Modulation of Neovascularization and Metastasis by Species of Heparin

Vlodavsky, Israël; Ishai-Michaeli, R.; Mohsen, M.; Bar-Shavit, Rachel; Catane, Raphael; Ekre, H P; Svahn, Carl M.

doi:10.1007/978-1-4899-2444-5_31

Cited by 37 publications

(48 citation statements)

References 34 publications

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“…However, most of these studies failed to show a clinical benefit (19,20). Nevertheless, further studies continued to show an effect of heparin or low-molecular-weight heparin on reducing metastasis and prolonging survival in mice (11,(21)(22)(23). Meanwhile, other studies showed that heparin is not just an anticoagulant, but a complex set of multifunctional glycosaminoglycan molecules with many other potential biological effects (24)(25)(26).…”

Section: Biochemistry For the Article ''Functional Transitions In Mymentioning

confidence: 99%

“…Thus, we suggest that the use of heparin therapy to inhibit human carcinoma metastasis deserves to be reexamined. Of course, heparin may well have other beneficial effects in cancer via inhibition of angiogenesis or heparanases (10,16,21,24,28,29). All previously recognized heparanase inhibitors we have tested can also inhibit tumor cell adhesion to P-selectin (unpublished data).…”

Section: Enhanced Monocyte (Macrophage Precursor) Association With Tumormentioning

confidence: 99%

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Heparin and cancer revisited: Mechanistic connections involving platelets, P-selectin, carcinoma mucins, and tumor metastasis

Borsig

Wong

Feramisco

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

627

650

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Independent studies indicate that expression of sialylated fucosylated mucins by human carcinomas portends a poor prognosis because of enhanced metastatic spread of tumor cells, that carcinoma metastasis in mice is facilitated by formation of tumor cell complexes with blood platelets, and that metastasis can be attenuated by a background of P-selectin deficiency or by treatment with heparin. The effects of heparin are not primarily due to its anticoagulant action. Other explanations have been suggested but not proven. Here, we bring together all these unexplained and seemingly disparate observations, showing that heparin treatment attenuates tumor metastasis in mice by inhibiting P-selectin-mediated interactions of platelets with carcinoma cell-surface mucin ligands. Selective removal of tumor mucin P-selectin ligands, a single heparin dose, or a background of P-selectin deficiency each reduces tumor cell-platelet interactions in vitro and in vivo . Although each of these maneuvers reduced the in vivo interactions for only a few hours, all markedly reduce long-term organ colonization by tumor cells. Three-dimensional reconstructions by using volume-rendering software show that each situation interferes with formation of the platelet “cloak” around tumor cells while permitting an increased interaction of monocytes (macrophage precursors) with the malignant cells. Finally, we show that human P-selectin is even more sensitive to heparin than mouse P-selectin, giving significant inhibition at concentrations that are in the clinically acceptable range. We suggest that heparin therapy for metastasis prevention in humans be revisited, with these mechanistic paradigms in mind.

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Section: Biochemistry For the Article ''Functional Transitions In Mymentioning

confidence: 99%

Section: Enhanced Monocyte (Macrophage Precursor) Association With Tumormentioning

confidence: 99%

Heparin and cancer revisited: Mechanistic connections involving platelets, P-selectin, carcinoma mucins, and tumor metastasis

Borsig

Wong

Feramisco

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

627

650

View full text Add to dashboard Cite

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“…(tail vein) inoculation of rat C-6 glioma cells (1 Â 10 5 cells/mouse) that were either incubated with 5-aza-2dC (5 days; 0.2 mM) or left untreated. The animals were sacrificed 20 days later; following fixation, their lungs surface was examined for the number of glioma cell colonies (Vlodavsky et al, 1994). The data were analyzed for significance by using two tailed Student's t-test.…”

Section: Experimental Metastasismentioning

confidence: 99%

“…The ability of HSPG to interact with various ECM macromolecules and with different attachment sites on plasma membranes suggests a key role for this proteoglycan in the self-assembly and insolubility of ECM components, as well as in cell adhesion and locomotion (Wight et al, 1992;Iozzo, 1998;Bernfield et al, 1999). Cleavage of HS therefore plays a significant role in extravasation and dissemination of normal and malignant blood-borne cells (Vlodavsky et al, 1992;Vlodavsky et al, 1994;Parish et al, 2001). HS is unique in its ability to sequester a multitude of proteins, ensuring that a wide variety of bioactive molecules, including heparin-binding proangiogenic factors, adhere to the cell surface and ECM (Iozzo, 1998;Bernfield et al, 1999;Gallagher, 2001).…”

Section: Introductionmentioning

confidence: 99%

Role of promoter methylation in regulation of the mammalian heparanase gene

et al. 2003

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Mammalian heparanase (endo-b-glucuronidase) degrades heparan sulfate proteoglycans and is an important modulator of the extracellular matrix and associated factors. The enzyme is preferentially expressed in neoplastic tissues and contributes to tumour metastasis and angiogenesis. To investigate the epigenetic regulation of the heparanase locus, methylation-specific and bisulfite PCR were performed on a panel of 22 human cancer cell lines. Cytosine methylation of the heparanase promoter was associated with inactivation of the affected allele. Despite lack of sequence homology, extensively methylated CpG islands were found both in human choriocarcinoma (JAR) and rat glioma (C-6) cells which lack heparanase activity. Treatment of these cells with demethylating agents (5-azacytidine, 5-aza-2 0 -deoxycytidine) resulted in stable dose-and time-dependant promoter hypomethylation accompanied by reappearance of heparanase mRNA, protein and enzymatic activity. An inhibitor of histone deacetylase, Trichostatin A, failed to induce either of these effects. Upregulation of heparanase expression and activity by demethylating drugs was associated with a marked increase in lung colonization by pretreated C-6 rat glioma cells. The increased metastatic potential in vivo was inhibited in mice treated with laminaran sulfate, a potent inhibitor of heparanase activity. We propose a model wherein expression of mammalian heparanase gene is modulated by the interplay between trans-activating genetic and cis-inhibitory epigenetic elements in its promoter.

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“…Such enzymes, commonly referred to as "heparanases," contribute to the intracellular degradation of HS proteoglycans (15,16) but are also released into the extracellular matrix, where they appear to modulate several processes of pathophysiological importance. Heparanases thus contribute to the remodeling of extracellular matrix and basement membranes prerequisite to angiogenesis (17) and to the egress of metastatic tumor cells (18) and other types of blood-borne cells (19) from the vasculature. They may regulate growth factor action by releasing heparan sulfate-bound growth factors such as basic fibroblast growth factor from cell surfaces or from the extracellular matrix (20,21).…”

mentioning

confidence: 99%

Substrate Specificity of Heparanases from Human Hepatoma and Platelets

Pikas¹,

Li²,

Vlodavsky³

et al. 1998

Journal of Biological Chemistry

252

186

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Heparan sulfate proteoglycans, attached to cell surfaces or in the extracellular matrix, interact with a multitude of proteins via their heparan sulfate side chains. Degradation of these chains by limited (endoglycosidic) heparanase cleavage is believed to affect a variety of biological processes. Although the occurrence of heparanase activity in mammalian tissues has been recognized for many years, the molecular characteristics and substrate recognition properties of the enzyme(s) have remained elusive.In the present study, the substrate specificity and cleavage site of heparanase from human hepatoma and platelets were investigated.

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Modulation of Neovascularization and Metastasis by Species of Heparin

Cited by 37 publications

References 34 publications

Heparin and cancer revisited: Mechanistic connections involving platelets, P-selectin, carcinoma mucins, and tumor metastasis

Heparin and cancer revisited: Mechanistic connections involving platelets, P-selectin, carcinoma mucins, and tumor metastasis

Role of promoter methylation in regulation of the mammalian heparanase gene

Substrate Specificity of Heparanases from Human Hepatoma and Platelets

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