Heparanases and tumor metastasis

Nakajima, Motowo; Irimura, Tatsuro; Nicolson, Garth L.

doi:10.1002/jcb.240360207

Cited by 295 publications

(280 citation statements)

References 53 publications

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“…MMP-2 and -9 are suggested to play a major role in metastasis (Kugler, 1999;Westermarck and Kahari, 1999). Heparanase activity has also been found to correlate with the metastatic potential of various types of cancer cells (Nakajima et al, 1988). In this study the dose-dependent inhibition of NAC-HCPS on the invasion of tumour cells into Matrigel has been observed ( Figure 6).…”

Section: Discussionsupporting

confidence: 54%

Periodate-treated, non-anticoagulant heparin-carrying polystyrene (NAC-HCPS) affects angiogenesis and inhibits subcutaneous induced tumour growth and metastasis to the lung

et al. 2002

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Periodate-treated, non-anticoagulant heparin-carrying polystyrene consists of about ten periodate-oxidized, alkaline-degraded low molecular weight-heparin chains linked to a polystyrene core and has a markedly lower anti-coagulant activity than heparin. In this study, we evaluated the effect of non-anticoagulant heparin-carrying polystyrene on tumour growth and metastasis. Non-anticoagulant heparin-carrying polystyrene has a higher activity to inhibit vascular endothelial growth factor-165-, fibroblast growth factor-2-or hepatocyte growth factor-induced human microvascular endothelial cell growth than heparin, ten periodate-oxidized-heparin and ten periodate-oxidized-low molecular weight-heparin, which is probably due to the heparin-clustering effect of non-anticoagulant heparin-carrying polystyrene. Non-anticoagulant heparin-carrying polystyrene inhibited human microvascular endothelial cell, B16 melanoma and Lewis lung cancer cell adhesion to Matrigel-coated plates. Non-anticoagulant heparin-carrying polystyrene also showed strong inhibitory activities in the tubular formation of endothelial cells on Matrigel and B16-melanoma and Lewis lung cancer cell invasion in a Matrigel-coated chamber assay. In vivo studies showed that growth of subcutaneous induced tumours and lung metastasis of B16-melanoma and Lewis lung cancer cells were more effectively inhibited by non-anticoagulant heparin-carrying polystyrene than ten periodate-oxidized-heparin and ten periodate-oxidized-low molecular weight-heparin. Furthermore, non-anticoagulant heparin-carrying polystyrene markedly reduced the number of CD34-positive vessels in subcutaneous Lewis lung cancer tumours, indicating a strong inhibition of angiogenesis. These results suggest that non-anticoagulant heparin-carrying polystyrene has an inhibitory activity on angiogenesis and tumour invasion and may be very useful in cancer therapy.

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Section: Discussionsupporting

confidence: 54%

Periodate-treated, non-anticoagulant heparin-carrying polystyrene (NAC-HCPS) affects angiogenesis and inhibits subcutaneous induced tumour growth and metastasis to the lung

et al. 2002

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“…Previous studies showed that heparanase is capable of degrading the heparan sulfate chains of HSPGs widely ranged in BM and ECM and enhancing the invasion and metastasis of malignant cells (4,5,8,19,20). In this study, we have observed heparanase message expression even in very early invasive carcinomas within the lamina propria of gastric mucosa, but not in the normal epithelium or noninvasive carcinomas.…”

Section: Discussionmentioning

confidence: 99%

Heparanase: A Key Enzyme in Invasion and Metastasis of Gastric Carcinoma

et al. 2002

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Previous reports have shown that the biochemical activity of heparanase is significantly correlated with the invasion and metastasis of malignant cells in vitro. Recently, it was found that the human heparanase gene was cloned and highly expressed in malignant cell lines and human solid malignant tumors. In the present study, we investigated the heparanase mRNA expression by using in situ hybridization in 116 paraffin-embedded tissues of primary gastric carcinomas. To explore its clinicopathologic significance, it was detected in the various steps of tumor progression and then compared with prognostic indicators. As a result, the heparanase expression was more prevalent in late-stage rather than early-stage carcinomas (P < .0001) and was more frequent in tumors of large size (P ‫؍‬ .0212). Expression also correlated with lymphatic (P ‫؍‬ .0086) and venous (P ‫؍‬ .0171) invasion and with negative prognostic factors such as lymph nodal (P < .0001) and distant (P ‫؍‬ .0221) metastases. However, in a multivariate analysis, messenger RNA expression of heparanase was not an independent prognostic factor. It was concluded that heparanase might play an important role in the development of invasion and metastasis of the gastric cancer. It was indicated that patients with heparanase-positive gastric carcinoma would have a greater chance of metastasis with a poor prognosis.

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“…Indeed, HSPG catabolism is observed in inflammation, wound repair, diabetes, and cancer metastasis, suggesting that enzymes that degrade the HS chains play important roles in pathologic processes (3, 4). Furthermore, malignant cells are capable of modulating cellular interactions with HSPGs by producing and releasing a HS-degrading enzyme, heparanase (3,7,27,28). Recently, we reported that purified, high M r subpopulations of cell surface HS were more sensitive to heparanase action than secreted HS (29).…”

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confidence: 99%

Heparanase and a Synthetic Peptide of Heparan Sulfate-interacting Protein Recognize Common Sites on Cell Surface and Extracellular Matrix Heparan Sulfate

Marchetti¹,

Liu²,

Spohn³

et al. 1997

Journal of Biological Chemistry

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Metastasis occurs via a sequential and complex series of interactions between tumor cells and normal host cells and tissues (1, 2). During the formation of metastases, migrating cells are confronted by natural tissue barriers, such as connective tissue stroma and basal lamina (2, 3). The ability of malignant cells to penetrate these barriers depends upon the presence of enzymes capable of degrading extracellular matrix (ECM) 1 components (1-5). For these reasons, considerable effort has been focused on the study of tissue-degradative enzymes produced and secreted by metastatic tumor cells as well as normal cells of the tissue being invaded.Important ECM targets for degradation by invading melanoma cells are the heparan sulfate (HS) chains found on proteoglycans (3, 6, 7). HS are highly negatively charged linear polysaccharides consisting of alternating residues of uronic acids and glucosamine. Proteins containing one or more covalently attached HS chains are called HS proteoglycans (HSPGs). The dynamic role of HSPGs in biology has become increasingly apparent (8 -23). As a result of characterizing heparin (HP) and HS binding sites related to the initial attachment of trophoblast cells to uterine epithelial cells of murine and human origin, we recently reported the cell surface expression and molecular cloning of a novel HP/HS-interacting protein (HIP) of human epithelial and endothelial cells (24 -26). HIP not only recognizes HS and HP in a highly specific fashion, but it also binds a subset of HP and forms of HS enriched at cell surfaces and in ECM. In contrast, HIP does not bind intracellular or secreted forms of HS. Furthermore, HIP also appears to bind the anticoagulantly active species of HP efficiently and with high affinity. 2 HP octasaccharides, but not hexasaccharides, are large enough to bind HIP with high affinity. Thus, HIP appears to recognize a motif that at least overlaps the anticoagulant motif in HP and HS chains.In light of the above findings, activities that mediate HSPG degradation are expected to have significant regulatory consequences. Indeed, HSPG catabolism is observed in inflammation, wound repair, diabetes, and cancer metastasis, suggesting that enzymes that degrade the HS chains play important roles in pathologic processes (3, 4). Furthermore, malignant cells are capable of modulating cellular interactions with HSPGs by producing and releasing a HS-degrading enzyme, heparanase (3,7,27,28). Recently, we reported that purified, high M r subpopulations of cell surface HS were more sensitive to heparanase action than secreted HS (29). In the present study, we have investigated the relationship between tumor (melanoma) heparanase activity and HIP binding in HS subpopulations whether on the cell surface, secreted, or deposited in the ECM. By use of sensitive heparanase assays that separate

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Heparanases and tumor metastasis

Cited by 295 publications

References 53 publications

Periodate-treated, non-anticoagulant heparin-carrying polystyrene (NAC-HCPS) affects angiogenesis and inhibits subcutaneous induced tumour growth and metastasis to the lung

Periodate-treated, non-anticoagulant heparin-carrying polystyrene (NAC-HCPS) affects angiogenesis and inhibits subcutaneous induced tumour growth and metastasis to the lung

Heparanase: A Key Enzyme in Invasion and Metastasis of Gastric Carcinoma

Heparanase and a Synthetic Peptide of Heparan Sulfate-interacting Protein Recognize Common Sites on Cell Surface and Extracellular Matrix Heparan Sulfate

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