Factor X-activating activity from Lewis lung carcinoma

Hilgard, P.; Whur, P

doi:10.1038/bjc.1980.109

Cited by 30 publications

(15 citation statements)

References 6 publications

(3 reference statements)

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“…A proteolytic enzyme, cancer procoagulant, has been purified from rabbit V2 carcinoma and some of its physical, chemical, and enzymatic properties have been determined.' In addition, cancer procoagulant activity has been identified in extracts of several human malignant tumors (9) and in cultured malignant cells2 (10)(11)(12)(13) Citrated bovine and human plasma were obtained fresh and prepared as described previously (14) for use in the singlestage recalcified coagulation time assay. Pure bovine Factor X was kindly provided by Dr. Earl Davie and used in the twostage clotting assay as described previously (14).…”

Section: Introductionmentioning

confidence: 99%

A factor X-activating cysteine protease from malignant tissue.

Gordon¹,

Cross²

1981

J. Clin. Invest.

224

109

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A B S T R A C T A proteolytic procoagulant has been identified in extracts of human and animal tumors and in cultured malignant cells. It directly activated Factor X but its similarity to other Factor X-activating serine proteases was not clear. This study describes work done to determine whether this enzyme, cancer procoagulant, is a serine or cysteine protease. Purified cancer procoagulant from rabbit V2 carcinoma was bound to a p-chloromercurialbenzoate-agarose affinity column and was eluted with dithiothreitol. The initiation of recalcified, citrated plasma coagulation activity by cancer procoagulant was inhibited by 5 mM diisopropylfluorophosphate, 1 mM phenylmethylsulfonylfluoride, 0.1 mM HgCl2, and 1 mM iodoacetamide. Activity was restored in the diisopropylfluorophosphate-, phenylmethylsulfonylfluoride-, and HgCl2-inhibited samples by 5 mM dithiothreitol; iodoacetamide inhibition was irreversible. Russell's viper venom, a control Factor Xactivating serine protease, was not inhibited by either 0.1 mM HgCl2 or 1 mM iodoacetamide. The direct activation ofFactor X by cancer procoagulant in a two-stage assay was inhibited by diisopropylfluorophosphate and iodoacetamide. Diisopropylfluorophosphate inhibits serine proteases, and an undefined impurity in most commercial preparations inhibits cysteine proteases. Hydrolysis of diisopropylfluorophosphate with CuS04 and imidazole virtually eliminated inhibition of thrombin, but cancer procoagulant inhibition remained complete, suggesting that cancer procoagulant was inhibited by the undefined impurity. These results suggest that cancer procoagulant is a cysteine endopeptidase, which distinguishes it from other coagulation factors including tissue factor. This and other data suggest that neoplastic cells produce this unique cysteine protease which may initiate blood coagulation.

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Section: Introductionmentioning

confidence: 99%

A factor X-activating cysteine protease from malignant tissue.

Gordon¹,

Cross²

1981

J. Clin. Invest.

224

109

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“…The ability of tumour cells to form fibrin is related to the presence of tumour procoagulant activity (Cajot et al, 1986). The PCA is largely tissue thromboplastin-like, being FVIIdependent, although alternate mechanisms which involve direct FX activation exist (Hilgard & Whur, 1980;Gordon & Cross, 1981). Zacharski et al (1987) have reported the occurrence of thrombin-generated cleavage sites of human fibrinogen within the connective tissue stroma adjacent to viable tumour cells in fresh frozen sections of small cell carcinoma of lung by means of immunohistochemistry, thereby providing indirect evidence of thrombin in tumour cells.…”

Section: Discussionmentioning

confidence: 99%

“…O'Meara (1958) first described the procoagulant activity of cancer cells. PCA could be present at the cancer cell surface or secreted by it, and may be of two types: (a) FVII-dependent, tissue thromboplastin activity (Rickles & Edwards, 1983;Markus, 1984;Cajot et al, 1986); (b) FVII-independent, direct FX activator (Curatolo et al, 1979;Hilgard & Whur, 1980;Gordon & Cross, 1981 …”

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confidence: 99%

Procoagulant activity of human tumours: existence of Xa and thrombin-like activities

Sarode

Marwaha²,

Gupta³

1990

Br J Cancer

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Summary We have analysed 15 infiltrating duct carcinomas of the breast, 10 gastrointestinal adenocarcinomas, one each of the thyroid and larynx, and four mesenchymal tumours for the presence and the nature of procoagulant activity (PCA). The metastatic tumours had a significantly higher PCA (P = 0.01-0.001) as compared to the non-metastatic tumours in the respective groups, and almost 20-25 times the activity as comnpared to normal tissue (P = 0.001). Although the majority of the tumours had FVII-dependent tissue thromboplastin-like activity, some of the tumour homogenates revealed the presence of an FVII-independent PCA. Unlike the known alternate PCA, which acts via factor X activation, this PCA was factor X independent. It caused clot formation in FX-deficient plasma (six cases) and purified fibrinogen solution (four cases), indicating the presence of a Xa-like enzyme or a thrombin-like activity respectively.As early as 1938, Sproule recognised the association between malignancy and alterations in haemostasis. Since then, it is well known that malignant disease is associated with a high incidence of vascular thrombosis or disseminated intravascular coagulation (Rickles & Edwards, 1983). Deposition of fibrin within and around the tumour has been convincingly demonstrated immunohistochemically and ultrastructurally (Rickles & Edwards, 1983) but its precise role in the growth and spread of the tumour is largely unknown. O'Meara (1958) first described the procoagulant activity of cancer cells. PCA could be present at the cancer cell surface or secreted by it, and may be of two types: (a) FVII-dependent, tissue thromboplastin activity (Rickles & Edwards, 1983;Markus, 1984;Cajot et al., 1986); (b) FVII-independent, direct FX activator (Curatolo et al., 1979;Hilgard & Whur, 1980;Gordon & Cross, 1981 Results PCA of breast tumoursThe mean PCA of metastatic infiltrating duct carcinoma was 76.1 % (range 15-150% of HBT) and was significantly higher

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“…Factor X activators have been described in various types of malig nant cells such as B16 mouse melanoma [20], Lewis lung carcinoma [21] and others [11]. Microvesicles shed by several guinea pig, mouse and human tumor cells have been shown to contain procoagulant activity, acting at the level of prothrombinase, that is in the activation of factor X [22],…”

Section: Generation O F Thrombinmentioning

confidence: 99%

Platelet Contribution to the Formation of Metastatic Foci: The Role of Cancer Cell-Induced Platelet Activation

Bastida¹,

Ordinas²

1988

Pathophysiol Haemos Thromb

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Platelets are thought to be involved in the development of blood borne metastasis. Ultrastructural and experimental studies demonstrate that association between tumor cells and platelets with subsequent activation of the coagulation cascade takes place in malignancy. Several hypotheses have been proposed to explain the mechanisms by which tumor cells activate platelets including generation of thrombin, ADP release and involvement of arachidonate metabolism. Perfusion studies with human homologous systems showed that intact tumor cells and tumor cell microvesicles were able to induce platelet thrombogenicity under defined flow conditions. The presence of divalent cations and plasma factors was necessary for the cancer cells to exert their activating capacity. These results suggest a role for platelets in the development of secondary metastasis as well as in the thrombotic events of malignancy.

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Factor X-activating activity from Lewis lung carcinoma

Cited by 30 publications

References 6 publications

A factor X-activating cysteine protease from malignant tissue.

A factor X-activating cysteine protease from malignant tissue.

Procoagulant activity of human tumours: existence of Xa and thrombin-like activities

Platelet Contribution to the Formation of Metastatic Foci: The Role of Cancer Cell-Induced Platelet Activation

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