Mammalian heparanase: Gene cloning, expression and function in tumor progression and metastasis

Vlodavsky, Israël; Friedmann, Yael; Elkin, Michael; Aingorn, Helena; Atzmon, Ruth; Ishai-Michaeli, Rivka; Bitan, Menachem; Pappo, Orit; Peretz, Tuvia; Michal, Israel; Spector, Larissa; Pecker, Iris

doi:10.1038/10518

Cited by 736 publications

(979 citation statements)

References 46 publications

Supporting

Mentioning

946

Contrasting

Unclassified

Order By: Relevance

“…This confirmed earlier findings that heparanase mRNA is highly expressed in metastatic rat and human breast cancer cell lines in vitro, whereas the nonmetastatic variants express little or no heparanase mRNA. [14][15][16] The incidence of heparanase expression in primary cancers was significantly higher in patients with lymph node metastases than those without metastases. Two of the essential processes required for metastasis are angiogenesis and tumor cell invasion of the basement membrane and extracellular matrix.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Positive association of heparanase expression with tumor invasion and lymphatic metastasis in gastric carcinoma

Wang

Jiang

et al. 2005

Modern Pathology

View full text Add to dashboard Cite

Tumor invasion and metastasis are the most common causes of death in gastric carcinoma. Human heparanase influences tumor invasiveness and angiogenesis. Analysis of its expression in gastric carcinoma has been hindered by our inability to procure pure cancer cells from heterogeneous tissue. In the present study, we analyzed heparanase expression in human primary and metastatic gastric carcinoma cells as well as in paired normal gastric epithelial cells by laser capture microdissection coupled with reverse transcriptionpolymerase chain reaction (RT-PCR). Tumor tissues, metastatic lymph nodes, and apparently uninvolved normal gastric tissues were collected from 30 patients who had undergone gastrectomy with radical lymph node dissection for gastric carcinoma without preoperative treatment. Bulk tissues and laser capture microdissected cell groups were separately subjected to RT-PCR analysis with heparanase-specific primers. For bulk tissues, heparanase-specific transcripts were detectable in all primary tumor tissues, metastatic lymph nodes, and almost all matching normal tissues. RT-PCR analysis after laser capture microdissection showed no detectable heparanase expression in matching normal epithelial cell groups. Of the laser capture microdissected primary gastric carcinoma cells, 47% (14/30) were heparanase positive. Expression was closely associated with greater tumor invasiveness, including Borrmann gross type and depth of wall infiltration. For metastatic cell groups dissected from lymph nodes, 95% showed clear heparanase expression. Furthermore, the extent of lymphatic spread was directly correlated to heparanase expression at the primary site. In conclusion, laser capture microdissection coupled with RT-PCR is a reliable approach for molecular analysis of heparanase expression in gastric carcinoma. Heparanase may facilitate invasion and metastasis of gastric carcinoma cells. Keywords: gastric carcinoma; laser capture microdissection; lymphatic metastasis; heparanase expression It is generally accepted that the invasion of the basement membrane and extracellular matrix is one of the critical steps for cancer cell metastasis. 1 Heparan sulfate proteoglycans, composed of a protein core covalently linked to heparan sulfate side-chains, represent a principal component of the extracellular matrix and, in particular, basement membranes. Cell surface heparan sulfate can also serve as coreceptors, along with the other cell surface molecules, to form functional receptor complexes that facilitate signal transduction. 2 Furthermore, heparan sulfate chains bind a large number of bioactive molecules and regulate their availability and function. These include growth factors, chemokines, cytokines, and enzymes that are essential for angiogenesis, cell adhesion, and locomotion. 3 Accordingly, enzymatic degradation of heparan sulfate may play a critical role in cancer cell invasion and metastasis. Heparanase is an endoglycosidase that cleaves heparan sulfate side chains of heparan sulfate proteoglycans at a limited number ...

show abstract

Section: Discussionmentioning

confidence: 99%

“…A Volume of 7 ml of total RNA isolated from approximately 10 000 cells were mixed with 1 ml of oligo-(dT) [12][13][14][15][16][17][18] primer, 1 ml of random hexamers primer (N 6 ), and 1 ml of 10 mM dNTPs in a total volume of 10 ml. They were heat denaturated at 651C for 5 min, and then chilled in ice.…”

Section: Rt-pcr Of Microdissected Cellsmentioning

confidence: 99%

Positive association of heparanase expression with tumor invasion and lymphatic metastasis in gastric carcinoma

Wang

Jiang

et al. 2005

Modern Pathology

View full text Add to dashboard Cite

show abstract

“…Indeed, previous studies have suggested a role for heparanase in various pathophysiological conditions, including tumor metastasis (Escobar Galvis et al, 2007;Vlodavsky and Friedmann, 2001), experimental autoimmune disease (Lider et al, 1989), amyloidosis (Li et al, 2005) and delayed type hypersensitivity (DTH) reactions . A role for heparanase in tumour metastasis is supported by the strong correlation between levels of heparanase expression and metastatic potential of B16 melanoma (Vlodavsky et al, 1999) and T lymphoma (Goldshmidt et al, 2002b) cells. Further, it has been shown by RNA interference that suppression of heparanase expression ameliorates DTH reactions as well as reduces lung colonization of B16 melanoma cells (Edovitsky et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Accumulation of Ym1 and formation of intracellular crystalline bodies in alveolar macrophages lacking heparanase

Waern

Jia

Pejler

et al. 2010

Molecular Immunology

Self Cite

View full text Add to dashboard Cite

Heparanase is a heparan sulfate (HS) degrading endoglucuronidase that has been implicated in cell migration and inflammatory conditions. Here we used mice deficient of heparanase (Hpse -/-) to study the impact of heparanase on airway leukocytes. Normal numbers of macrophages and lymphocytes were present in bronchoalveolar lavage fluid of Hpse-/-mice, indicating that heparanase is not essential for proper homing of leukocytes to airways. While lymphocytes fromHpse -/-mice displayed normal morphology, Hpse -/-alveolar macrophages showed a striking, age-dependent appearance of granule-like structures in the cytoplasm.Transmission electron microscopy revealed that these structures corresponded to membrane-enclosed crystalline bodies that closely resembled the intracellular crystals known to be formed by the HS-binding protein Ym1, suggesting that heparanase deficiency is associated with intracellular Ym1 deposition. Indeed, applying immunocytochemistry, we found markedly higher levels of intracellular

show abstract

“…Three other sites of transcription initiation, at nucleotides À330, À101, and À98 (sites A and B/C in Fig. 6), have also been described for the human gene (Hulett et al, 1999;Vlodavsky et al, 1999;Dong et al, 2000;Jiang et al, 2002). Alternative transcriptional start sites do not alter the putative translation initiation start codon, which remains unaffected and localized inside exon 2.…”

Section: Expression Of Heparanase In X Laevis Is Driven By Two Promomentioning

confidence: 67%

“…Not surprisingly, given the different transcription sites in the promoters of the two species, the human promoter was not functional in any of the Xenopus systems studied. Yet, certain aspects of the exonintron distribution appear to be conserved between the two species, including: (i) 14 coding exons; (ii) the presence of a spliced exon 1 constitutive of a 5 0 untranslated region (UTR); (iii) alternative transcription initiation sites with the start translation codon localized in exon 2 (Hulett et al, 1999;Vlodavsky et al, 1999;Dong et al, 2000;Jiang et al, 2002;Bertolesi et al, 2008); and (iv) the presence of cis-elements in the first intron able to drive heparanase expression in both species, as we showed in this study.…”

Section: Developmental Expression Of Heparanase 2667mentioning

confidence: 99%

Two promoters with distinct activities in different tissues drive the expression of heparanase in Xenopus

Bertolesi

Michaiel

et al. 2011

Developmental Dynamics

View full text Add to dashboard Cite

In Xenopus laevis embryos, heparanase, the enzyme that degrades heparan sulfate, is synthesized as a preproheparanase (XHpaL) and processed to become enzymatically active (XHpa active). A short nonenzymatic heparanase splice variant (XHpaS) is also expressed. Using immunohistochemistry, Western blot, and heparanase promoter analysis, we studied the dynamic developmental expression of the three heparanases. Our results indicate that (1) all three isoforms are maternally expressed; (2) XHpaS is a developmental variant; (3) in the early embryo, heparanase is localized to both the plasma membrane and the nucleus; (4) several tissues express heparanase, but expression in the developing nervous system is most evident; (5) two promoters with distinct activities in different tissues drive heparanase expression; (6) Oct binding transcription factors may modulate heparanase promoter activity in the early embryo. These data argue that heparanase is expressed widely during development, but localization and levels are finely regulated.

show abstract

Mammalian heparanase: Gene cloning, expression and function in tumor progression and metastasis

Cited by 736 publications

References 46 publications

Positive association of heparanase expression with tumor invasion and lymphatic metastasis in gastric carcinoma

Positive association of heparanase expression with tumor invasion and lymphatic metastasis in gastric carcinoma

Accumulation of Ym1 and formation of intracellular crystalline bodies in alveolar macrophages lacking heparanase

Two promoters with distinct activities in different tissues drive the expression of heparanase in Xenopus

Contact Info

Product

Resources

About