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Table of Contents   
REVIEW ARTICLE  
Year : 2011  |  Volume : 22  |  Issue : 6  |  Page : 823-826
Perlecan (basement membrane heparan sulfate proteoglycan) and its role in oral malignancies: An overview


1 Department of Oral Pathology, ITS Dental College and Hospital, Greater Noida, Delhi-NCR, India
2 Department of Oral Pathology, KLE VK Institute of Dental Sciences, Belgaum, Karnataka, India
3 Department of Community Dentistry, KLE VK Institute of Dental Sciences, Belgaum, Karnataka, India
4 Department of Pathology, JN Medical College, KLE University, Belgaum, Karnataka, India

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Date of Submission13-Jan-2010
Date of Decision16-Jun-2010
Date of Acceptance19-Feb-2011
Date of Web Publication5-Apr-2012
 

   Abstract 

Perlecan means pearl-like structures. Perlecan is a large proteoglycan (400-500 kDa) present in virtually all vascularized tissues with a distribution that is primarily confined to basement membranes including those of oral mucosa. It is a basement membrane-type heparan sulfate proteoglycan. Perlecan is synthesized by basal cells and fibroblasts adjacent to the basal lamina . Perlecan is also synthesized by vascular endothelial and smooth muscle cells present in the extracellular matrix. It has been demonstrated in recent years that perlecan is distributed in the stromal space of various pathophysiological conditions. The complex pleiotropy of perlecan suggests that this gene product is involved in several developmental processes, at both early and late stages of embryogenesis, as well as in cancer and diabetes. In the oral cavity, perlecan expression is reported to basal cells in normal mucosa and its expression increases in precancer and cancerous conditions. It is also expressed in various odontogenic tumors such as ameloblastoma, keratocyst odontogenic tumor, and also salivary gland tumors such as adenoid cystic carcinoma, mucoepidermoid carcinoma, etc.

Keywords: Cancer, perlecan, proteoglycan

How to cite this article:
Mishra M, Naik VV, Kale AD, Ankola AV, Pilli GS. Perlecan (basement membrane heparan sulfate proteoglycan) and its role in oral malignancies: An overview. Indian J Dent Res 2011;22:823-6

How to cite this URL:
Mishra M, Naik VV, Kale AD, Ankola AV, Pilli GS. Perlecan (basement membrane heparan sulfate proteoglycan) and its role in oral malignancies: An overview. Indian J Dent Res [serial online] 2011 [cited 2014 Jul 22];22:823-6. Available from: http://www.ijdr.in/text.asp?2011/22/6/823/94678
The neologism perlecan, a mnemonic from "perl" (bead or gem like) and "can" (glycosaminoglycan), was coined by Hassell and co-workers to symbolize the "beads-on-a-string" appearance of an isolated perlecan molecule as visualized by an electron microscope. Perhaps their work had the greatest impact on the understanding of perlecan. This landmark study undoubtedly stimulated the work on perlecan and set the stage for more recent discoveries, including the molecular cloning of the complimentary DNA (cDNA), elucidation of protein-core modules, and chromosomal mapping of the gene. Perlecan is an archetypal molecule from which multiple species of proteoglycan can be derived. [1] The first evidence for the presence of perlecan on the telomeric region of human chromosome 1 was obtained by cross-species, in situ hybridization (ISH) using the mouse cDNA probe encompassing the neural cell adhesion molecule (N-CAM) domain of perlecan. [2] Further studies have clearly shown that the perlecan gene, whose genomic designation is HSPG2, is located within a narrow region of the telomeric portion of chromosome 1 with the most likely primary site being the 1p36.1 band [Figure 1].
Figure 1: Location of the perlecan gene and its domains

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   Domains of Perlecan Top


These are five distinct domains of the human perlecan core protein as shown in [Figure 2]. Domain I is a module unique to perlecan of 172 amino acids that contains three consecutive Ser-Gly-Asp (SGD) tripeptides, the predicted site for the attachment of the heparan sulfate side chains [Figure 2]. Domain 1 lacks cysteine residues and is quite enriched in acidic amino acids. The second discrete domain of perlecan is homologous to the ligand-binding portion of the low-density lipoprotein (LDL) receptor [Figure 1]. Binding of lipids to the basement membrane and extracellular matrices of blood vessels is an established observation, and this property has been generally attributed to the glycosaminglycan chains. Domain III exhibits an extensive similarity with the internal segments of laminin, particularly with the region of the A chain that comprises one of the short arms of a laminin multimer [Figure 1]. The globular regions have an overall amino acid configuration which resembles that of two subregions of the laminin A chain, the IVa and IVb subdomains, and to a lesser extent the laminin B2 subdomain IV. [3] Domain IV is homologous with the immunoglobulin superfamily and N-CAM. Domain IV has two distinguishing features. It is the largest domain of human perlecan, encoding a polypeptide of over 200 kDa and contains 21 consecutive repeats typically observed in the members of the immunoglobulin gene superfamily, thus contributing to the stabilization of the matrix or enhancement of the adhesion of neighboring cells carrying perlecan at their surfaces. [4] Domain V is encoded by 16 exons and composed of 3 globular and 4 epidermal growth factor (EGF)-like motifs, exhibiting structural similarity with the C-terminal and globular region of the laminin A chain.
Figure 2: Schematic molecular structure of perlecan

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   Binding Properties of Perlecan Top


The discovery that this large multimeric macromolecule can self-assemble into a dynamic structure implies that perlecan is directly involved in the formation of basement membranes in living organisms. [5] Perlecan has been reported to be involved in interactions with numerous extracellular macromolecules including laminin, nidogen, and fibronectin. Recent discoveries in the field of growth factor and cytokine research have provided novel information regarding the role of pericellular heparan sulfate proteoglycans (HSPGs) in the storage, binding, and delivery of such compounds. A cluster of important papers have reported a close association between basic fibroblast growth factor (bFGF) which is a heparin-binding angiogenic protein, and basement membrane constituents including mouse perlecan. [6] The abnormal release of bFGF during wound healing or cancer invasion may contribute to local tissue neovascularization. It is likely that specific sequences in the heparan sulfate chains covalently attached to the perlecan protein core are directly implicated in the control of angiogenesis.


   Metabolism of Heparan Sulfate Proteoglycans Top


The metabolic turnover of cell surface HSPGs has been studied in several cell culture systems. Many factors, such as cell type, developmental stage, stage in cell cycle, or malignant transformation, greatly affect their metabolism. Generally, cell surface proteoglycans are in a metabolic steady state, with the synthesis equal to catabolism, and their half-lives are short (5-20 h). The core protein precursor is synthesized in the rough endoplasmic reticulum, where N-linked oligosaccharide precursors are added onto Asn-X-Ser (Thr) sequences. The core protein precursors are then translocated to the Golgi apparatus where they undergo modifications including N-linked oligosaccharide modification, O-linked oligosaccharide synthesis if appropriate Ser (Thr) acceptor residues are present, and glycosaminoglycan synthesis. The synthesis of heparan sulfate (HS) involves stepwise sugar transfer reactions to elongate the chain and then to modify it with sulfation and epimerization steps. Sulfation is the last modification step after HS chain elongation and occurs rapidly. In most cells, membrane-associated HSPGs are rapidly transferred to the cell surface after adding the HS chains. The time required for the transfer of newly sulfated, and hence newly completed, HSPGs from the Golgi body to the cell surface is 12-15 min, a time similar to that required for the transit of most constitutively secreted proteins. [7] Once HSPGs reach the cell surface, they are either endocytosed or shed into the extracellular space with typical half-lives on the cell surface of 3-8 h. Endocytosis of cell surface HSPGs is usually a major route of metabolic turnover from the cell surface. Most of the endocytosed HSPGs are eventually degraded in lysosomes where exoglycosidases, sulfatases, and N-acetyltransferase act in sequence to degrade chains to individual sugars. Deficiency of any one of these enzymes, as occurs in various mucopolysaccharidoses, results in the accumulation of undegraded glycosaminglycan fragments in the cells. In some cells, HS chains from partially degraded HSPGs are released into the extracellular space. Soon after endocytosis (t½ =30 min), the core protein is extensively digested to liberate single HS chains and these chains are rapidly cleaved by an endoglycosidase activity to generate HS fragments with an average size of 10 kDa. These proteolytic and endoglycosidic processes are closely coordinated. [8]


   Functions of Perlecan Top


It is now becoming apparent that perlecan is diffusely present in the pericellular matrices of a number of organs, and that the fibroblast, a cell type that does not assemble into traditional basement membrane, is a main producer of the proteoglycan. For example, ISH of human skin has demonstrated perlecan message in the fibroblasts of the upper dermis but not in keratinocytes. [9] Perlecan has been localized to the dermoepidermal basement membrane of fetal skin during the first trimester of life and as early as 54 days of intrauterine development. The presence of perlecan at the earliest time at which the basement membrane is formed supports the hypothesis that this large proteoglycan contributes to the early structural integrity of the epidermal connective tissue interface. [10] These findings suggest that basement membranes are the product of both ectoderm and mesoderm and that cooperation between different cells is necessary for correct orientation and assembly into a functionally complete basement membrane. The localization and synthesis of perlecan in developing tooth germs by using murine molars in neonatal and postnatal stages, in primary cultured cells of the enamel organ and dental papilla, was demonstrated and its role in odontogenesis was found by Hiroko et al. Perlecan was immunolocalized in the stellate reticulum of enamel organs of developing tooth germs though a constant overexpression of perlecan interferes with normal tooth development. [11],[12]

Initial cell bindings of the herpes simplex virus [13] and human immunodeficiency virus (HIV) are specifically enhanced by the presence of cell surface HSPGs. Interactions between cell surface HSPGs and viral envelope proteins, such as the gp120 of HIV, which has been shown to bind heparin, have been postulated. The viruses may take advantage of the ubiquitous presence of cell surface HSPGs and use them as an efficient absorption mechanism on the cell surface to increase the chance of subsequent infection. The exceptionally wide distribution of cell surface HSPGs clearly indicates their involvement in fundamental cell activities.

Perlecan is a key component of the vascular extracellular matrix. Here it interacts with a variety of other matrix components and helps to maintain the endothelial barrier function. Perlecan is a potent inhibitor of smooth muscle cell proliferation and is thus thought to help maintain vascular homeostasis. In a series of experiments, perlecan was identified as a major candidate for promoting basic fibroblast growth factor (bFGF) receptor binding, mitogenesis, and angiogenesis. [14] Perlecan is a potent inducer of bFGF-mediated neovascularization. In various experimental procedures, it was demonstrated that the protein core of the perlecan binds specifically to fibroblast growth factor-7, an interaction that could influence cancer growth and tissue remodeling. [15]


   Perlecan in Head and Neck Tumors Top


The overexpression of perlecan along with other extracellular matrix molecules like tenascin and fibronectin in lamina propria and submucosal layer, in cases of early stage oral submucous fibrosis, have been seen. [16] Studies have demonstrated the expression of perlecan in dysplastic epithelium and oral squamous cell carcinomas. With the increase in the severity of epithelial dysplasia, the core protein was heavily and extensively deposited in the intraepithelial space as well as in the cytoplasm of epithelial cells from the basal to surface layers. In squamous cell carcinoma, core protein is reported to be found scarcely in tumor cells but abundantly in the stromal spaces. [17]

The localization and biosynthesis of basement membrane HSPG was studied in ameloblastomas using surgical tissue sections and cells in primary culture to demonstrate the existence of extracellular matrix molecules in the intercellular space of the epithelial tissue. The results indicated that ameloblastoma cells synthesize HSPGs and deposit it in their intercellular space. The intercellular HSPG might act as a carrier for the transport of nutrients to tumor cells within ameloblastomatous foci. [18] Various other studies conducted on odontogenic tumors have demonstrated that enamel proteins such as amelogenin and enamelin are co-localized with other ECM molecules, especially those that are basement membrane associated such as HSPG, type- IV collagen, laminin, and fibronectin. [19] Recently, expression of perlecan in keratocystic odontogenic tumor has been found. Results suggest that the characteristic intraepithelial deposit of perlecan in the keratocystic odontogenic tumor, which has never been seen in other cystic jaw lesions, is a new evidence supporting the neoplastic nature of keratocystic odontogenic tumor. [20]

A study showed perlecan gene expression in the characteristic histological architecture of salivary adenoid cystic carcinoma. In order to determine the role of perlecan in the formation of the characteristic cribriform structures of salivary adenoid cystic carcinomas, the mode of expression of mRNA for the core protein of the HSPG was investigated by using ISH both in surgical specimens and in a cell system of adenoid cystic carcinomas. The results indicated that HSPG is biosynthesized by adenoid cystic carcinoma cells which are in the proliferation phase, and that tumor cells producing HSPGs tend to form initial structures of stromal pseudocysts. [21] Its expression has also been reported in other salivary gland tumors such as mucoepidermoid carcinoma, pleomorphic adenoma, etc.

Perlecan binds to various growth factors like bFGF and TGF-β. It can be hypothesized that perlecan can be broken down by various enzymes in the stroma which releases growth factors that help in tumor proliferation. Probably now is the dawn of perlecan but still lot more endeavors are needed to unfold its secrets.

 
   References Top

1.Iozzo RV, Cohen IR, Grässel S, Murdoch AD. The biology of perlecan: The multifaceted heparan sulphate proteoglycan of basement membranes and pericellular matrices. Biochem J 1994;302:625-39.  Back to cited text no. 1
    
2.Wintle RF, Kisilevsky R, Noonan D, Duncan AM. In situ hybridization to human chromosome 1 of a cDNA probe for the gene encoding the basement membrane-heparan sulfate proteoglycan. Cytogenet Cell Genet 1990;54:60-1.  Back to cited text no. 2
    
3.Sasaki M, Kleinman HK, Huber H, Deutzmann R, Yamada Y. Laminin, a multidomain protein. The A chain has a unique globular domain and homology with the basement membrane proteoglycan and the laminin B chains. J Biol Chem 1988;263:16536-44.  Back to cited text no. 3
    
4.Rutishauser U, Acheson A, Hall Kaman DM, Sunshine J. The neural cell adhesion molecule (N-CAM) as a regulator of cell-cell interactions. Science 1988;48:53-7.  Back to cited text no. 4
    
5.Yurchenco PD, Cheng YS, Ruben GC. Self assembly of a high molecular weight basement membrane heparan sulfate proteoglycan into dimmers and oligomers. J Biol Chem 1987;262:17668-76.  Back to cited text no. 5
    
6.Folkman J, Klagsbrun M, Sasse J, Wadzinski M, Ingber D, Vlodavsky I. A heparin binding angiogenic protein, basic fibroblast growth factor is stored within basement membrane. Am J Pathol 1988;130:393-400.  Back to cited text no. 6
    
7.Yanagishita M, Hascall VC. Cell surface heparan sulfate proteoglycans. J Biol Chem 1992;267:9451-4.  Back to cited text no. 7
    
8.Gallagher JT, Walker A, Lyon M, Evans WH. Heparan sulfate degrading endoglycosidase in liver plasma membranes. Biochem J 1988;250:719-26.  Back to cited text no. 8
    
9.Murdoch AD, Liu B, Schwarting R, Tuan RS, Iozzo RV. Widespread expression of perlecan proteoglycan in basement membranes and extracellular matrices of human tissue as detected by a novel monoclonal antibody against domain III and by in situ hybridization. J Histochem Cytochem 1994;42:239-49.  Back to cited text no. 9
    
10.Horiguchi Y, Fine JD, Couchman JR. Human skin basement membrane associated HSPG: Distinctive differences in ultrastructural localization as a function of developmental age. Br J Dermatol 1991;124:410-4.  Back to cited text no. 10
    
11.Ida-Yonemochi H, Ohshiro K, Swelam W, Metwaly H, Saku T. Perlecan, a basement membrane-type heparan sulfate proteoglycan, in the enamel organ: Its intraepithelial localization in the stellate reticulum. J Histochem Cytochem 2005;53:763-72.  Back to cited text no. 11
    
12.Ida-Yonemochi H, Saku T. Perlecan, a heparan sulfate proteoglycan, Is a major constituent of the intraepithelial stroma functioning in tooth morphogenesis. J Oral Biosci 2006;48:233-43.  Back to cited text no. 12
    
13.Shieh MT, WuDunn D, Montgomery RI, Esko JD, Spear PG. Cell surface receptors for herpes simplex virus is heparan sulfate proteoglycans. J Cell Biol 1992;116:1273-81.  Back to cited text no. 13
    
14.Aviezer D, Hecht D, Safran M, Eisinger M, David G, Yayon A. Perlecan, basal lamina proteoglycan promotes bFGF-receptor binding, mitogenesis and angiogenesis. Cell 1994;79:1005-13.  Back to cited text no. 14
    
15.Mongiat M, Taylor K, Otto J, Aho S, Uitto J, Whitelock JM, et al. The protein core of the proteoglycan perlecan binds specifically to Fibroblast Growth Factor-7. J Biolo Chem 2000;275:7095-100.  Back to cited text no. 15
    
16.Utsunomiya H, Tilakaratne WM, Oshiro K, Maruyama S, Suzuki M, Ida- Yonemochi H, et al. Extracellular matrix remodeling in oral submucous fibrosis: Its stage-specific modes revealed by immunohistochemistry and in situ hybridization. J Oral pathol Med 2005;34:498-507.  Back to cited text no. 16
    
17.Ikarashi T, Ida-Yonemochi H, Ohshiro K, Cheng J, Saku T. Intraepithelial expression of perlecan, a basement membrane-type heparan sulfate proteoglycan reflects dysplastic changes of the oral mucosal epithelium. J Oral Pathol Med 2004;33:87-95.  Back to cited text no. 17
    
18.Ida-Yonemochi H, Ikarashi T, Nagata M, Hoshina H, Takagi R, Saku T. The basement membrane-type heparan sulfate proteoglycan (perlecan) in ameloblastomas; its intercellular localization in stellate reticulum-like foci and biosynthesis by tumor cells in culture. Virchows Arch 2002;441:165-73.  Back to cited text no. 18
    
19.Murata M, Cheng J, Horino M, Hara K, Shimokawa H, Saku T. Enamel proteins and extracellular matrix molecules are co-localized in the pseudocystic stromal space of adenomatoid odontogenic tumor. J Oral Pathol Med 2000;29:483-90.  Back to cited text no. 19
    
20.Tsuneki M, Cheng J, Maruyama S, Ida-Yonemochi H, Nakajima M, Saku T. Perlecan - rich epithelial linings as a background of proliferative potentials of keratocystic odontogenic tumor. J Oral Pathol Med 2008;37:287-93.  Back to cited text no. 20
    
21.Kimura S, Cheng J, Ida H, Hao N, Fujimori Y, Saku T. Perlecan gene expression reflected in the characteristic histological architecture of salivary adenoid cystic carcinoma. Virchows Arch 2000;437:122-8.  Back to cited text no. 21
    

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Correspondence Address:
Mithilesh Mishra
Department of Oral Pathology, ITS Dental College and Hospital, Greater Noida, Delhi-NCR
India
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DOI: 10.4103/0970-9290.94678

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