Disease relevance of HPSE

• Metastatic melanoma cell heparanase. Characterization of heparan sulfate degradation fragments produced by B16 melanoma endoglucuronidase [1].
• Heparanase, overexpressed by most cancer cells, facilitates extravasation of blood-borne tumor cells and causes release of growth factors sequestered by HS chains, thus accelerating tumor growth and metastasis [2].
• On the other hand, heparanase of the highly metastatic variant (ESb) of a methylcholanthrene-induced T lymphoma, which is an extracellular enzyme released by the cells to the incubation medium, was more sensitive to heparin and arteparon than the macrophages' heparanase, inhibited at concentrations of 1 and 3 micrograms/ml, respectively [3].
• A-72363 A-1, A-2, and C, novel heparanase inhibitors from Streptomyces nobilis SANK 60192, II. Biological activities [4].
• Heparanase activity correlates with metastatic potentials of lymphoma, melanoma and mammary adenocarcinoma cell lines [5].

High impact information on HPSE

• We hypothesize that atherogenic lipoproteins stimulate endothelial cell production of heparanase [6].
• Among these molecular mediators of inflammation is a heparanase enzyme that degrades the heparan sulfate scaffold of the extracellular matrix (ECM) [7].
• A disaccharide that inhibits tumor necrosis factor alpha is formed from the extracellular matrix by the enzyme heparanase [7].
• Using immunohistochemistry, confocal microscopy, RT-PCR, Western blot analysis, assays for heparanase activity, and Matrigel transmigration, we show that heparanase is expressed in both nuclei and cytoplasm of immature DCs, and that gene expression and synthesis take place mainly in monocytes and early immature DCs [8].
• Translocation of active heparanase to cell surface regulates degradation of extracellular matrix heparan sulfate upon transmigration of mature monocyte-derived dendritic cells [8].

Chemical compound and disease context of HPSE

• B16-BL6 metastatic melanoma cell heparanase, which is also a cell-associated enzyme, was inhibited by heparin to the same extent as the macrophage heparanase [3].
• Heparanase, an endo-beta-D-glucuronidase initially detected in B16 melanoma cells, has been described as a M(r) 96,000 glycoprotein with pI of 5.2, and has been immunolocalized to the cell surface and cytoplasm [9].

Biological context of HPSE

• Expression of heparanase mRNA in bovine placenta during gestation [10].
• The 364 amino acid residues deduced from the 1092 bp cDNA fragment share 81.9% and 80.5% identity with amino acid sequences of human and rat heparanase, respectively [10].
• These results demonstrate that heparanase mRNA is expressed in the placentome, indicating that heparanase may play a role in implantation, and in placental development and function [10].
• The macrophages do not store the heparanase intracellularly but it is instead found pericellularly and requires a continuous cell-matrix contact at the optimal pH for maintaining cell growth [3].
• Structure-activity relationships of heparin-mimicking compounds in induction of bFGF release from extracellular matrix and inhibition of smooth muscle cell proliferation and heparanase activity [11].

Anatomical context of HPSE

• Furthermore, heparanase mRNA was detected in the cotyledon, intercotyledonary fetal membrane and caruncle after days 60-64 of gestation [10].
• However, no significant expression of heparanase mRNA was observed in intercaruncular endometrium at all stages of gestation examined [10].
• We hypothesize that decreased vessel wall HSPG, as occurs in atherogenic conditions, allows increased monocyte retention within the vessel and is due to the actions of an endothelial heparanase [12].
• Our data suggests that the non-reducing end of bovine kidney heparan sulfate is not trimmed by heparanase and is capable of supporting fibroblast growth factor signaling complex formation [13].
• Cell lysates of T lymphocytes contained heparanase activity [14].

Associations of HPSE with chemical compounds

• The growth factor appears to be bound to heparan sulfate and is released from the cornea by treatment with heparin, a hexasaccharide heparin fragment, heparan sulfate, or heparanase, but not by chondroitin sulfate or chondroitinase [15].
• Indeed N-acetylated heparins in their glycol-split forms inhibited heparanase as effectively as the corresponding N-sulfated derivatives [2].
• Since 3H-reduced terminal monosaccharides from HS fragments were overwhelmingly (greater than 90%) L-gulonic acid, the HS-degrading enzyme responsible is an endoglucuronidase (heparanase) [1].
• Whereas heparin and N-acetylheparins containing unmodified D-glucuronic acid residues inhibited heparanase by acting, at least in part, as substrates, their glycol-split derivatives were no more susceptible to cleavage by heparanase [2].
• Trichostatin A abolished the inhibitory effect of wt p53, suggesting the involvement of histone deacetylation in negative regulation of the heparanase promoter [16].

Analytical, diagnostic and therapeutic context of HPSE

• Quantitative real-time RT-PCR analysis showed very low expression of heparanase mRNA in the conceptus before implantation (day 17), but high expression in the cotyledon-containing fetal membrane (days 27-34) after implantation [10].
• Western blot analysis of bovine placental extracts (day 60) was performed using anti-bovine HPA antibody prepared by immunization of rabbits with synthetic peptide conjugate corresponding to amino acid residues 474-489 of bovine HPA; it showed two immunoreactive proteins with approximate molecular weights of 55kDa and 65kDa [17].
• In placentomes of 60 and 210 days' gestation, in situ hybridization demonstrated HPA mRNA expression in binucleate cells [17].

References