Tumor cell surface heparan sulfate as cryptic promoters or inhibitors of tumor growth and metastasis

Liu, Dongfang; Shriver, Zachary; Venkataraman, Ganesh; Shabrawi, Yosuf El; Sasisekharan, Ram

doi:10.1073/pnas.012578299

Cited by 207 publications

(113 citation statements)

References 41 publications

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“…Alternatively, heparanase plays critical roles in tumor growth and metastasis by releasing bioactive HS fragments from the tumor cell surface HS-PGs, which can serve as potent promoters of tumor progression. Being consistent with this concept, HS fragments generated from tumor cell surface HS-PGs by the treatment with bacterial heparinase promoted tumor cell growth mediated through basic fibroblast growth factor signaling pathways (63). In the transition to malignancy in human colon adenoma cells, the overall molecular organization of HS is preserved but distinctly modified in the sulfated domains, and it may contribute to the aberrant behavior of the cancer cells (15).…”

Section: Discussionsupporting

confidence: 53%

Structural Recognition by Recombinant Human Heparanase That Plays Critical Roles in Tumor Metastasis

Okada

Yamada

Toyoshima

et al. 2002

Journal of Biological Chemistry

124

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Human heparanase is an endo-␤-D-glucuronidase that degrades heparan sulfate/heparin and has been implicated in a variety of biological processes, such as inflammation, tumor angiogenesis, and metastasis. Although the cloned enzyme has been demonstrated to have a critical role in tumor metastasis, the substrate specificity has been poorly understood. In the present study, the specificity of the purified recombinant human heparanase was investigated for the first time using a series of structurally defined oligosaccharides isolated from heparin/heparan sulfate. The best substrates were GlcN(NS,6S) (where HexUA represents hexuronic acid) has been proposed as a probable physiological target octasaccharide sequence. These findings will aid establishing a quantitative assay method using the above tetrasaccharide and designing heparan sulfate-based specific inhibitors of the heparanase for new therapeutic strategies.

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Section: Discussionsupporting

confidence: 53%

Structural Recognition by Recombinant Human Heparanase That Plays Critical Roles in Tumor Metastasis

Okada

Yamada

Toyoshima

et al. 2002

Journal of Biological Chemistry

124

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“…MMP-14 can shed CD44, and the intracellular CD44 fragment subsequently generated by presenilin/␥-secretase action may function as a transcription factor (70,86). In turn, the soluble CD44/CSPG may modulate tumor growth and spreading (87,88) in an analogous fashion to other liberated tumor cell surface proteoglycans (89,90). Because MMP-14 is initially up-regulated by the ␣ 2 ␤ 1 integrin, this integrin may modulate CD44 shedding and subsequent signaling by liberated CD44 domains.…”

Section: Discussionmentioning

confidence: 99%

Differential Modulation of Human Melanoma Cell Metalloproteinase Expression by α2β1 Integrin and CD44 Triple-helical Ligands Derived from Type IV Collagen

Baronas-Lowell

Lauer‐Fields

Borgia³

et al. 2004

Journal of Biological Chemistry

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Tumor cell binding to components of the basement membrane is well known to trigger intracellular signaling pathways. Signaling ultimately results in the modulation of gene expression, facilitating metastasis. Type IV collagen is the major structural component of the basement membrane and is known to be a polyvalent ligand, possessing sequences bound by the ␣ 1 ␤ 1 , ␣ 2 ␤ 1 , and ␣ 3 ␤ 1 integrins, as well as cell surface proteoglycan receptors, such as CD44/chondroitin sulfate proteoglycan (CSPG). The role of ␣ 2 ␤ 1 integrin and CD44/CSPG receptor binding on human melanoma cell activation has been evaluated herein using triple-helical peptide ligands incorporating the ␣1(IV)382-393 and ␣1(IV)1263-1277 sequences, respectively. Gene expression and protein production of matrix metalloproteinases-1 (MMP-1), -2, -3, -13, and -14 were modulated with the ␣ 2 ␤ 1 -specific sequence, whereas the CD44-specific sequence yielded significant stimulation of MMP-8 and lower levels of modulation of MMP-1, -2, -13, and -14. Analysis of enzyme activity confirmed different melanoma cell proteolytic potentials based on engagement of either the ␣ 2 ␤ 1 integrin or CD44/CSPG. These results are indicative of specific activation events that tumor cells undergo upon binding to select regions of basement membrane collagen. Based on the present study, triple-helical peptide ligands provide a general approach for monitoring the regulation of proteolysis in cellular systems.Melanoma is one of the most rapidly increasing malignancies in the world in both young and old patients, with over 50,000 newly diagnosed patients each year (1). 1 Mortality from cancer is frequently due to metastasis, given that surgical excision of the primary tumor considerably enhances the prognosis of a patient and prolongs survival (2). Metastasis is a complex series of finely coordinated events that results in cancer cells circulating in lymph and blood vascular systems to invade remote tissues and establish secondary sites of tumor growth (3). Extravasation of the tumor cell into secondary tissues requires alterations in cellular behaviors, resulting from specific adhesion to components of the basement membrane. Tumor cells respond to each of the various components of the ECM, 2 including the collagens; noncollagenous glycoproteins, such as fibronectin and laminin; and proteoglycans, such as decorin and syndecan (4). These interactions are known to occur through several families of cell surface receptors, including the integrins and cell surface proteoglycans.Integrins are heterodimeric proteins composed of one ␣ and one ␤ subunit and are the best described of the cell surface adhesion molecules. To date, there are 18 different ␣ subunits and 8 distinct ␤ subunits identified that combine to form at least 24 heterodimers (5-7). Although the specific integrin expression profile can fluctuate with tumor type and stage of progression, highly metastatic melanoma cells are known to up-regulate expression of, and ␣ 6 ␤ 4 integrins while down-regulating the expression ...

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“…16,25 Similarly, specific saccharide sequences within HSPGs play critical roles, influencing which FGF receptor isoform is activated and also acting as positive or negative regulators of FGF signaling. 15,26 Liu et al 27 have demonstrated that tumor cell surface heparan sulfate contains both cryptic promoters and inhibitors of growth and metastasis that can be differentially released by specific heparanases, and these influence the activity of FGF-2. Similarly, Zhang et al 28 have recently shown that membrane-associated HSPGs were effective promoters of FGF-2-initiated FGF receptor 1 phosphorylation, whereas equal amounts of soluble trypsinized HSPG were not.…”

Section: Discussionmentioning

confidence: 99%

Heparin Inhibition of Endothelial Cell Proliferation and Organization Is Dependent on Molecular Weight

Khorana

Sahni

Altland

et al. 2003

ATVB

132

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Objective-Studies have shown improved survival in cancer patients treated with low molecular weight heparins (LMWHs). Tumors depend on an expanding vasculature, and heparins may affect vessel growth and function. We investigated the effect of heparins differing in M r on selected endothelial cell properties. Methods and Results-Human umbilical vein endothelial cells were cultured with fibroblast growth factor-2 and heparins differing in M r . Cell proliferation was assessed by [ 3 H]thymidine incorporation, and vascular organization was assessed by in vitro assays. Maximum inhibition of 94Ϯ2% was observed with 6-kDa LMWH, greater than the inhibition seen with unfractionated heparin (58Ϯ8%) or 3-kDa LMWH (60Ϯ9%, Pϭ0.02 for both). No inhibition of proliferation was observed with heparin tetrasaccharide, octasaccharide, or pentasaccharide (fondaparinux). Three-and 6-kDa fractions decreased endothelial tube formation in Matrigel to 58Ϯ15% and 67Ϯ9% (PϽ0.05), respectively, of that with fibroblast growth factor-2, whereas no inhibition was observed with unfractionated heparin, tetrasaccharide, pentasaccharide, or octasaccharide. LMWH (6 kDa) also inhibited vessel formation in a placental explant. Conclusions-Heparin inhibition of endothelial cell proliferation and organization requires a chain length of Ͼ8 saccharide units, with maximal inhibition at M r of 6 kDa. This M r dependence differs from that required for anticoagulant activity. Key Words: low molecular weight heparins Ⅲ cancer Ⅲ angiogenesis Ⅲ endothelium Ⅲ thrombosis U nfractionated heparin is a heterogeneous mixture of polysaccharide molecules with a mean M r between 12 and 15 kDa containing glycosaminoglycan chains from 200 to 300 saccharide units. 1 Low molecular weight heparins (LMWHs) are fragments of unfractionated heparin produced by controlled enzymatic or chemical depolymerization with lower mean M r between 3 and 6 kDa and chain lengths of 12 to 18 saccharide units. 2 These structural differences result in important functional and pharmacokinetic differences, inasmuch as LMWHs have an increased anti-Xa/anti-IIa activity ratio, reduced plasma protein binding, decreased interaction with platelets and platelet factor 4, a prolonged half-life, and increased bioavailability after subcutaneous administration. 2,3 These changes give LMWHs an improved therapeutic profile compared with unfractionated heparin and have led to their increasing use in the treatment of venous and arterial thrombosis. See page 1954Individual studies 4,5 and meta-analyses 6,7 have found significant improvements in 3-and 6-month mortality in patients with cancer who were treated with LMWHs compared with unfractionated heparin. This survival advantage was found in subgroups differing in age, sex, and primary site of malignancy and could not be attributed to differences in thrombosis or bleeding complications. 8 The mechanism of this effect remains unknown but appears to be independent of the anticoagulant action of LMWH and may be related to effects on the vasculature. Prior studie...

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Tumor cell surface heparan sulfate as cryptic promoters or inhibitors of tumor growth and metastasis

Cited by 207 publications

References 41 publications

Structural Recognition by Recombinant Human Heparanase That Plays Critical Roles in Tumor Metastasis

Structural Recognition by Recombinant Human Heparanase That Plays Critical Roles in Tumor Metastasis

Differential Modulation of Human Melanoma Cell Metalloproteinase Expression by α2β1 Integrin and CD44 Triple-helical Ligands Derived from Type IV Collagen

Heparin Inhibition of Endothelial Cell Proliferation and Organization Is Dependent on Molecular Weight

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