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Proteoglycans in health and disease: new concepts for heparanase function in tumor progression and metastasis.
- Source :
-
The FEBS journal [FEBS J] 2010 Oct; Vol. 277 (19), pp. 3890-903. Date of Electronic Publication: 2010 Aug 31. - Publication Year :
- 2010
-
Abstract
- Heparanase is an endo-β-D-glucuronidase capable of cleaving heparan sulfate side chains at a limited number of sites, yielding heparan sulfate fragments of still appreciable size. Importantly, heparanase activity correlates with the metastatic potential of tumor-derived cells, attributed to enhanced cell dissemination as a consequence of heparan sulfate cleavage and remodeling of the extracellular matrix and basement membrane underlying epithelial and endothelial cells. Similarly, heparanase activity is implicated in neovascularization, inflammation and autoimmunity, involving the migration of vascular endothelial cells and activated cells of the immune system. The cloning of a single human heparanase cDNA 10 years ago enabled researchers to critically approve the notion that heparan sulfate cleavage by heparanase is required for structural remodeling of the extracellular matrix, thereby facilitating cell invasion. Progress in the field has expanded the scope of heparanase function and its significance in tumor progression and other pathologies. Notably, although heparanase inhibitors attenuated tumor progression and metastasis in several experimental systems, other studies revealed that heparanase also functions in an enzymatic activity-independent manner. Thus, inactive heparanase was noted to facilitate adhesion and migration of primary endothelial cells and to promote phosphorylation of signaling molecules such as Akt and Src, facilitating gene transcription (i.e. vascular endothelial growth factor) and phosphorylation of selected Src substrates (i.e. endothelial growth factor receptor). The concept of enzymatic activity-independent function of heparanase gained substantial support by the recent identification of the heparanase C-terminus domain as the molecular determinant behind its signaling capacity. Identification and characterization of a human heparanase splice variant (T5) devoid of enzymatic activity and endowed with protumorigenic characteristics, elucidation of cross-talk between heparanase and other extracellular matrix-degrading enzymes, and identification of single nucleotide polymorphism associated with heparanase expression and increased risk of graft versus host disease add other layers of complexity to heparanase function in health and disease.<br /> (© 2010 The Authors Journal compilation © 2010 FEBS.)
- Subjects :
- Antineoplastic Agents therapeutic use
Disease Progression
Enzyme Inhibitors therapeutic use
ErbB Receptors physiology
Glucuronidase genetics
Head and Neck Neoplasms drug therapy
Head and Neck Neoplasms pathology
Head and Neck Neoplasms physiopathology
Heparitin Sulfate metabolism
Humans
Multiple Myeloma drug therapy
Multiple Myeloma genetics
Multiple Myeloma pathology
Multiple Myeloma physiopathology
Neoplasms drug therapy
Neoplasms genetics
Neoplasms physiopathology
Signal Transduction
Glucuronidase metabolism
Neoplasm Metastasis pathology
Neoplasms pathology
Proteoglycans metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1742-4658
- Volume :
- 277
- Issue :
- 19
- Database :
- MEDLINE
- Journal :
- The FEBS journal
- Publication Type :
- Academic Journal
- Accession number :
- 20840586
- Full Text :
- https://doi.org/10.1111/j.1742-4658.2010.07799.x