Cancer cell procoagulant: A novel vitamin K-dependent activity

Delaini, Federica; Colucci, Mario; Vitti, G. De Bellis; Locati, Daniela; Poggi, Andreina; Semeraro, Nicola; Donati, Maria Benedetta

doi:10.1016/0049-3848(81)90097-9

Cited by 31 publications

(18 citation statements)

References 6 publications

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“…11,12 This procoagulant factor exerts vitamin K-dependent activity and directly activates FX in the absence of FVII. Increased levels of CP have been reported in different types of advanced tumours and in acute promyelocytic leukaemia.…”

Section: à10mentioning

confidence: 99%

The heparins and cancer: review of clinical trials and biological properties

2004

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Abstract:The association between cancer and thromboembolic disease is a well-known phenomenon and can contribute significantly to the morbidity and mortality of cancer patients. The spectrum of thromboembolic manifestations in cancer patients includes deep vein thrombosis, pulmonary embolism, but also intravascular disseminated coagulation and abnormalities in the clotting system in the absence of clinical manifestations. Unfractioned heparin (UFH) and particularly low molecular weight heparins (LMWHs) are widely used for the prevention and treatment of thromboembolic manifestations that commonly accompany malignancies. Malignant growth has also been linked to the activity of heparin-like glycosoaminoglycans, to neoangiogenesis, to protease activity, to immune function and gene expression. All these factors contribute in the proliferation and dissemination of malignancies. Heparins may play a role in tumour cell growth and in cancer dissemination. The aims of the study are to review the efficiency of heparins in the prevention and treatment of cancer-related thromboembolic complications, and review the biological effects of heparins. Heparins are effective in reducing the frequency of thromboembolic complications in cancer patients. Meta-analyses comparing unfractioned heparins and LMWHs for the treatment of deep vein thrombosis have shown better outcome with a reduction of major bleeding complications in patients treated with LMWHs. LMWH have antitumour effects in animal models of malignancy: heparin oligosaccharides containing less than 10 saccharide residues have been found to inhibit the biological activity of basic fibroblast growth factor (bFGF), whereas heparin fragments with less than 18 saccharide residues have been reported to inhibit the binding of vascular endothelial growth factor (VEGF) to its receptors on endothelial cells. It has been shown that LMWH, in contrast with UFH, can hinder the binding of growth factors to their high-affinity receptors as a result of its smaller size. In vitro heparin fragments of less than 18 saccharide residues reduce the activity of VEGF, and fragments of less than 10 saccharide residues inhibit the activity of bFGF. Small molecular heparin fractions have also been shown to inhibit VEGF-and bFGF-mediated angiogenesis in vivo, in contrast with UFH. Moreover, heparin may influence malignant cell growth through other different interrelated mechanisms: inhibition of (1) heparin-binding growth factors that drive malignant cell growth; (2) tumour cell heparinases that mediate tumour cell invasion and metastasis; (3) cell surface selectin-mediated tumour cell metastasis and blood coagulation. The above evidence, together with favourable pharmaco-properties and with a reduction in major bleeding complications, suggests an important role for LMWHs in thromboprophylaxis and in the therapy of venous thromboembolism in cancer patients. There is sufficient experimental data to suggest that heparins may interfere with various aspects of cancer proliferation, angiogenesis, and meta...

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Section: à10mentioning

confidence: 99%

The heparins and cancer: review of clinical trials and biological properties

2004

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“…It is confined to the malignant phenotype and, in murine tumors, it is associated with the metastatic potential of tumor cells. CP appears to be a novel vitamin K-dependent activity, since both in murine and in human tumors it is depressed by treatment with warfarin ® or vitamin K-deficient diet [36, 37, 38, 39]. …”

Section: Pathogenetic Mechanismsmentioning

confidence: 99%

Pathogenetic Mechanisms of Thrombosis in Malignancy

Donati¹,

Falanga

2001

Acta Haematol

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The interactions between components of the hemostatic system and cancer cells are multifaceted. Strong clinical evidence is accumulating on the prothrombotic tendency of cancer patients, which is enhanced by anticancer therapy, such as surgery and chemotherapy. The mechanisms of thrombus promotion in malignancy include some general responses of the host to the tumor (acute phase, inflammation, angiogenesis) and specific interactions of tumor cells with the clotting/fibrinolysis systems and with blood (leukocytes, platelets) or vascular cells. It is at present difficult to rank the relative weight of these multiple interactions on the basis of the well-recognized clinical evidence of enhanced thrombotic episodes in tumor patients. In any case, the mechanisms explored so far offer a sound experimental basis for prevention/treatment of thrombosis in tumor patients and leave open the possibility that some antithrombotic strategies may also affect the processes of tumor growth and dissemination.

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“…The experimental approaches reviewed in this paper were aimed to offer a biochemical basis to the observation that a new vitamin K-dependent activity was peculiar of some tumor tissues [2][3][4], We have shown indeed that, among extra hepatic sites, also tumor tissues can express carboxylase activity, the substrate of which accumulates during warfa rin pretreatment. This carboxylase system appears to be functioning in vivo, since war farin was shown to possess some direct ef fects on tumor tissues, such as the depression Carboxylase activity was measured in microsomal preparations of tissues harvested from rabbits im planted 18 days previously.…”

Section: Discussionmentioning

confidence: 99%

“…We have repeatedly observed that vitamin K deficiency, either dietarily or pharmaco logically induced by warfarin, inhibits the activity of a procoagulant principle in var ious types of murine tumor cells [1,2], Whether these observations may lead to the discovery of a new vitamin K-dependent protein [3,4], specifically present in some tumor cells, is a stimulating hypothesis which deserves further biochemical basis. Roncaglioni Carboxylase activity was measured in microsomal preparations of tissues harvested from animals implanted with 10s 3LL cells intramuscularly 18 days previously [11,12]; warfarin was given in drinking water as described elsewhere [2,4], Vitamin K is considered to act at the mi crosomal level as a coenzyme in a post trans lational carboxylation reaction which trans forms residues of glutamic acid (Glu) in some proteins into y-carboxylated glutamic acid (Gla) residues [5], This activity was first dis covered in the liver [6], where the y-carboxylation involved proteins of blood coagula tion.…”

Section: Introductionmentioning

confidence: 99%

γ-Glutamyl Carboxylase Activity in Experimental Tumor Tissues: A Biochemical Basis for Vitamin K Dependence of Cancer Procoagulant

Roncaglioni

Dalessandro

Casali³

et al. 1986

Pathophysiol Haemos Thromb

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Rabbit V2 carcinoma tissues have been described to possess a procoagulant activity with specific characteristics; this material has been purified and identified as a cysteine proteinase able to directly activate coagulation factor X. We have shown here that the procoagulant activity of V2 carcinoma extracts is depressed in warfarin-treated animals, thus suggesting that cancer procoagulant could represent a new vitamin K-dependent protein. The biochemical basis for this effect is offered by the identification of γ-glutamyl carboxylase in the microsomal fraction of tumor tissues. The V2 carcinoma has a carboxylase activity which is increased in warfarin-treated animals. An endogenous substrate of tumor carboxylase, the nature of which has not been identified, has been found 5-fold increased in warfarin-treated animals. The presence of γ-glutamyl carboxylase was also described in several murine tumors including both carcinomas and fibrosarcomas. It is worth mentioning that all the tumors tested produce a procoagulant with the peculiar characteristics of that described in V2 carcinoma. It is conceivable that cancer procoagulant could represent at least one of the substrates for γ-glutamyl carboxylase in these experimental tumor tissues.

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Cancer cell procoagulant: A novel vitamin K-dependent activity

Cited by 31 publications

References 6 publications

The heparins and cancer: review of clinical trials and biological properties

The heparins and cancer: review of clinical trials and biological properties

Pathogenetic Mechanisms of Thrombosis in Malignancy

γ-Glutamyl Carboxylase Activity in Experimental Tumor Tissues: A Biochemical Basis for Vitamin K Dependence of Cancer Procoagulant

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