Mammalian heparanase: involvement in cancer metastasis, angiogenesis and normal development

Vlodavsky, Israël; Goldshmidt, Orit; Zcharia, Eyal; Atzmon, Ruth; Rangini-Guatta, Zehava; Elkin, Michael; Peretz, Tamar; Friedmann, Yael

doi:10.1006/scbi.2001.0420

Cited by 218 publications

(194 citation statements)

References 34 publications

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“…In addition to the inhibitory role of Sulfs described here, two other forms of enzymatic remodeling are known to occur in myeloma and other tumors. These include proteoglycan shedding from the cell surface, which promotes myeloma growth and metastasis in vivo, and fragmentation of heparan sulfate chains by heparanase, which promotes tumor growth, angiogenesis, and metastasis in a number of cancers (17,34). These three known enzymatic mechanisms (sulfatases, sheddases, and heparanase), which are active within the tumor microenvironment, point out the importance of regulated remodeling of heparan sulfate proteoglycans.…”

Section: Discussionmentioning

confidence: 99%

HSulf-1 and HSulf-2 Are Potent Inhibitors of Myeloma Tumor Growth in Vivo

Dai

Yang

MacLeod

et al. 2005

Journal of Biological Chemistry

127

131

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To participate as co-receptor in growth factor signaling, heparan sulfate must have specific structural features. Recent studies show that when the levels of 6-O-sulfation of heparan sulfate are diminished by the activity of extracellular heparan sulfate 6-O-endosulfatases (Sulfs), fibroblast growth factor 2-, heparin binding epidermal growth factor-, and hepatocyte growth factor-mediated signaling are attenuated. This represents a novel mechanism for regulating cell growth, particularly within the tumor microenvironment where the Sulfs are known to be misregulated. To directly test the role of Sulfs in tumor growth control in vivo, a human myeloma cell line was transfected with cDNAs encoding either of the two known human endosulfatases, HSulf-1 or HSulf-2. When implanted into severe combined immunodeficient (SCID) mice, the growth of these tumors was dramatically reduced on the order of 5-to 10-fold as compared with controls. In addition to an inhibition of tumor growth, these studies revealed the following. Heparan sulfate proteoglycans act as co-receptors for numerous heparin-binding growth factors and cytokines and are thus key regulators of cell signaling (1). Previous studies have demonstrated that growth factor binding to heparan sulfate and the resulting mitogenic activity occur only when specific structural features are present within the heparan sulfate chains. These features include sulfation at specific positions within a disaccharide (N, 2-O, 3-O, 6-O) by the enzymes that orchestrate heparan sulfate synthesis within the Golgi (2). However, recent studies show that following its synthesis and expression, heparan sulfate can also be structurally and functionally modified within the extracellular compartment. The two enzymes presently known to have these effects are heparanase, which cleaves heparan sulfate chains into small, biologically active fragments, and the heparan sulfate 6-O-endosulfatases (Sulfs).2 Sulfs represent a newly discovered family of enzymes that are secreted via the Golgi and become localized to the cell surface or are released into the extracellular matrix. These enzymes selectively remove the 6-O-sulfate groups from heparan sulfate with preference for the 6-O-sulfates present on trisulfated disaccharides (3, 4).The first member of the endosulfatase family to be described was sulfatase-1 from quail (QSulf1), where the activity of this enzyme is required for Wnt-mediated signaling in developing muscle (5). In separate studies, Qsulf1 was shown to restore bone morphogenetic protein signaling in cells by releasing its functional inhibitor, Noggin, from cell surfaces (3). In contrast, QSulf1 can also inhibit growth factor signaling, as removal of the 6-O-sulfation required for the formation of the FGF⅐HS⅐FR1c ternary complex blocks FGF2 signaling (6). Thus, the Sulfs can have activities that promote or inhibit growth factor signaling depending on the specific factor involved.In addition to quail, the Sulf-1 enzyme has also been cloned from rat, mouse, and human, and a second family me...

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Section: Discussionmentioning

confidence: 99%

HSulf-1 and HSulf-2 Are Potent Inhibitors of Myeloma Tumor Growth in Vivo

Dai

Yang

MacLeod

et al. 2005

Journal of Biological Chemistry

127

131

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“…Indeed, many metastatic tumor cells produce heparanase, which acts to break down HS in the ECM facilitating their migration. 37 Metastatic tumor cells use the same selectinmediated pathway as neutrophils (Figure 3) to enter and exit the vasculature in establishing a secondary tumor. In angiogenesis, tumor cells release chemokines that recruit blood vessels from the surrounding tissues and utilize neovascularization to provide oxygen necessary for rapid tumor growth.…”

Section: Glycosaminoglycans In Cellular Communicationmentioning

confidence: 99%

Role of Glycosaminoglycans in Cellular Communication

2004

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Glycosaminoglycans are of critical importance in intercellular communication in organisms. This ubiquitous class of linear polyanions interacts with a wide variety of proteins, including growth factors and chemokines, which regulate important physiological processes. The presence of glycosaminoglycans on cell membranes and in the extracellular matrix also has resulted in their exploitation by infectious pathogens to gain access and entry into animal cells. This Account examines the structural and physical characteristics of these molecules responsible for their interaction with proteins important in cell-cell communication.

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“…The basement membrane is biologically active with endothelial cells and Matrigel has been shown to promote capillary-like formation of endothelial cells in vitro [62]. Since the basement membranes serve as a storage depot for a large number of angiogenic growth factors, such as bFGF and EGF, the degradation of the matrix leads to the release of angiogenic factors that can in turn promote angiogenesis [63]. Several extracellular matrix protein fragments have been identified to modulate angiogenesis [64].…”

Section: Angiogenesismentioning

confidence: 99%

The basement membrane matrix in malignancy

Engbring

Kleinman

2003

The Journal of Pathology

216

167

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Cancer is the second most common cause of death among Americans, although for several age groups it ranks first. Most of these deaths are not due to the primary tumour but rather to tumour cell metastases to distant organs. There are many steps that lead to metastasis, all of which are being studied with the goal of preventing these fatalities. Normally, cells attach to the extracellular matrix to maintain tissue integrity. During cancer progression, cells become more motile and acquire invasive qualities. Tumour cells move along blood and lymph vessels or invade into them to travel to distant sites. Then, the tumour cells must attach to the vessel wall, extravasate from the vessel, invade the new tissue, proliferate, and form a secondary tumour. Angiogenesis, the formation of new blood vessels, is critical to survival of these cells at the new site and is also important for primary tumour growth and spread. Tumour cell metastasis is a complex cascade of sequential steps, each of which is not yet fully understood. Progress has been made in identifying several key activators, one of which is the extracellular matrix. A major tumour promoter is the glycoprotein laminin, which is predominantly found in the extracellular matrix produced by endothelial and epithelial cells. This review will follow the metastatic process with particular attention to the effect of laminin on tumour cells.

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Mammalian heparanase: involvement in cancer metastasis, angiogenesis and normal development

Cited by 218 publications

References 34 publications

HSulf-1 and HSulf-2 Are Potent Inhibitors of Myeloma Tumor Growth in Vivo

HSulf-1 and HSulf-2 Are Potent Inhibitors of Myeloma Tumor Growth in Vivo

Role of Glycosaminoglycans in Cellular Communication

The basement membrane matrix in malignancy

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