Heparanase induces tissue factor expression in vascular endothelial and cancer cells

Abstract

Summary. Background: Over-expression of tissue factor (TF) and activation of the coagulation system are common in cancer patients. Heparanase is an endo-b-D-glucuronidase that cleaves heparan sulfate chains on cell surfaces and in the extracellular matrix, activity that closely correlates with cell invasion, angiogenesis and tumor metastasis. The study was undertaken to investigate the involvement of heparanase in TF expression. Methods: Tumor-derived cell lines were transfected with heparanase cDNA and TF expression was examined. The effect of exogenous addition of active and inactive heparanase on TF expression and activity was studied in tumor cell lines and primary human umbilical vein endothelial cells. TF expression was also explored in heparanase over-expressing transgenic (Tg) mice. Blast cells were collected from acute leukemia patients and TF and heparanase expression levels were analyzed. Results: Over-expression of heparanase in tumor-derived cell lines resulted in a 2-fold increase in TF expression levels, and a similar trend was observed in heparanase Tg mice in vivo. Likewise, exogenous addition of heparanase to endothelial or tumor-derived cells resulted in enhanced TF expression and activity. Interestingly, TF expression was also induced in response to enzymatically inactive heparanase, suggesting that this effect was independent of heparanase enzymatic activity. The regulatory effect of heparanase on TF expression involved activation of the p38 signaling pathway. A positive correlation between TF expression levels and heparanase activity was found in blasts collected from 22 acute leukemia patients. Conclusions: Our results indicate that in addition to its well-known function as an enzyme paving a way for invading cells, heparanase also participates in the regulation of TF gene expression and its related coagulation pathways.

Heparanase enhances the generation of activated factor X in the presence of tissue factor and activated factor VII

“…Overall, our results support the notion that heparanase is a potential modulator of blood hemostasis, and suggest a novel mechanism by which heparanase is involved in direct activation of the coagulation cascade. Our previous findings on the regulation of TF 14 and TFPI 15 by heparanase indicate a more fundamental role of heparanase in coagulation. The elevation of heparanase levels in human tumors, together with the pro-thrombotic state of most neoplasms, suggests possible clinical relevance of the procoagulant function of heparanase, as demonstrated for leukemia patients (Figure 4).…”

“…Recently, we demonstrated that heparanase may also affect the hemostatic system. Heparanase was shown to up-regulate TF expression 14 and interact with TFPI on the cell surface, leading to dissociation of TFPI from the cell membrane, resulting in increased cell surface coagulation activity. 15 The present work further investigates the role of heparanase in activation of the coagulation system.…”

Increased Tissue Factor Expression Is Associated with Reduced Survival in Non–Small Cell Lung Cancer and with Mutations of TP53 and PTEN

“…However, recent studies have also shown that heparanase protein is synthesized by tumor cells (10 ) with an expression possibly regulated by p53 (11 ) and EGR1 (early growth response 1) (12 ). On the other hand, heparanase can induce TF synthesis in endothelial cells and cancer cells (13 ) and can be involved in tumor angiogenesis and metastasis (14,15 ).…”

Lack of association of the heparanase gene single-nucleotide polymorphism Arg307Lys with acute lymphoblastic leukaemia in patients from Northern Ireland

“…4 Expression of heparanase has been detected in blasts of human leukaemias, including acute myeloid leukaemia and acute lymphoblastic leukaemia (ALL); however, its involvement in haematological malignancies has not been systematically assessed. 5,6 Ostrovsky et al 7 have recently shown that a single-nucleotide polymorphism (SNP) of the heparanase gene (rs11099592), which causes the substitution of arginine with lysine at position 307 (Arg307Lys) of the heparanase polypeptide, was significantly associated with ALL. They reported that genotype and allele frequencies of the SNP in a group of 43 Israeli ALL patients were significantly different from a group of 103 healthy control individuals ( w 2…”