reviews, see references 8 and 33). One of the enzymes whose role in metastasis is most controversial is plasminogen activator (PA), a serine proteinase that converts the ubiquitous extracellular zymogen plasminogen into the trypsinlike proteinase plasmin. Plasmin, in turn, dissolves the fibrin network of the blood clot, degrades interstitial glycoproteins such as fibronectin and laminin, and converts procollagenases into collagenases necessary for degradation of basement membrane collagen (8). Such a spectrum of activities renders the plasminogen activation system an ideal candidate to participate in tumor invasion and metastasis, since high levels of PA are closely associated with neoplasia-related phenomena (8, 41). The hypothesis concerning the role of the plasminogen activation system in tumor invasion has recently been supported by studies measuring cellular invasion in vitro in assay systems designed to simplify study of tumor cell invasion and metastasis (30,42). These studies have demonstrated that the passage of tumor cells through a barrier of basement membrane in vitro requires a proteolytic cascade of which the final proteinase collagenase is generated by PA-activated plasmin. That PA may also be involved in tumor invasion under physiological conditions is suggested by the immunocytochemical localization of urokinase-type PA (uPA) in areas of invasive growth of the Lewis lung carcinoma (47). Furthermore, the metastatic spread of the Hep-3 human carcinoma in an avian system was significantly inhibited by antibodies specifically blocking the activity of human uPA without affecting either the local growth of the tumor or the avian uPA activity (37,38). Similarly, inhibition by antibod-* Corresponding author.ies of surface-localized uPA on B16 melanoma cells reduced the capacity of the cells to generate experimental metastasis in mice (20). In contrast to the latter cases, in numerous other studies the role of PA in tumor metastasis was inferred from circumstantial rather than direct evidence (for reviews and detailed lists of references, see references 6, 8, 14, 22, 26, 34, 40, and 43). For example, in sublines derived from transplanted tumors, such as the B16 melanoma and the Lewis lung carcinoma, comparison was made between PA production and metastatic capacity (6,9,14,40,54). Comparison was also made between PA levels of spontaneously arising human tumors of the colon, breast, and prostate and PA produced by their invasive and metastatic derivatives (5,22,26,27,36

show abstract

The Role of Hemostasis and Fibrinolysis in the Metastatic Spread of Cancer

Cited by 100 publications

References 34 publications

Plasminogen activator inhibitor is associated with the extracellular matrix of cultured bovine smooth muscle cells.

Plasminogen activator inhibitor is associated with the extracellular matrix of cultured bovine smooth muscle cells.

The Use of Heparin for Treating Human Malignancies

Expression of human recombinant plasminogen activators enhances invasion and experimental metastasis of H-ras-transformed NIH 3T3 cells.

Contact Info

Product

Resources

About