Review ArticleThe Motile Breast Cancer Phenotype Roles ofProteoglycansGlycosaminoglycans

Dragana Nikitovic1 Katerina Kouvidi1 Kallirroi Voudouri1 Aikaterini Berdiaki1

Evgenia Karousou2 Alberto Passi2 and George N Tzanakakis1

1 Laboratory of Anatomy-Histology-Embryology Medical School University of Crete 71003 Heraklion Greece2 Dipartimento di Scienze Chirurgiche e Morfologiche Universita degli Studi dellrsquoInsubria Via JH Dunant 5 21100 Varese Italy

Correspondence should be addressed to George N Tzanakakis tzanakakmeduocgr

Received 9 May 2014 Accepted 2 July 2014 Published 22 July 2014

Academic Editor Ilona Kovalszky

Copyright copy 2014 Dragana Nikitovic et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

The consecutive stages of cancer growth and dissemination are obligatorily perpetrated through specific interactions ofthe tumor cells with their microenvironment Importantly cell-associated and tumor microenvironment glycosaminoglycans(GAGs)proteoglycan (PG) content and distribution are markedly altered during tumor pathogenesis and progression GAGs andPGs performmultiple functions in specific stages of themetastatic cascade due to their defined structure and ability to interact withboth ligands and receptors regulating cancer pathogenesis Thus GAGsPGs may modulate downstream signaling of key cellularmediators including insulin growth factor receptor (IGFR) epidermal growth factor receptor (EGFR) estrogen receptors (ERs) orWntmembers In the present review we will focus on breast cancer motility in correlation with their GAGPG content and criticallydiscuss mechanisms involved Furthermore new approaches involving GAGsPGs as potential prognosticdiagnostic markers oras therapeutic agents for cancer-related pathologies are being proposed

1 Introduction

Cancer Microenvironment It is now increasingly recognizedthat the microenvironment plays a critical role in the pro-gression of tumors The consecutive steps of tumor growthlocal invasion intravasation extravasation and invasionof anatomically distant sites are obligatorily perpetratedthrough specific interactions of the tumor cells with theirmicroenvironment Free glycosaminoglycans (GAGs) andproteoglycan- (PG-) containing GAGs key effectors of cellsurface pericellular and extracellular microenvironmentsperform multiple functions in cancer by virtue of theircoded structure and their ability to interact with both ligandsand receptors that regulate cancer growth [1ndash4] Specifi-cally these extracellular matrix (ECM) components criticallymodulate the tumor cell ldquomotile phenotyperdquo affecting theiradhesivemigratory abilities which are directly correlated tothe metastatic cascade [5 6]

Glycosaminoglycans (GAGs) comprise a class of linearnegatively charged polysaccharides composed of repeatingdisaccharide units of acetylated hexosamines (N-acetyl-galactosamine in the case of chondroitin sulphate anddermatan sulfate or N-acetyl-glucosamine in the case ofheparin sulphate and heparin) andmainly of uronic acids (d-glucuronic acid or l-iduronic acid) being sulfated at variouspositions The exception constitutes keratan sulphate whoseuronic acid is substituted by galactose Based on the epimericform of uronic acid and the type of hexosamine in theirrepeating disaccharide units GAGs are classified into fourmajor types hyaluronan (HA) chondroitin sulfate (CS) anddermatan sulfate (DS) heparin and heparan sulphate (HS)and keratan sulfate (KS) HA is synthesized in the absenceof a protein core at the inner face of the plasma membraneand consequently found in the form of free chains whereasother GAG types are covalently bound into protein coresto form proteoglycans (PGs) With the exception of HA all

Hindawi Publishing CorporationBioMed Research InternationalVolume 2014 Article ID 124321 13 pageshttpdxdoiorg1011552014124321

2 BioMed Research International

GAG types are variably sulfated which contributes to theintricate complexity of their structures Free GAGs chainsare secreted to the extracellular space and distributed bothin the pericellular matrix and extracellular matrix properGAGs bound into PGs are located to the extracellular matrixbasal membrane and cell surface [7] Cell type and tissuespecific alterations in fine GAG structure which are strictlypredetermined [8ndash10] allow these molecules to modulatewith high specificity different cellular processes [7] Cell-associated and tumor microenvironment GAG content anddistribution is markedly altered during tumor pathogenesisand progression [11 12]

PGs molecules which consist of a protein core that iscovalently modified with GAG chains are distributed bothto the ECM ldquoproperrdquo associated with the cell membrane aswell as located to intracellular compartment These mainPG groups are further classified into families according totheir gene homology core protein properties size and mod-ular composition Thus secreted to the ECM PGs includelarge aggregating PGs named hyalectans small leucine-rich PGs (SLRPs) and basement membrane PGs Cell-surface-associated PGs are distributed into twomain families(syndecans and glypicans) whereas serglycin is the onlyintracellular PG characterized to date [13 14] The widemolecular diversity of PGs is derived from the multitudeof possible combinations of protein cores and GAG chainsThus PGs are also classified regarding their GAG contentinto heparan sulfate PGs (HSPG) chondroitindermatansulfate PGs (CSDSPGs) and keratan sulphate PGs Thespecific structural characteristics of both the protein coresandGAG types provide the structural basis for the plethora oftheir biological functions which include acting as structuralcomponents in tissue organization or dynamic regulators ofcellular behaviour [3]

2 Is the Expression of PGsGAGs in BreastCancer Correlated to Disease Progression

Importantly ECM components including PGs and GAGsare involved in the molecular events that are associated withtumor progression It is well established that during malig-nant transformation significant changes can be observed inthe structural and mechanical properties of respective ECMcomponents Indeed the alteration of cell shape and changesin the interactions with the ECM are considered as importanthallmarks of cancer cells [15 16] Changes in the compositionand organization of ECM regulate cancer progression bypromoting cellular transformation andmetastasis Moreoveraltered expression of ECM molecules also deregulates thebehavior of stromal cells and promotes tumor-associatedangiogenesis and inflammation leading to the generation ofa tumorigenic microenvironment [17ndash19]

HSPGs have been closely correlated to breast cancertumorigenesis Major HSPGs members are the transmem-brane proteins syndecans (SDCs) with the SDC family con-sisting of four members SDC1 SDC2 SDC3 and SDC4 [20]A complex pattern describing SDCsrsquo expression in tumor andstroma compartments during the progression of malignancyis emerging Most reports have focused on the involvement

of SDC1 an epithelial marker during the progression of thisinsidious disease Thus increased expression of SDC1 wasdemonstrated in the stroma of invasive breast cancer [21ndash23] Moreover the expression of SDC1 in both epitheliumand stroma may be a predictor of unfavorable prognosis inbreast cancer whereas loss of epithelial SDC1 was associatedwith a more favorable outcome [21] Importantly SDC1 hasalso been linked with the promotion of proliferation ofhuman breast cancer cells in vitro [23] The distribution ofSDC1 to cell membrane has predominantly been describedin breast cancer however shed SDC1 in other tumor typeshas been directly associated with increased invasion andcancer progression [24 25] Indeed in breast cancer SDC1is suggested to be a poor prognostic factor for breast cancersince its upregulation at both the mRNA and protein levelshas been associated with higher histological tumor gradeas well as increased mitotic index and tumor size [26] Theexpression of other SDC family members in breast cancertissues has also been studied Thus in estrogen receptor-negative and highly proliferative breast carcinoma subtypesSDC1 and SDC4 were found to be overexpressed [27]Similarly the overexpression of these two PGs has beendemonstrated in a highly invasive breast cancer cell line(MDA-MB-231) [28] However another report suggests thatSDC4 expression is downregulated in malignant breast tissue[29] The data on SDC1rsquo roles seem to be more uniformas high expression of SDC1 has been linked with increasedtumor aggressiveness and poorer prognosis in breast carcino-mas [30] Functionally this correlates well with the proposedrole of SDC1 as a coreceptor which activates mitogenicgrowth factor signaling which in turn modulates tumorangiogenesis cell adhesion and motility [31] Moreovera study conducted in postmenopausal women with breastcancer or dense-mammographic breast tissue demonstratedthat the distribution of SDC1 changes from the epitheliumto the stroma [32 33] Interestingly SDC1 expressing breastcarcinomas show decreased response to chemotherapy [34]whereas it has also been indicated that the loss of SDC1expression may be a potential predictive factor for responseto preoperative systemic therapy [35]These data define SDC1as a potentially significant therapy target

The glypicans (GPCs) are HSPGs anchored through theglycosylphosphatidylinositol (GPI) link to the outer layerof cell membranes GPCs have been shown to regulate thebinding properties of bone morphogenetic protein (BMP)and fibroblast growth factor (FGF) [36] Most of the studiesconcerning the roles of GPCs in breast cancer progressionfocus on the role of the GPC3 member Intriguingly theGPC3 gene silencing has been identified in human breastcancer cells through a mechanism which involves the hyper-methylation of the GPC3 promoter Thus GPC3 seems tobe a negative regulator of breast cancer cell proliferationsince it was shown that its ectopic expression inhibited thegrowth rates of 8 in a panel of 10 breast cancer cell lines[37] Furthermore it has been established that GPC3 guidesMCF-7 breast cancer cells to apoptosis through a mechanismthat involves the anchorage of the GPC3 core protein to thecell membrane [38] The role of the other members of theGPC family in breast cancer pathogenesis has not beenwidely

BioMed Research International 3

investigated The up to now obtained data suggest that theexpression of GPC3 and GPC4 was negligibly increased intumor as compared to normal tissues whereas the expressionof GPC5 and GPC6 was below the level of detection in bothnormal and cancerous breast tissues On the contrary inthe same study GPC1 was found to be strongly expressed inhuman breast cancers with a low expression in normal breasttissues [39]

The family of PGs secreted to the ECM and known ashyalectans is comprised of versican aggregan neuroscanand brevican [12] Versican seems to have a prominent rolein breast cancer progression due to its ability to interactwith molecules determined to be regulators of key cellularprocesses [40] Importantly extracellular versican has beenfound to be elevated in a variety of human tumors includingbreast carcinoma [41ndash43] The distribution of versican intissue samples is mostly allocated to breast cancer marginsIndeed the high expression of versican has been described inthe interstitium at the invasive margins of breast carcinomaVersican is suggested to be a prognostic marker as it has beenfound to be predictive of cancer relapse negatively affectingoverall survival rates of breast cancer patients [44] On theother hand the increased expression of versican within peri-tumoral stromal matrix was predictive of relapse-free diseaseprognosis in womenwith node-negative breast cancerTheseauthors therefore propose that versican may be a predictorfor risk and rate of relapse independent of tumor size inpatients with node negative disease [45] Recently varioushistotypes of breast in situ carcinomas have been examinedin order to assess the immunohistochemical expression ofversican in the stroma and correlate these findings to diseaseprogression This study provided evidence that versican isstrongly expressed in the perilesional stroma of a subclass ofductal in situ carcinomas and that the extension of versicanimmunostaining is statistically related to the high grade Onthe other hand the expression of versican in the cases of clas-sic lobular in situ carcinomas was confined to the anatomicalstructures that usually contain this PG in adult breast tissues[46] Thus Canavese et al suggest that various histotypesof breast in situ carcinomas could follow different pathwaysof epithelial stromal interactions Structure-function studiesfocusing on versican suggest that its G3 domain is closelycorrelated to breast cancer progression Thus expressionof versican G3 domain both increases breast cancer cellproliferation in vitro and in vivo and also enhances tumor cellmigration in vitro and systemic metastasis in vivo [47 48]The exogenous expression of a versicanG3 construct in breastcancer cell lines enhanced their resistance to anthracycline-dependent apoptosis when cultured in serum free mediumby upregulating pERK and GSK-3b (S9P) [49] On theother hand versican G3 promoted cell apoptosis inducedby C2-ceramide or Docetaxel by enhancing expression ofpSAPKJNK and decreasing expression of GSK-3120573 (S9P)Inhibition of endogenous versican expression by siRNA orreduction of versican G3rsquos expression by linking G3 with31015840UTR prevented G3 modulated cell apoptosis Thus the G3domain appears to have a dual role in modulating breastcancer cell resistance to chemotherapeutic agents [49] Theimportance of versican in breast cancer pathogenesis is well

illustrated in a recent study by Kischel et al These authorsdemonstrate that all known versican isoforms as well asnew alternatively spliced versican isoform named V4 weresignificantly overexpressed in the malignant lesions [50]

The small leucine-rich proteoglycans (SLRPs) are charac-terized by a relatively small protein core with leucine rich-repeat (LRR) motifs into which GAG chains are covalentlybound [13 51 52] These secreted proteins have the abilityto interact with collagen modifying the deposition andorganization of collagen fibers in the extracellular matrixA study on SLRP expression in breast tumors showed thatlumican and decorin are the most frequently expressedSLRPswhereas biglycan andfibromodulin are rarely detected[53] Decorin is physiologically secreted by stromal fibrob-lasts of normal breast tissue [54] Indeed the expressionof decorin which is abundant in the stroma can be usedas an indicator of tumor progression [55] Specifically lowexpression of decorin has been correlated to large tumor sizea shorter time to progression and poorer survival [55] Ina study by Reed et al it has been shown that the primarytumor growth was strongly diminished after treatment withdecorin protein core In the same study the utilizationof an adenoviral vector containing the decorin transgenecaused the elimination of metastases [56] Decorin hasalso been shown to decrease tumor growth in experimentsconducted in a ratmodel [56]Moreover it has been indicatedthat decorin inactivates the oncogenic ErbB2 protein [57]Another important member of the SLRP family lumicanis specifically expressed in breast cancer tissues but not innormal breast tissues Furthermore it has been proposedthat lumican is differentially expressed during breast tumorprogression [58] The overexpression of lumican in breastcancer tissues is associated with a high tumor grade a lowestrogen receptor (ER) expression level and young age ofpatients [58]

Hyaluronan (HA) is an anionic nonsulfated GAG whichdiffers from the other members of the GAG family as itneither contains sulfate groups nor is it covalently linked intoa core protein [59] This GAG is synthesized by three typesof integral membrane proteins denominated hyaluronansynthases HAS1 HAS2 and HAS3 The degradation of HAwithin tissues on the other hand is performed by enzymesknown as hyaluronidases (HYAL) A significant numberof studies demonstrate that HA deposition is elevated invarious types of cancer tissues including breast cancer [60]Specifically immunochemistry revealed elevated amounts ofHA in the stroma of human breast cancer correlating withtumor invasion metastasis and adverse clinical outcome[61 62] The magnitude of the HA accumulation in thetumor stroma (breast ovarian and prostate cancers) stronglycorrelates with an unfavorable prognosis of the patient thatis advancement of the malignancy [59] HYAL1 and HYAL2are found to be overexpressed in breast cancer tumorsdownregulating the expression of HA [63]

Taking into consideration all the above it can be con-cluded that PGsGAGs which are abundantly present inthe stromal compartment of breast cancer cells play amajor role in several biological processes of carcinogenesisThe overexpression of many of these molecules has been

4 BioMed Research International

associated with the malignant phenotype and with poorprognosis The de facto contribution of these molecules totumor cellsrsquo malignant properties defines them as relevanttherapeutic agents

3 The lsquolsquoMotilersquorsquo Phenotype

Tumors of solid organs (carcinomas sarcomas and centralnervous system tumors) kill patientsmainly by disseminationfrom the primary site as once the cells migrate beyondthe primary site into adjacent or distant tissue they aredifficult to extirpate This dissemination may take two forms(i) localized invasion throughout the tissue and into theadnexa or (ii) metastatic dissemination [64] An obligatorycomponent of the dissemination process is the obtainingof a ldquomotile phenotyperdquo In order for the tumor cells toefficiently migrate specific cytoskeleton modifications mustbe executed First actin cytoskeleton organization has awell-established role in cell migration and is regulatedby a plethora of extensively studied molecular mediatorsSpecifically Rho GTPases cAMPPKA and integrins werefound to have a central role inmodulating the actin cytoskele-ton alterations during migration and have been shown to beclosely regulated during epithelial to mesenchymal transition(EMT) processes [65 66] Integrins are heterodimeric cell-surface molecules that on one side link the actin cytoskeletonto the cell membrane and on the other side mediate cell-matrix interactions [67] In addition to their structuralfunctions integrins mediate signaling from the extracellularspace into the cell through integrin-associated signallingand adaptor molecules such as FAK (focal adhesion kinase)[68] or ILK (integrin-linked kinase) [69] Intermediate fila-ments (IFs) play a central role in maintaining cell structurestiffness and integrity The IF network of epithelial cellscomprises cytokeratins while the mesenchymal IF networkis primarily constituted of vimentin During EMTs manycytokeratins are downregulated and vimentin is upregulated[70] Overexpression of vimentin IFs in the breast carcinomamodel leads to augmentation of motility and invasivenessin vitro which can be transiently downregulated by treat-ment with antisense oligonucleotides to vimentin Addi-tional experimental evidence suggests that the mechanism(s)responsible for the differential expression of metastatic prop-erties associated with the interconverted phenotype rest(s)in the unique interaction either direct or indirect of IFswith specific integrins interacting with the extracellularmatrix [71]

The ldquomotile phenotyperdquo of cancer cells is expressed onlythrough direct interactions with the tumor environment asinevitably the tumor cells will respond to local stimuli Thesestimuli include cues for motility and migration which nor-mally appear in tissues undergoing formation remodelingor healing Carcinoma cells are likely to be sensitive to themotility cues that normally regulate epithelialmorphogeneticmovements such as ingression delamination invaginationand tube or sheet migration [72] Understanding how suchmotility cues arise and act in tumor tissue may provide oneof the key ldquoanswersrdquo in cancer research

4 The Role of Matrix Moleculesin Breast Cancer Cell Epithelial-to-Mesenchymal Transition

The huge proliferative ability of tumor cells leads to geneticdiversity which facilitates their responsiveness to microen-vironmental factors resulting in an increased degree ofphenotypic plasticity [73 74] Therefore during primarygrowth some tumor cells can acquire traits that endow themwith a malignant phenotype that leads to increased tumorcell motility invasiveness and propensity to metastasize [75]Importantly during epithelial-to-mesenchymal transition(EMT) tumor cells acquire a phenotype that encompasses allthese traits as EMT is characterized by a loss of cell polar-ity and adhesion and gain of motile characteristics Thusthe EMT promotes the detachment of cells from the primarytumor facilitating their migration and metastatic dissem-ination [76] Moreover a strong link between EMT andacquisition of a tumor-initiating phenotype is suggested [77]Early studies suggested the involvement of EMT in aggressivebreast cancer behaviour as cells exhibiting a mesenchymal-like phenotype (vimentin expression lack of cell borderassociated uvomorulin) show dramatically increased motil-ity invasiveness and metastatic potential in nude mice [78]Moreover using an intravital imaging approach Giampieriet al showed that single breast tumor motile cells that havean active TGF-120573-Smad23 EMT promoting signaling werecapable of hematogenous metastasis to distal organs whilethose lacking this signaling pathway were prone to passivelymph metastasis [79] However EMT is not the ldquoultimaterdquoevent as it involves various morphological and functionalalterations [80] and is not always correlated to a moreaggressive phenotype [81] In addition an apparent contra-diction to the association betweenEMTandmetastasis comesfrom clinical observations that distant metastases derivedfrom a variety of primary carcinomas resemble an epithelialphenotype

Importantly the EMT as well as the mesenchymal toepithelial transition (MET) is partly regulated through theldquocrosstalkrdquo between the tumor microenvironment and thecancer cells [82] Growth factor stimulation appears to bea part of this ldquocrosstalkrdquo as epidermal growth factor (EGF)leads to epitheliomesenchymal transition-like changes inhuman breast cancer cells including upregulation of vimentinand downregulation of E-cadherin EMT was associatedwith increased ability of these cells to adhere to ECMmolecules aswell as tomigrate [78] Furthermore TGF-beta1-mediated breast cancer invasion is associated with EMT andmatrix proteolysis [83] Likewise constitutively active typeI insulin-like growth factor receptor causes transformationand xenograft growth of immortalized mammary epithelialcells and is accompanied by an epithelial-to-mesenchymaltransition mediated by NF-kappaB and snail [84] Inter-estingly TGF120573-dependent hyaluronan synthase expression(HAS2) expression but not extracellular hyaluronan hasan important regulatory role in TGF120573-induced EMT [85]Furthermore when breast cells were induced to exhibit EMTthere was a strong upregulation of HAS2 [86]

BioMed Research International 5

Indeed the implication of matrix molecules contributionto EMT was evident even from early studies [87] LOX isa secreted amine oxidase that catalyses collagen and elastincross-linking in the extracellular matrix previously shown toregulate breast cancer metastasis and is correlated to EMT[88] Enhanced tenascin-C expression and matrix depositionduring RasTGF-beta-induced EMT of mammary tumorcells was reported [89] Noteworthy there seems to be ashift in proteoglycans expression as significant correlationwas found between the loss of the HSPG SDC1 and epithe-lial expression during EMT This loss was correlated withincreased SDC1 stromal expression and a high grade ofmalignancy (119875 = 0011) Therefore the authors concludedthat the loss of SDC1 epithelial expression was of strongprognostic value in breast carcinomas [90] Along the samelines SDC1 coexpression with E-cadherin was found to besynchronously regulated during EMT in breast cancer [91]

Importantly the mesenchymal to epithelial transition(MET) of metastatic breast cancer cells upon reachingdistant metastatic sites appears also to be regulated byECM molecules as a unique paracrine crosstalk between themicroenvironment and the cancer cells has been identified[92] Thus versican stimulated MET of metastatic breastcancer cells by attenuating phospho-Smad2 levels whichresulted in elevated cell proliferation and accelerated metas-tases Analysis of clinical specimens showed elevated versicanexpression within the metastatic lung of patients with breastcancer [92] Thus mechanisms regulating both the EMTandMET processes are dependent on PGGAG participationhighlighting their relevance in breast cancer progression

5 The Roles of GAGsPGs inBreast Cancer Cell Motility

Breast cancer is characterized by significant quantitativechanges of extracellular network constituents Previouslyit has been well established that changes in unique ECMproperties of tumor cells and their microenvironment maylead to changes in cell behavior during cancer progression[12 93] The PG component of the ECM has been shown toparticipate in and regulate key cellular events acting eitherdirectly on cells or modulating growth factor activities [94]

Thus HSPGs are involved in multiple cellular events andfunctions such as cell adhesion ECM assembly and growthfactors storage [95] Their HS chains have the ability to bindnot only to numerous ldquoheparin-rdquo binding growth factorsand morphogens [31] but also to ldquoheparin-rdquo binding sitespresent in matrix ligands including fibronectin vitronectinlaminins and the fibrillar collagens [31] The SDCs arebelieved to have roles in cell adhesion and signaling possiblyas coreceptors with integrins and cell-cell adhesionmolecules[96]

Each of the four SDCs has been proposed to connectto the actin cytoskeleton via their cytoplasmic domains[97 98] for example through ezrin in SDC2 and a-actininin the case of SDC4 For SDC1 SDC2 and SDC4 at leastthe external core protein can trigger integrin-mediated celladhesion events which may be direct or in the case of SDC4probably indirect [98]

Many studies indicate a strong correlation between theexpression of specific HSPGs and the metastatic and invasivepotential of breast cancer cells [26 99 100] In fact theexpression of SDC4 and the overexpression of SDC2 areassociated with the high invasive potential of MDA-MB-231cell line [29] Interestingly estradiol (E2) as well as IGF andEGF signaling pathways have significant roles in regulatingthe expression of certain cell surface HSPGs such as SDC2SDC4 and GPC1 which are crucial for cell motility [101]

SDC1 participates in the generation of a proangiogenicmicroenvironment supporting tumor growth andmetastaticspread [11 12 102] This HSPG regulates downstream signal-ing pathways that are traditionally associated with the inte-grins [12 103 104] thus mediating cell migration by creatinga dynamic linkage between the ECM and the cytoskeletonand by modulating Rho family members that control theactivation of focal adhesion kinase (FAK) Indeed it has beenobserved that in MDA-MB-231 human breast cancer cellsSDC1 physically interactswith FAK [105] Furthermore SDC1regulates the activation of 120572]1205733 andor 120572]1205735 integrins Thisactivation stimulates adhesion spreading and migration oftumor cells with clear consequences on tumor progression[106] Beauvais and Rapraeger [106] also demonstrated thatSDC1 collaborates with 120572]1205733 integrin to initiate a positiveadhesion signal which is integrin ligand independent Theactivation of 1205731 integrins is not required for SDC1 mediatedcell spreading consequently SDC1 is sufficient for adhesionActually the inhibition of 1205731 integrins activity induces cellsspreading presumably by attenuating the suppression ofSDC1 binding perpetrated by integrins Additionally SDC1participates in the IGF-I receptor (IGF-IR) signaling pathwayon adhesion Specifically it colocalizes with the integrinand IGF-IR and regulates activation of 120572]1205733 and 120572]1205735integrins by coupling these integrins to the IGF-IR in humanmammary carcinoma and endothelial cells resulting in theactivation of an inside-out signaling pathway [107] There-fore SDC1 is an obligatory component in the formation ofthis adhesion complex [107] Additionally SDC1 expressioncoordinates 120573-integrin dependent and interleukin-6 (IL-6)dependent cell functions such as cell adhesion migrationand resistance to irradiation in MDA-MB-231 breast cancercells [108]

SDC2 has likewise been implicated in cell adhesion andsignaling [109] as well as in the progression of cancer [96]The expression of SDC2 in breast cancer cells is regulated byestradiol (E2) through the action of estrogen receptor alpha(ER120572) [110] The increased levels of SDC2 after E2 treatmentmay be connected with the ability of SDC2 to modulate thetumorigenic and invasive behavior of breast cancer cells [110]

SDC3 has not been widely studied with respect to eitherbreast or ovarian carcinoma [111] but its aberrant upregu-lation in vasculature associated with ovarian carcinoma hasbeen noted [112]

SDC4 is a focal adhesion component in a range ofcell types adherent to different matrix molecules includingfibronectin [113 114] and mediating breast cancer cell adhe-sion and spreading [103 106] The attachment of SDC4 tofibronectin triggers intracellular signaling including proteinkinase C120572 and focal adhesion kinase activation to promote

6 BioMed Research International

focal adhesion formation [115 116] SDC4 null cells aredeficient in phosphorylated FAK and show impaired cellmigration [116 117] When overexpressed SDC4 promotesexcess focal adhesion formation resulting in reduced cellmigration [118] Huang et al [119] reported that tenascin-C an adhesion-modulatory ECM molecule [120] binds tofibronectin (specifically to the FNIII13 of the HepII site)thereby specifically blocking cell adhesion to fibronectinthrough SDC4This binding inhibits the coreceptor functionof SDC4 in integrin signaling [119] Nevertheless the roleof SDC4 on tumor progression needs more investigation asdifferent facets of its actions remain unclear

An important feature of the SDC molecule necessaryfor signaling appears to be its ectodomain [96 121] Indeeddepleting epithelia of cell surface SDC1 alters cellmorphologyand organization the arrangement and expression of adhe-sion molecules and anchorage-dependent growth controls[121] Therefore Kato et al [121] suggested a regulatory rolefor SDC1 ectodomain in the control of epithelial cell mor-phology Soluble murine SDC4 ectodomain competes withthe endogenous SDC4 for a critical cell surface interactionrequired for signaling during cell spreading [122 123] Theability of SDC4 to interact with molecules at the cell surfacevia its core protein as well as its GAG chains may uniquelyregulate the formation of cell surface signaling complexesfollowing engagement of this PGwith its extracellular ligands[122 123] Moreover shedding and membrane-associatedSDC1 play distinct roles in different stages of ER120572a+ breastcancer cell progression Proteolytic conversion of SDC1 froma membrane bound into a soluble molecule marks a switchfrom a proliferative to an invasive phenotype with implica-tions for breast cancer diagnostics and potential GAG-basedtherapies [124]

A number of mutations related to SDCs have beenrecorded in breast carcinomas [111] The mutations mayinfluence the sequence of amino acids of the core proteinand the enzymes that are involved in GAG chains synthesisImportantly these mutations may affect the interactionsbetween SDCs and growth factors resulting in altered behav-ior of cells [125] including cell motility

The expression of the GPC1 gene in the MDA-MB-231may be indicative of its higher metastatic potential [29]The expression of GPC3 is silenced in human breast cancerbut ectopic expression of GPC3 revealed that this moleculecan act as a negative regulator of breast cancer cell growth[37 39] GPC3 may inhibit IGF and Wnt signaling whichare critical for cell motility and tumor progression indicatingthat GPC3 may act as a metastasis suppressor [126 127]Another member of GPC family GPC6 seems to have a keyrole in promoting the invasive migration of MDA-MB-231cells through the inhibition of canonical-120573-catenin and Wntsignaling and upregulation of noncanonical Wnt5a signalingthrough the activation of JNK (c-Jun-N-terminal kinase)and p38 MAPK (mitogen-activated protein kinase) [128]Evidence suggests that GPCs are important in growth factorand morphogens responses whereas roles in cell adhesionseem to be the prerogative of SDCs [111]

An important member of hyalectans versican is able tointeract with ECMcomponents and to bind to the cell-surface

proteins CD44 integrin 1205731 and epidermal growth factorreceptor (EGFR) [129 130] to regulate cell processes suchas adhesion proliferation migration and ECM assembly[40 130] The expression of versican in breast carcinomashas been correlated to invasiveness [131] Moreover versicanG3 domain enhanced breast cancer cell growth migrationand metastasis by upregulating the EGFRmediated signalingpathways that contribute to a more metastatic phenotype[48] Also versican enhances breast cancer cell metastasis inmouse breast cancer cell lines not only through facilitatingcell motility and invasion but also by inhibiting preosteoblastcell growth and differentiation which supply favourablemicroenvironments for tumor metastases [132] Enhancedunderstanding of the regulation and the involvement ofversican in cancer may offer a novel approach to cancertherapy by targeting the tumor microenvironment [12]

The overexpression of decorin in the stroma of solidtumors counteracts cell growth indicating that decorin mayhave a protective role in tumor progression [133] Also itseems to be a negative regulator for EGF signaling Decorinrsquosbinding to EGFR initially leads to receptorrsquos prolonged acti-vation followed by EGFR internalization and degradationeliminating tumor growth and metastases [134] Iozzo et al[135] suggest that decorin loss may contribute to increasedIGF-IR activity in the progression of breast cancer whereIGF plays a role on cell motility Another member of SLRPslumican may act as an inhibitor of migration angiogenesisand invasion by interfering with 12057221205731 integrin activity anddownregulating MMP-14 expression to induce apoptosis[136]Moreover winter action of lumicanwith growth factorsaffects mobility adhesion and cell growth [137 138]

Serglycin is the only characterized intracellular PG foundin hepatopoietic and endothelial cells [12] It carriers eitherheparan sulfate or chondroitin sulfate chains depending oncell type Korpetinou et al [139] have shown for the firsttime that serglycin is highly expressed in an aggressivebreast cancer cell line (MDA-MB-231) The same authorsdemonstrated that the overexpression of serglycin promotesbreast cancer cell growth migration and invasion [139]Interestingly overexpression of serglycin lacking the GAGattachment sites failed to promote these cellular functionssuggesting that glycanation of serglycin is necessary forits oncogenic properties This study suggests that serglycinpromotes a more aggressive cancer cell phenotype and mayprotect breast cancer cells from complement attack support-ing their survival and expansion

HA is one of the principal ECM molecules and togetherwith its CD44 cell surface receptor it is implicated in cancercell invasion and metastasis [62] Indeed high levels ofHA are documented in malignant tumors not only to thetumor stroma but also at the cell surface [62] The elevatedlevels of the HA degrading HYAL1 seems to regulate cellgrowth adhesion invasion and angiogenesis of breast cancer[63] Basal-like breast cancers (BL-BCa) have the worstprognosis of all subgroups of this disease Indicatively HA-induced CD44 signaling increases a diverse spectrum ofprotease activity including MTI-MMP and cathepsin K tofacilitate the invasion associatedwith BL-BCa cells providingnew insights into the molecular basis of CD44-promoted

BioMed Research International 7

(A)

SDC1 SD

C4

PKCa

Invasivemigration

Src

Fibronectin

(B)(D)

FAKFAK

Cellspreading

Focal adhesionformation

Glyp

ican6

Wnt5a

JNK

NoncanonicalWnt pathway

p38

EGFR

Versican

EGFR

Decorin

Degradationblocking of EGFR

signaling

ERK12

pERK12

P

Metastasis

(C)

(E)In

t-1205721205733

Int-120573

L

Figure 1 Roles of PGsGAGs on the breast cancer motile phenotype (A) Complex formation between syndecan1 (SDC1) and integrin-120572]1205733activate focal adhesion kinase to facilitate breast cancer cell spreading (B)The specific binding of SDC4 through its HS chains to fibronectinactivates FAKprotein kinase Ca (PKCa) downstream signaling to initiate focal adhesion formation (C)Wnt5a attaches to glypican6 in orderto enhance breast cancer cell invasive migration through the involvement of noncanonical Wnt pathway and JNKp38 downstream signaling(D) Complex formation among versican EGFR and Int-120573L activates extracellular matrix regulated kinase (ERK12) signaling to promotebreast cancer metastasis (E) Binding of decorin to EGFR causes receptor internalization degradation and subsequent inhibition of EGFRsignaling

invasion [140] Moreover the cell surface HA which issecreted by breast cancer cells increases the adhesion abilityof tumor cells to lymphatic endothelial receptor (LYVE-1)[132] Importantly the molecular weight of HA seems toplay a key role in the process of cell adhesion [141 142]and particularly low molecular weight of HA promotes celladhesion while high molecular weight HA has no effect[143] Indeed LMW-HA plays an important role in CD44-TLR-associated AFAP-110-actin interaction and MyD88-NF-120581B signaling required for tumor cell behaviors which maycontribute to the progression of breast cancer [143]The rolesof PGsGAGs on breast cancer cell motile phenotype areschematically depicted in Figure 1

6 PGsGAGs Potential Targetsin Breast Cancer

In many in vitro studies breast cancer cells were treated withvarious anticancer agents including inhibitors of tyrosinekinase receptors and other molecules such as small peptideswhich are related to the expression of proteoglycans in orderto observe changes in cell functions [29 144 145] Thus anew generation of bisphosphonate zoledronate (zoledronicacid Zometa) downregulates the expression levels of SDC1SDC2 and GPC1 and upregulates the expression of SDC4

in breast cancer cells of low and high metastatic capability[144] Furthermore the downregulation in the expression ofHA and its receptor CD44 which is directly associated withthemigration andmatrix-associated invasion of breast cancercells was also observed [144] Imatinib a specific tyrosinekinase inhibitor which targets PDGFRs had a similar effecton breast cancer cells Imatinib resulted in an inhibitionof the PDGF-BB mediated expression of HSPGs which isassociated with its inhibitory effect on the invasive andmigratory potential of breast cancer cells [29] A differentapproach was utilized by Rapraeger [145] These authorsused a small peptide synstatin to target SDC1 Thus thesite in the SDC1 ectodomain that is responsible for captureand activation of the 120572]1205733 or 120572]1205735 integrins by IGF1Rcan be mimicked by this short peptide which competitivelydisplaces the integrin and IGF1R kinase from the syndecanand inactivates the complexThe blocking in the formation ofthe receptor complex attenuates breast cancer cell metastasis[145]

It has been demonstrated that degradation of HS chainsby heparanase 1 (HPSE-1) reveals cryptic HS fragments thatplay a significant role in controlling tumor cell growth andmetastasis It is thus likely that enzymatic degradation ofHS could be used as a potential treatment against car-cinogenesis since HS chains are involved in fundamentalbiological processes of both normal andmetastatic cells [146]

8 BioMed Research International

Synthetic proteoglycans such as neoheparin and neoCS pro-duced by carbodiimide (EDAC) conjugation of glycosamino-glycan (GAG) chains to a protein scaffold reduce cell viabilityby induction of apoptosis of myeloma and breast cancer cellsin vitroThese results demonstrate the anticancer activities ofthis new class of GAG-based molecules [147]

In summary this review focused on the roles ofPGsGAGs on breast cancer motility in order to identifypossible therapeutic targets The emerging mechanisms ofPGGas action could potentially be exploited for designatingdiscrete therapy targets for specific breast cancer grades

Abbreviations

(PG) Proteoglycan(GAG) Glycosaminoglycan(ECM) Extracellular matrix(SLRPs) Small leucine-rich PGs(GPC) Glypican(SDC) Syndecan(HYAL) Hyaluronidase(HAS) Hyaluronan synthase(EMT) Epithelial-to-mesenchymal transition(MET) Mesenchymal to epithelial transition(E2) Estradiol(ERs) Estrogen receptors

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Acknowledgments

This research has been cofinanced by the European Union(European Social Fund (ESF)) and Greek national fundsthrough the Operational Program ldquoEducation and LifelongLearningrdquo of the National Strategic Reference Framework(NSRF) Research Funding Program THALES Investing inknowledge society through the European Social Fund

References

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[2] D Nikitovic K Kouvidi N K Karamanos and G NTzanakakis ldquoThe roles of hyaluronanRHAMMCD44 andtheir respective interactions along the insidious pathways offibrosarcoma progressionrdquo BioMed Research International vol2013 Article ID 929531 12 pages 2013

[3] DNikitovicMMytilinaiou A Berdiaki N K Karamanos andG N Tzanakakis ldquoHeparan sulfate proteoglycans and heparinregulate melanoma cell functionsrdquo Biochimica et BiophysicaActa vol 1840 no 8 pp 2471ndash2481 2014

[4] K Kouvidi A Berdiaki D Nikitovic et al ldquoRole of Receptor forHyaluronic Acid-mediated Motility (RHAMM) in Low Molec-ular Weight Hyaluronan (LMWHA)-mediated fibrosarcoma

cell adhesionrdquo Journal of Biological Chemistry vol 286 no 44pp 38509ndash38520 2011

[5] MMytilinaiou A BanoDNikitovic et al ldquoSyndecan-2 is a keyregulator of transforming growth factor beta 2smad2-mediatedadhesion in fibrosarcoma cellsrdquo IUBMB Life vol 65 no 2 pp134ndash143 2013

[6] G Chalkiadaki D Nikitovic P Katonis et al ldquoLow molecularweight heparin inhibits melanoma cell adhesion and migra-tion through a PKCaJNK signaling pathway inducing actincytoskeleton changesrdquo Cancer Letters vol 312 no 2 pp 235ndash244 2011

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[8] A Syrokou G Tzanakakis T Tsegenidis A Hjerpe and N KKaramanos ldquoEffects of glycosaminoglycans on proliferation ofepithelial and fibroblast human malignant mesothelioma cellsa structure-function relationshiprdquo Cell Proliferation vol 32 no2-3 pp 85ndash99 1999

[9] T N Mitropoulou G N Tzanakakis D Nikitovic A Tsatsakisand N K Karamanos ldquoIn vitro effects of genistein on thesynthesis and distribution of glycosaminoglycans proteogly-cans by estrogen receptor-positive and -negative human breastcancer epithelial cellsrdquo Anticancer Research vol 22 no 5 pp2841ndash2846 2002

[10] C B N Mendes de Aguiar B Lobao-Soares M Alvarez-Silvaand A Goncalves Trentin ldquoGlycosaminoglycans modulate C6glioma cell adhesion to extracellular matrix components andalter cell proliferation and cellmigrationrdquoBMCCell Biology vol6 article 31 2005

[11] N Afratis C Gialeli D Nikitovic et al ldquoGlycosaminoglycanskey players in cancer cell biology and treatmentrdquo The FEBSJournal vol 279 no 7 pp 1177ndash1197 2012

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[13] R V Iozzo ldquoMatrix proteoglycans from molecular design tocellular functionrdquo Annual Review of Biochemistry vol 67 pp609ndash652 1998

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[15] P P Provenzano K W Eliceiri J M Campbell D R Inman JGWhite and P J Keely ldquoCollagen reorganization at the tumor-stromal interface facilitates local invasionrdquo BMC Medicine vol4 article 38 2006

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[19] J L Andres D DeFalcis M Noda and J Massague ldquoBindingof two growth factor families to separate domains of theproteoglycan betaglycanrdquo Journal of Biological Chemistry vol267 no 9 pp 5927ndash5930 1992

BioMed Research International 9

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[24] M V Dhodapkar T Kelly A Theus A B Athota B Barlogieand R D Sanderson ldquoElevated levels of shed syndecan-1 corre-late with tumourmass and decreasedmatrixmetalloproteinase-9 activity in the serum of patients with multiple myelomardquoBritish Journal of Haematology vol 99 no 2 pp 368ndash371 1997

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[26] M E Lendorf T Manon-Jensen P Kronqvist H A BMulthaupt and J R Couchman ldquoSyndecan-1 and syndecan-4 are independent indicators in breast carcinomardquo Journal ofHistochemistry and Cytochemistry vol 59 no 6 pp 615ndash6292011

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[29] C Mundhenke K Meyer S Drew and A Friedl ldquoHeparansulfate proteoglycans as regulators of fibroblast growth factor-2 receptor binding in breast carcinomasrdquo American Journal ofPathology vol 160 no 1 pp 185ndash194 2002

[30] M Barbareschi P Maisonneuve D Aldovini et al ldquoHighsyndecan-1 expression in breast carcinoma is related to anaggressive phenotype and to poorer prognosisrdquo Cancer vol 98no 3 pp 474ndash483 2003

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[32] E Lundstrom L Sahlin L Skoog et al ldquoExpression ofSyndecan-1 in histologically normal breast tissue from post-menopausal women with breast cancer according to mammo-graphic densityrdquo Climacteric vol 9 no 4 pp 277ndash282 2006

[33] L Lofgren L Sahlin S Jiang et al ldquoExpression of syndecan-1 in paired samples of normal and malignant breast tissue frompostmenopausal womenrdquoAnticancer Research vol 27 no 5 pp3045ndash3050 2007

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[37] Y Y Xiang V Ladeda and J Filmus ldquoGlypican-3 expression issilenced in human breast cancerrdquo Oncogene vol 20 no 50 pp7408ndash7412 2001

[38] A D GonzalezM KayaW Shi et al ldquoOCI-5GPC3 a glypicanencoded by a gene that is mutated in the Simpson-Golabi-Behmel overgrowth syndrome induces apoptosis in a cell line-specificmannerrdquo Journal of Cell Biology vol 141 no 6 pp 1407ndash1414 1998

[39] K Matsuda H Maruyama F Guo et al ldquoGlypican-1 is overex-pressed in human breast cancer and modulates the mitogeniceffects of multiple heparin-binding growth factors in breastcancer cellsrdquo Cancer Research vol 61 no 14 pp 5562ndash55692001

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[42] Y Nara Y Kato Y Torii et al ldquoImmunohistochemical local-ization of extracellular matrix components in human breasttumours with special reference to PG-MversicanrdquoHistochemi-cal Journal vol 29 no 1 pp 21ndash30 1997

[43] C Ricciardelli J H Brooks S Suwiwat et al ldquoRegulation ofstromal versican expression by breast cancer cells and impor-tance to relapse-free survival in patients with node-negativeprimary breast cancerrdquo Clinical Cancer Research vol 8 no 4pp 1054ndash1060 2002

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[45] S Suwiwat C Ricciardelli R Tammi et al ldquoExpression ofextracellular matrix components versican chondroitin sulfatetenascin and hyaluronan and their association with dis-ease outcome in node-negative breast cancerrdquo Clinical CancerResearch vol 10 no 7 pp 2491ndash2498 2004

[46] G Canavese G Candelaresi I Castellano and M P ManoldquoExpression of proteoglycan versican in in situ breast lesionsrelations between stromal changes histotype and invasionrdquoPathology Research and Practice vol 207 no 2 pp 97ndash103 2011

[47] A JM YeeMAkens B L Yang J Finkelstein P Zheng andZDeng ldquoThe effect of versican G3 domain on local breast cancerinvasiveness and bony metastasisrdquo Breast Cancer Research vol9 no 4 article R42 2007

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[49] W W Du B B Yang B L Yang et al ldquoVersican G3 domainmodulates breast cancer cell apoptosis a mechanism for breastcancer cell response to chemotherapy and egfr therapyrdquo PLoSONE vol 6 no 11 Article ID e26396 2011

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[51] P A McEwan P G Scott P N Bishop and J Bella ldquoStructuralcorrelations in the family of small leucine-rich repeat proteinsand proteoglycansrdquo Journal of Structural Biology vol 155 no 2pp 294ndash305 2006

[52] L Schaefer and R V Iozzo ldquoBiological functions of the smallleucine-rich proteoglycans from genetics to signal transduc-tionrdquo Journal of Biological Chemistry vol 283 no 31 pp 21305ndash21309 2008

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[70] P Savagner ldquoThe epithelial-mesenchymal transition (EMT)phenomenonrdquo Annals of Oncology vol 21 supplement 7 ppvii89ndashvii92 2010

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[75] F Marcucci M Bellone C A Caserta and A Corti ldquoPushingtumor cells towards a malignant phenotype stimuli from themicroenvironment intercellular communications and alterna-tive roadsrdquo International Journal of Cancer vol 135 no 6 pp1265ndash1276 2014

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[79] S Giampieri C Manning S Hooper L Jones C S Hill andE Sahai ldquoLocalized and reversible TGF120573 signalling switchesbreast cancer cells from cohesive to single cell motilityrdquo NatureCell Biology vol 11 no 11 pp 1287ndash1296 2009

[80] AWicki F LehembreNWick BHantuschDKerjaschki andG Christofori ldquoTumor invasion in the absence of epithelial-mesenchymal transition podoplanin-mediated remodeling ofthe actin cytoskeletonrdquo Cancer Cell vol 9 no 4 pp 261ndash2722006

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[92] D Gao N Joshi H Choi et al ldquoMyeloid progenitor cellsin the premetastatic lung promote metastases by inducingmesenchymal to epithelial transitionrdquo Cancer Research vol 72no 6 pp 1384ndash1394 2012

[93] C Gialeli A D Theocharis and N K Karamanos ldquoRolesof matrix metalloproteinases in cancer progression and theirpharmacological targetingrdquo The FEBS Journal vol 278 no 1pp 16ndash27 2011

[94] R V Iozzo ldquoThe family of the small leucine-rich proteoglycanskey regulators of matrix assembly and cellular growthrdquo CriticalReviews in Biochemistry andMolecular Biology vol 32 no 2 pp141ndash174 1997

[95] S Sarrazin W C Lamanna and J D Esko ldquoHeparan sulfateproteoglycansrdquo Cold Spring Harbor Perspectives in Biology vol3 no 7 Article ID a004952 2011

[96] D M Beauvais and A C Rapraeger ldquoSyndecans in tumor celladhesion and signalingrdquo Reproductive Biology and Endocrinol-ogy vol 2 article 3 2004

[97] J R Couchman ldquoSyndecans proteoglycan regulators of cell-surfacemicrodomainsrdquoNature ReviewsMolecular Cell Biologyvol 4 no 12 pp 926ndash937 2003

[98] J R Couchman ldquoTransmembrane signaling proteoglycansrdquoAnnual Review of Cell and Developmental Biology vol 26 pp89ndash114 2010

[99] T Manon-Jensen Y Itoh and J R Couchman ldquoProteoglycansin health and disease the multiple roles of syndecan sheddingrdquoFEBS Journal vol 277 no 19 pp 3876ndash3889 2010

[100] X Xian S Gopal and J R Couchman ldquoSyndecans as receptorsand organizers of the extracellular matrixrdquo Cell and TissueResearch vol 339 no 1 pp 31ndash46 2010

[101] A I Tsonis N Afratis C Gialeli et al ldquoEvaluation of the coor-dinated actions of estrogen receptors with epidermal growthfactor receptor and insulin-like growth factor receptor in theexpression of cell surface heparan sulfate proteoglycans and cellmotility in breast cancer cellsrdquo FEBS Journal vol 280 no 10 pp2248ndash2259 2013

[102] G W Yip M Smollich and M Gotte ldquoTherapeutic value ofglycosaminoglycans in cancerrdquo Molecular Cancer Therapeuticsvol 5 no 9 pp 2139ndash2148 2006

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[104] K Lambaerts S A Wilcox-Adelman and P ZimmermannldquoThe signaling mechanisms of syndecan heparan sulfate pro-teoglycansrdquo Current Opinion in Cell Biology vol 21 no 5 pp662ndash669 2009

[105] S A Ibrahim GW Yip C Stock et al ldquoTargeting of syndecan-1 by microRNA miR-10b promotes breast cancer cell motilityand invasiveness via aRho-GTPase- andE-cadherin-dependentmechanismrdquo International Journal of Cancer vol 131 no 6 ppE884ndashE896 2012

[106] D M Beauvais and A C Rapraeger ldquoSyndecan-1-mediated cellspreading requires signaling by 120572v1205733 integrins in human breastcarcinoma cellsrdquo Experimental Cell Research vol 286 no 2 pp219ndash232 2003

[107] D M Beauvais and A C Rapraeger ldquoSyndecan-1 couplesthe insulin-like growth factor-1 receptor to inside-out integrinactivationrdquo Journal of Cell Science vol 123 no 21 pp 3796ndash3807 2010

[108] HHassan B GreveM S G Pavao L Kiesel S A Ibrahim andM Gotte ldquoSyndecan-1 modulates 120573-integrin-dependent andinterleukin-6-dependent functions in breast cancer cell adhe-sion migration and resistance to irradiationrdquo FEBS Journalvol 280 no 10 pp 2216ndash2227 2013

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[110] O C Kousidou A Berdiaki D Kletsas et al ldquoEstradiol-estrogen receptor a key interplay of the expression of syndecan-2 and metalloproteinase-9 in breast cancer cellsrdquo MolecularOncology vol 2 no 3 pp 223ndash232 2008

[111] A Yoneda M E Lendorf J R Couchman and H A BMulthaupt ldquoBreast and ovarian cancers a survey and possibleroles for the cell surface heparan sulfate proteoglycansrdquo Journalof Histochemistry and Cytochemistry vol 60 no 1 pp 9ndash212012

[112] E J Davies F H Blackhall J H Shanks et al ldquoDistribution andclinical significance of heparan sulfate proteoglycans in ovariancancerrdquo Clinical Cancer Research vol 10 no 15 pp 5178ndash51862004

12 BioMed Research International

[113] A Woods and J R Couchman ldquoSyndecan 4 heparan sulfateproteoglycan is a selectively enriched and widespread focaladhesion componentrdquo Molecular Biology of the Cell vol 5 no2 pp 183ndash192 1994

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[115] A C Rapraeger ldquoSyndecan-regulated receptor signalingrdquo Jour-nal of Cell Biology vol 149 no 5 pp 995ndash997 2000

[116] AWoods ldquoSyndecans transmembranemodulators of adhesionand matrix assemblyrdquo Journal of Clinical Investigation vol 107no 8 pp 935ndash941 2001

[117] L A Cary J F Chang and J Guan ldquoStimulation of cellmigration by overexpression of focal adhesion kinase and itsassociation with Src and Fynrdquo Journal of Cell Science vol 109no 7 pp 1787ndash1794 1996

[118] R L Longley A Woods A Fleetwood G J Cowling JT Gallagher and J R Couchman ldquoControl of morphologycytoskeleton and migration by syndecan-4rdquo Journal of CellScience vol 112 no 20 pp 3421ndash3431 1999

[119] W Huang R Chiquet-Ehrismann J V Moyano A Garcia-Pardo and G Orend ldquoInterference of tenascin-C withsyndecan-4 binding to fibronectin blocks cell adhesion andstimulates tumor cell proliferationrdquoCancer Research vol 61 no23 pp 8586ndash8594 2001

[120] GVollmerM I TanWWunsche andK Frank ldquoExpression oftenascin-C by human endometrial adenocarcinoma and stromacells heterogeneity of splice variants and induction by TGF-120573rdquoBiochemistry and Cell Biology vol 75 no 6 pp 759ndash769 1997

[121] M Kato S Saunders H Nguyen and M Bernfield ldquoLossof cell surface syndecan-1 causes epithelia to transforminto anchorage-independentmesenchyme-like cellsrdquoMolecularBiology of the Cell vol 6 no 5 pp 559ndash576 1995

[122] A J McFall and A C Rapraeger ldquoIdentification of an adhesionsite within the syndecan-4 extracellular protein domainrdquo TheJournal of Biological Chemistry vol 272 no 20 pp 12901ndash129041997

[123] A J McFall and A C Rapraeger ldquoCharacterization of the highaffinity cell-binding domain in the cell surface proteoglycansyndecan-4rdquo Journal of Biological Chemistry vol 273 no 43 pp28270ndash28276 1998

[124] V Nikolova C Koo S A Ibrahim et al ldquoDifferential rolesformembrane-bound and soluble syndecan-1 (CD138) in breastcancer progressionrdquo Carcinogenesis vol 30 no 3 pp 397ndash4072009

[125] I Vlodavsky M Elkin and N Ilan ldquoImpact of heparanaseand the tumor microenvironment on cancer metastasis andangiogenesis basic aspects and clinical applicationsrdquo RambamMaimonides Medical Journal vol 2 no 1 Article ID e0019 2011

[126] M G Peters E Farıas L Colombo J Filmus L Puricelli andE Bal de Kier Joffe ldquoInhibition of invasion and metastasis byglypican-3 in a syngeneic breast cancer modelrdquo Breast CancerResearch and Treatment vol 80 no 2 pp 221ndash232 2003

[127] I Stigliano L Puricelli J Filmus M C Sogayar E B deKier Joffe and M G Peters ldquoGlypican-3 regulates migrationadhesion and actin cytoskeleton organization in mammarytumor cells through Wnt signaling modulationrdquo Breast CancerResearch and Treatment vol 114 no 2 pp 251ndash262 2009

[128] G K Yiu A Kaunisto Y R Chin and A Toker ldquoNFATpromotes carcinoma invasive migration through glypican-6rdquoBiochemical Journal vol 440 no 1 pp 157ndash166 2011

[129] Y J Wu D P La Pierre J Wu A J Yee and B B Yang ldquoTheinteraction of versican with its binding partnersrdquo Cell Researchvol 15 no 7 pp 483ndash494 2005

[130] A D Theocharis ldquoVersican in health and diseaserdquo ConnectiveTissue Research vol 49 no 3-4 pp 230ndash234 2008

[131] S S Skandalis V T Labropoulou P Ravazoula et al ldquoVersicanbut not decorin accumulation is related to malignancy in mam-mographically detected high density and malignant-appearingmicrocalcifications in non-palpable breast carcinomasrdquo BMCCancer vol 11 article 314 2011

[132] W W Du L Fang W Yang et al ldquoThe role of versicanG3 domain in regulating breast cancer cell motility includingeffects on osteoblast cell growth and differentiation in vitromdashevaluation towards understanding breast cancer cell bonemetastasisrdquo BMC Cancer vol 12 article 341 2012

[133] S S Skandalis N Afratis G Smirlaki D Nikitovic A DTheocharis and G N Tzanakakis ldquoCross-talk between estra-diol receptor andEGFRIGF-IR signaling pathways in estrogen-responsive breast cancers focus on the role and impact ofproteoglycansrdquoMatrix Biology vol 35 pp 182ndash193 2014

[134] J Zhu S Goldoni G Bix et al ldquoDecorin evokes protractedinternalization and degradation of the epidermal growth factorreceptor via caveolar endocytosisrdquo Journal of Biological Chem-istry vol 280 no 37 pp 32468ndash32479 2005

[135] R V Iozzo S Buraschi M Genua et al ldquoDecorin antagonizesIGF receptor I (IGF-IR) function by interfering with IGF-IRactivity and attenuating downstream signalingrdquo The Journal ofBiological Chemistry vol 286 no 40 pp 34712ndash34721 2011

[136] B Vuillermoz A Khoruzhenko M DrsquoOnofrio et al ldquoThesmall leucine-rich proteoglycan lumican inhibits melanomaprogressionrdquo Experimental Cell Research vol 296 no 2 pp294ndash306 2004

[137] S Brezillon C Zeltz L Schneider et al ldquoLumican inhibitsB16F1 melanoma cell lungmetastasisrdquo Journal of Physiology andPharmacology vol 60 pp 15ndash22 2009

[138] C Zeltz S Brezillon J Kapyla et al ldquoLumican inhibits cellmigration through 1205722Β1 integrinrdquo Experimental Cell Researchvol 316 no 17 pp 2922ndash2931 2010

[139] A Korpetinou S S Skandalis A Moustakas et al ldquoSerglycin isimplicated in the promotion of aggressive phenotype of breastcancer cellsrdquo PLoS ONE vol 8 Article ID e78157 2013

[140] N Montgomery A Hill S McFarlane et al ldquoCD44 enhancesinvasion of basal-like breast cancer cells by upregulating serineprotease and collagen-degrading enzymatic expression andactivityrdquo Breast Cancer Research vol 14 no 3 article R84 2012

[141] L E Dickinson C C Ho G M Wang K J Stebe andS Gerecht ldquoFunctional surfaces for high-resolution analysisof cancer cell interactions on exogenous hyaluronic acidrdquoBiomaterials vol 31 no 20 pp 5472ndash5478 2010

[142] C Yang M Cao H Liu et al ldquoThe high and low molecularweight forms of hyaluronan have distinct effects on CD44clusteringrdquoThe Journal of Biological Chemistry vol 287 no 51pp 43094ndash43107 2012

[143] L Y W Bourguignon G Wong C A Earle and W XialdquoInteraction of low molecular weight hyaluronan with CD44and toll-like receptors promotes the actin filament-associatedprotein 110-actin binding and MyD88-NF120581B signaling leading

BioMed Research International 13

to proinflammatory cytokinechemokine production andbreasttumor invasionrdquo Cytoskeleton vol 68 no 12 pp 671ndash693 2011

[144] P G Dedes C Gialeli A I Tsonis et al ldquoExpression of matrixmacromolecules and functional properties of breast cancercells are modulated by the bisphosphonate zoledronic acidrdquoBiochimica et Biophysica Acta vol 1820 no 12 pp 1926ndash19392012

[145] A C Rapraeger ldquoSynstatin A selective inhibitor of thesyndecan-1-coupled IGF1R-120572v1205733 integrin complex in tumori-genesis and angiogenesisrdquo The FEBS Journal vol 280 no 10pp 2207ndash2215 2013

[146] D Liu Z Shriver G Venkataraman Y El Shabrawi and RSasisekharan ldquoTumor cell surface heparan sulfate as crypticpromoters or inhibitors of tumor growth and metastasisrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 99 no 2 pp 568ndash573 2002

[147] C Y Pumphrey A M Theus S Li R S Parrish and R DSanderson ldquoNeoglycans carbodiimide-modified glycosamino-glycans a new class of anticancer agents that inhibit cancer cellproliferation and induce apoptosisrdquoCancer Research vol 62 no13 pp 3722ndash3728 2002

BioMed Research International 9

[20] M Bernfield R Kokenyesi M Kato et al ldquoBiology of thesyndecans a family of transmembrane heparan sulfate proteo-glycansrdquoAnnual Review of Cell Biology vol 8 pp 365ndash393 1992

[21] M Leivonen J Lundin S Nordling K von Boguslawski andCHaglund ldquoPrognostic value of syndecan-1 expression in breastcancerrdquo Oncology vol 67 no 1 pp 11ndash18 2004

[22] M J Stanley M W Stanley R D Sanderson and R ZeraldquoSyndecan-1 expression is induced in the stroma of infiltratingbreast carcinomardquo American Journal of Clinical Pathology vol112 no 3 pp 377ndash383 1999

[23] T Maeda C M Alexander and A Friedl ldquoInduction ofsyndecan-1 expression in stromal fibroblasts promotes prolifer-ation of human breast cancer cellsrdquoCancer Research vol 64 no2 pp 612ndash621 2004

[24] M V Dhodapkar T Kelly A Theus A B Athota B Barlogieand R D Sanderson ldquoElevated levels of shed syndecan-1 corre-late with tumourmass and decreasedmatrixmetalloproteinase-9 activity in the serum of patients with multiple myelomardquoBritish Journal of Haematology vol 99 no 2 pp 368ndash371 1997

[25] Y Yang S Yaccoby W Liu et al ldquoSoluble syndecan-1 promotesgrowth of myeloma tumors in vivordquo Blood vol 100 no 2 pp610ndash617 2002

[26] M E Lendorf T Manon-Jensen P Kronqvist H A BMulthaupt and J R Couchman ldquoSyndecan-1 and syndecan-4 are independent indicators in breast carcinomardquo Journal ofHistochemistry and Cytochemistry vol 59 no 6 pp 615ndash6292011

[27] F Baba K Swartz R van Buren et al ldquoSyndecan-1 andsyndecan-4 are overexpressed in an estrogen receptor-negativehighly proliferative breast carcinoma subtyperdquo Breast CancerResearch and Treatment vol 98 no 1 pp 91ndash98 2006

[28] C JMalavaki A E Roussidis C Gialeli et al ldquoImatinib as a keyinhibitor of the platelet-derived growth factor receptor medi-ated expression of cell surface heparan sulfate proteoglycansand functional properties of breast cancer cellsrdquo FEBS Journalvol 280 no 10 pp 2477ndash2489 2013

[29] C Mundhenke K Meyer S Drew and A Friedl ldquoHeparansulfate proteoglycans as regulators of fibroblast growth factor-2 receptor binding in breast carcinomasrdquo American Journal ofPathology vol 160 no 1 pp 185ndash194 2002

[30] M Barbareschi P Maisonneuve D Aldovini et al ldquoHighsyndecan-1 expression in breast carcinoma is related to anaggressive phenotype and to poorer prognosisrdquo Cancer vol 98no 3 pp 474ndash483 2003

[31] M Bernfield M Gotte P W Park et al ldquoFunctions ofcell surface heparan sulfate proteoglycansrdquo Annual Review ofBiochemistry vol 68 pp 729ndash777 1999

[32] E Lundstrom L Sahlin L Skoog et al ldquoExpression ofSyndecan-1 in histologically normal breast tissue from post-menopausal women with breast cancer according to mammo-graphic densityrdquo Climacteric vol 9 no 4 pp 277ndash282 2006

[33] L Lofgren L Sahlin S Jiang et al ldquoExpression of syndecan-1 in paired samples of normal and malignant breast tissue frompostmenopausal womenrdquoAnticancer Research vol 27 no 5 pp3045ndash3050 2007

[34] M Gotte C Kersting M Ruggiero et al ldquoPredictive valueof syndecan-1 expression for the response to neoadjuvantchemotherapy of primary breast cancerrdquo Anticancer Researchvol 26 no 1 pp 621ndash627 2006

[35] A M Tokes A M Szasz A Farkas et al ldquoStromal matrixprotein expression following preoperative systemic therapy inbreast cancerrdquo Clinical Cancer Research vol 15 no 2 pp 731ndash739 2009

[36] J FilmusM Capurro and J Rast ldquoGlypicansrdquoGenome Biologyvol 9 no 5 article 224 2008

[37] Y Y Xiang V Ladeda and J Filmus ldquoGlypican-3 expression issilenced in human breast cancerrdquo Oncogene vol 20 no 50 pp7408ndash7412 2001

[38] A D GonzalezM KayaW Shi et al ldquoOCI-5GPC3 a glypicanencoded by a gene that is mutated in the Simpson-Golabi-Behmel overgrowth syndrome induces apoptosis in a cell line-specificmannerrdquo Journal of Cell Biology vol 141 no 6 pp 1407ndash1414 1998

[39] K Matsuda H Maruyama F Guo et al ldquoGlypican-1 is overex-pressed in human breast cancer and modulates the mitogeniceffects of multiple heparin-binding growth factors in breastcancer cellsrdquo Cancer Research vol 61 no 14 pp 5562ndash55692001

[40] T N Wight ldquoVersican a versatile extracellular matrix proteo-glycan in cell biologyrdquo Current Opinion in Cell Biology vol 14no 5 pp 617ndash623 2002

[41] A R Jeffs A C Glover L J Slobbe et al ldquoA gene expressionsignature of invasive potential in metastatic melanoma cellsrdquoPLoS ONE vol 4 no 12 Article ID e8461 2009

[42] Y Nara Y Kato Y Torii et al ldquoImmunohistochemical local-ization of extracellular matrix components in human breasttumours with special reference to PG-MversicanrdquoHistochemi-cal Journal vol 29 no 1 pp 21ndash30 1997

[43] C Ricciardelli J H Brooks S Suwiwat et al ldquoRegulation ofstromal versican expression by breast cancer cells and impor-tance to relapse-free survival in patients with node-negativeprimary breast cancerrdquo Clinical Cancer Research vol 8 no 4pp 1054ndash1060 2002

[44] C Ricciardelli K Mayne P J Sykes et al ldquoElevated levels ofversican but not decorin predict disease progression in early-stage prostate cancerrdquo Clinical Cancer Research vol 4 no 4 pp963ndash971 1998

[45] S Suwiwat C Ricciardelli R Tammi et al ldquoExpression ofextracellular matrix components versican chondroitin sulfatetenascin and hyaluronan and their association with dis-ease outcome in node-negative breast cancerrdquo Clinical CancerResearch vol 10 no 7 pp 2491ndash2498 2004

[46] G Canavese G Candelaresi I Castellano and M P ManoldquoExpression of proteoglycan versican in in situ breast lesionsrelations between stromal changes histotype and invasionrdquoPathology Research and Practice vol 207 no 2 pp 97ndash103 2011

[47] A JM YeeMAkens B L Yang J Finkelstein P Zheng andZDeng ldquoThe effect of versican G3 domain on local breast cancerinvasiveness and bony metastasisrdquo Breast Cancer Research vol9 no 4 article R42 2007

[48] W W Du B B Yang T A Shatseva et al ldquoVersican G3promotes mouse mammary tumor cell growth migration andmetastasis by influencing EGF receptor signalingrdquo PLoS ONEvol 5 no 11 Article ID e13828 2010

[49] W W Du B B Yang B L Yang et al ldquoVersican G3 domainmodulates breast cancer cell apoptosis a mechanism for breastcancer cell response to chemotherapy and egfr therapyrdquo PLoSONE vol 6 no 11 Article ID e26396 2011

10 BioMed Research International

[50] P Kischel DWaltregny BDumont et al ldquoVersican overexpres-sion in human breast cancer lesions known and new isoformsfor stromal tumor targetingrdquo International Journal of Cancervol 126 no 3 pp 640ndash650 2010

[51] P A McEwan P G Scott P N Bishop and J Bella ldquoStructuralcorrelations in the family of small leucine-rich repeat proteinsand proteoglycansrdquo Journal of Structural Biology vol 155 no 2pp 294ndash305 2006

[52] L Schaefer and R V Iozzo ldquoBiological functions of the smallleucine-rich proteoglycans from genetics to signal transduc-tionrdquo Journal of Biological Chemistry vol 283 no 31 pp 21305ndash21309 2008

[53] E Leygue L Snell H Dotzlaw et al ldquoLumican and decorinare differentially expressed in human breast carcinomardquo TheJournal of Pathology vol 192 pp 313ndash320 2000

[54] P Bostrom A Sainio T Kakko M Savontaus M Soderstromand H Jarvelainen ldquoLocalization of decorin gene expressionin normal human breast tissue and in benign and malignanttumors of the human breastrdquo Histochemistry and Cell Biologyvol 139 no 1 pp 161ndash171 2013

[55] S Troup C Njue E V Kliewer et al ldquoReduced expression ofthe small leucine-rich proteoglycans lumican and decorin isassociated with poor outcome in node-negative invasive breastcancerrdquoClinical Cancer Research vol 9 no 1 pp 207ndash214 2003

[56] C C Reed A Waterhouse S Kirby et al ldquoDecorin preventsmetastatic spreading of breast cancerrdquo Oncogene vol 24 no 6pp 1104ndash1110 2005

[57] M Santra I Eichstetter and R V Iozzo ldquoAn anti-oncogenicrole for decorin down-regulation of ErbB2 leads to growthsuppression and cytodifferentiation of mammary carcinomacellsrdquo The Journal of Biological Chemistry vol 275 no 45 pp35153ndash35161 2000

[58] E Leygue L Snell H Dotzlaw et al ldquoExpression of lumicanin human breast carcinomardquo Cancer Research vol 58 no 7 pp1348ndash1352 1998

[59] R H Tammi A Kultti V Kosma R Pirinen P Auvinen andM I Tammi ldquoHyaluronan in human tumors pathobiologicaland prognostic messages from cell-associated and stromalhyaluronanrdquo Seminars in Cancer Biology vol 18 no 4 pp 288ndash295 2008

[60] B P Toole T N Wight and M I Tammi ldquoHyaluronan-cellinteractions in cancer and vascular diseaserdquo Journal of BiologicalChemistry vol 277 no 7 pp 4593ndash4596 2002

[61] M Jojovic B Delpech P Prehm and U Schumacher ldquoExpres-sion of hyaluronate andhyaluronate synthase in humanprimarytumours and their metastases in scid micerdquo Cancer Letters vol188 no 1-2 pp 181ndash189 2002

[62] P Auvinen R Tammi J Parkkinen et al ldquoHyaluronan inperitumoral stroma and malignant cells associates with breastcancer spreading and predicts survivalrdquo The American Journalof Pathology vol 156 no 2 pp 529ndash536 2000

[63] J X Tan X Y Wang H Y Li et al ldquoHYAL1 overexpression iscorrelatedwith themalignant behavior of human breast cancerrdquoInternational Journal of Cancer vol 128 no 6 pp 1303ndash13152011

[64] A Wells J Grahovac S Wheeler B Ma and D LauffenburgerldquoTargeting tumor cell motility as a strategy against invasion andmetastasisrdquo Trends in Pharmacological Sciences vol 34 no 5pp 283ndash289 2013

[65] A J Ridley ldquoRho GTPases and actin dynamics in membraneprotrusions and vesicle traffickingrdquo Trends in Cell Biology vol16 no 10 pp 522ndash529 2006

[66] A K Howe ldquoRegulation of actin-based cell migration bycAMPPKArdquo Biochimica et Biophysica Acta vol 1692 no 2-3pp 159ndash174 2004

[67] S Gehler S M Ponik K M Riching and P J Keely ldquoBi-Directional signaling Extracellular matrix and integrin regula-tion of breast tumor progressionrdquoCritical Reviews in EukaryoticGene Expression vol 23 no 2 pp 139ndash157 2013

[68] J Zhao and J Guan ldquoSignal transduction by focal adhesionkinase in cancerrdquo Cancer and Metastasis Reviews vol 28 no1-2 pp 35ndash49 2009

[69] G Hannigan A A Troussard and S Dedhar ldquoIntegrin-linkedkinase a cancer therapeutic target unique among its ILKrdquoNature Reviews Cancer vol 5 no 1 pp 51ndash63 2005

[70] P Savagner ldquoThe epithelial-mesenchymal transition (EMT)phenomenonrdquo Annals of Oncology vol 21 supplement 7 ppvii89ndashvii92 2010

[71] M J C Hendrix E A Seftor Y Chu K T Trevor and R EB Seftor ldquoRole of intermediate filaments in migration invasionand metastasisrdquo Cancer and Metastasis Reviews vol 15 no 4pp 507ndash525 1996

[72] V Quaranta ldquoMotility cues in the tumor microenvironmentrdquoDifferentiation vol 70 no 9-10 pp 590ndash598 2002

[73] DHanahan andRAWeinberg ldquoThehallmarks of cancerrdquoCellvol 100 no 1 pp 57ndash70 2000

[74] A V Marusyk A Almendro and K Polyak ldquoIntra-tumourheterogeneity a looking glass for cancerrdquo Nature ReviewsCancer vol 12 no 5 pp 323ndash334 2013

[75] F Marcucci M Bellone C A Caserta and A Corti ldquoPushingtumor cells towards a malignant phenotype stimuli from themicroenvironment intercellular communications and alterna-tive roadsrdquo International Journal of Cancer vol 135 no 6 pp1265ndash1276 2014

[76] J P Thiery H Acloque R Y J Huang and M A NietoldquoEpithelial-mesenchymal transitions in development and dis-easerdquo Cell vol 139 no 5 pp 871ndash890 2009

[77] A Morel M Lievre C Thomas G Hinkal S Ansieau andA Puisieux ldquoGeneration of breast cancer stem cells throughepithelial-mesenchymal transitionrdquo PLoS ONE vol 3 no 8Article ID e2888 2008

[78] M L Ackland D F Newgreen M Fridman et al ldquoEpidermalgrowth factor-induced epithelio-mesenchymal transition inhuman breast carcinoma cellsrdquo Laboratory Investigation vol 83no 3 pp 435ndash448 2003

[79] S Giampieri C Manning S Hooper L Jones C S Hill andE Sahai ldquoLocalized and reversible TGF120573 signalling switchesbreast cancer cells from cohesive to single cell motilityrdquo NatureCell Biology vol 11 no 11 pp 1287ndash1296 2009

[80] AWicki F LehembreNWick BHantuschDKerjaschki andG Christofori ldquoTumor invasion in the absence of epithelial-mesenchymal transition podoplanin-mediated remodeling ofthe actin cytoskeletonrdquo Cancer Cell vol 9 no 4 pp 261ndash2722006

[81] M Marsan G van den Eynden R Limame et al ldquoA coreinvasiveness gene signature reflects epithelial-to-mesenchymaltransition but not metastatic potential in breast cancer cell linesand tissue samplesrdquo PLoS ONE vol 21 Article ID e89262 2014

BioMed Research International 11

[82] D Gao L T Vahdat S Wong J C Chang and V Mit-tal ldquoMicroenvironmental regulation of epithelial-mesenchymaltransitionsin cancerrdquo Cancer Research vol 72 no 19 pp 4883ndash4889 2012

[83] Q Zheng A Safina and A V Bakin ldquoRole of high-molecularweight tropomyosins in TGF-120573-mediated control of cell motil-ityrdquo International Journal of Cancer vol 122 no 1 pp 78ndash902008

[84] H Kim B C Litzenburger X Cui et al ldquoConstitutively activetype I insulin-like growth factor receptor causes transformationand xenograft growth of immortalized mammary epithelialcells and is accompanied by an epithelial-to-mesenchymaltransitionmediated byNF-120581B and snailrdquoMolecular andCellularBiology vol 27 no 8 pp 3165ndash3175 2007

[85] H Porsch B Bernert M Mehic A D Theocharis CHeldin and P Heldin ldquoEfficient TGF120573-induced epithelial-mesenchymal transition depends on hyaluronan synthaseHAS2rdquo Oncogene vol 32 pp 4355ndash4365 2013

[86] H C Lien Y H Lee Y M Jeng C H Lin Y S Lu and Y TYao ldquoDifferential expression of hyaluronan synthase 2 in breastcarcinoma and its biological significancerdquoHistopathology 2014

[87] A K Kiemer K Takeuchi andM P Quinlan ldquoIdentification ofgenes involved in epithelial-mesenchymal transition and tumorprogressionrdquo Oncogene vol 20 no 46 pp 6679ndash6688 2001

[88] C Thomas and A E Karnoub ldquoLysyl oxidase at the crossroadsof mesenchymal stem cells and epithelial-mesenchymal transi-tionrdquo Oncotarget vol 4 no 3 pp 376ndash377 2013

[89] S Maschler S Grunert A Danielopol H Beug and G WirlldquoEnhanced tenascin-C expression andmatrix deposition duringRasTGF-120573-induced progression of mammary tumor cellsrdquoOncogene vol 23 no 20 pp 3622ndash3633 2004

[90] D Loussouarn L Campion C Sagan et al ldquoPrognostic impactof syndecan-1 expression in invasive ductal breast carcinomasrdquoBritish Journal of Cancer vol 98 no 12 pp 1993ndash1998 2008

[91] M Gotte C Kersting I Radke L Kiesel and P Wulfing ldquoAnexpression signature of syndecan-1 (CD138) E-cadherin and c-met is associated with factors of angiogenesis and lymphan-giogenesis in ductal breast carcinoma in siturdquo Breast CancerResearch vol 9 no 1 article R8 2007

[92] D Gao N Joshi H Choi et al ldquoMyeloid progenitor cellsin the premetastatic lung promote metastases by inducingmesenchymal to epithelial transitionrdquo Cancer Research vol 72no 6 pp 1384ndash1394 2012

[93] C Gialeli A D Theocharis and N K Karamanos ldquoRolesof matrix metalloproteinases in cancer progression and theirpharmacological targetingrdquo The FEBS Journal vol 278 no 1pp 16ndash27 2011

[94] R V Iozzo ldquoThe family of the small leucine-rich proteoglycanskey regulators of matrix assembly and cellular growthrdquo CriticalReviews in Biochemistry andMolecular Biology vol 32 no 2 pp141ndash174 1997

[95] S Sarrazin W C Lamanna and J D Esko ldquoHeparan sulfateproteoglycansrdquo Cold Spring Harbor Perspectives in Biology vol3 no 7 Article ID a004952 2011

[96] D M Beauvais and A C Rapraeger ldquoSyndecans in tumor celladhesion and signalingrdquo Reproductive Biology and Endocrinol-ogy vol 2 article 3 2004

[97] J R Couchman ldquoSyndecans proteoglycan regulators of cell-surfacemicrodomainsrdquoNature ReviewsMolecular Cell Biologyvol 4 no 12 pp 926ndash937 2003

[98] J R Couchman ldquoTransmembrane signaling proteoglycansrdquoAnnual Review of Cell and Developmental Biology vol 26 pp89ndash114 2010

[99] T Manon-Jensen Y Itoh and J R Couchman ldquoProteoglycansin health and disease the multiple roles of syndecan sheddingrdquoFEBS Journal vol 277 no 19 pp 3876ndash3889 2010

[100] X Xian S Gopal and J R Couchman ldquoSyndecans as receptorsand organizers of the extracellular matrixrdquo Cell and TissueResearch vol 339 no 1 pp 31ndash46 2010

[101] A I Tsonis N Afratis C Gialeli et al ldquoEvaluation of the coor-dinated actions of estrogen receptors with epidermal growthfactor receptor and insulin-like growth factor receptor in theexpression of cell surface heparan sulfate proteoglycans and cellmotility in breast cancer cellsrdquo FEBS Journal vol 280 no 10 pp2248ndash2259 2013

[102] G W Yip M Smollich and M Gotte ldquoTherapeutic value ofglycosaminoglycans in cancerrdquo Molecular Cancer Therapeuticsvol 5 no 9 pp 2139ndash2148 2006

[103] C Y Fears and A Woods ldquoThe role of syndecans in diseaseand wound healingrdquoMatrix Biology vol 25 no 7 pp 443ndash4562006

[104] K Lambaerts S A Wilcox-Adelman and P ZimmermannldquoThe signaling mechanisms of syndecan heparan sulfate pro-teoglycansrdquo Current Opinion in Cell Biology vol 21 no 5 pp662ndash669 2009

[105] S A Ibrahim GW Yip C Stock et al ldquoTargeting of syndecan-1 by microRNA miR-10b promotes breast cancer cell motilityand invasiveness via aRho-GTPase- andE-cadherin-dependentmechanismrdquo International Journal of Cancer vol 131 no 6 ppE884ndashE896 2012

[106] D M Beauvais and A C Rapraeger ldquoSyndecan-1-mediated cellspreading requires signaling by 120572v1205733 integrins in human breastcarcinoma cellsrdquo Experimental Cell Research vol 286 no 2 pp219ndash232 2003

[107] D M Beauvais and A C Rapraeger ldquoSyndecan-1 couplesthe insulin-like growth factor-1 receptor to inside-out integrinactivationrdquo Journal of Cell Science vol 123 no 21 pp 3796ndash3807 2010

[108] HHassan B GreveM S G Pavao L Kiesel S A Ibrahim andM Gotte ldquoSyndecan-1 modulates 120573-integrin-dependent andinterleukin-6-dependent functions in breast cancer cell adhe-sion migration and resistance to irradiationrdquo FEBS Journalvol 280 no 10 pp 2216ndash2227 2013

[109] E Tkachenko J M Rhodes and M Simons ldquoSyndecans newkids on the signaling blockrdquo Circulation Research vol 96 no 5pp 488ndash500 2005

[110] O C Kousidou A Berdiaki D Kletsas et al ldquoEstradiol-estrogen receptor a key interplay of the expression of syndecan-2 and metalloproteinase-9 in breast cancer cellsrdquo MolecularOncology vol 2 no 3 pp 223ndash232 2008

[111] A Yoneda M E Lendorf J R Couchman and H A BMulthaupt ldquoBreast and ovarian cancers a survey and possibleroles for the cell surface heparan sulfate proteoglycansrdquo Journalof Histochemistry and Cytochemistry vol 60 no 1 pp 9ndash212012

[112] E J Davies F H Blackhall J H Shanks et al ldquoDistribution andclinical significance of heparan sulfate proteoglycans in ovariancancerrdquo Clinical Cancer Research vol 10 no 15 pp 5178ndash51862004

12 BioMed Research International

[113] A Woods and J R Couchman ldquoSyndecan 4 heparan sulfateproteoglycan is a selectively enriched and widespread focaladhesion componentrdquo Molecular Biology of the Cell vol 5 no2 pp 183ndash192 1994

[114] A Woods R L Longley S Tumova and J R CouchmanldquoSyndecan-4 binding to the high affinity heparin-bindingdomain of fibronectin drives focal adhesion formation infibroblastsrdquoArchives of Biochemistry and Biophysics vol 374 no1 pp 66ndash72 2000

[115] A C Rapraeger ldquoSyndecan-regulated receptor signalingrdquo Jour-nal of Cell Biology vol 149 no 5 pp 995ndash997 2000

[116] AWoods ldquoSyndecans transmembranemodulators of adhesionand matrix assemblyrdquo Journal of Clinical Investigation vol 107no 8 pp 935ndash941 2001

[117] L A Cary J F Chang and J Guan ldquoStimulation of cellmigration by overexpression of focal adhesion kinase and itsassociation with Src and Fynrdquo Journal of Cell Science vol 109no 7 pp 1787ndash1794 1996

[118] R L Longley A Woods A Fleetwood G J Cowling JT Gallagher and J R Couchman ldquoControl of morphologycytoskeleton and migration by syndecan-4rdquo Journal of CellScience vol 112 no 20 pp 3421ndash3431 1999

[119] W Huang R Chiquet-Ehrismann J V Moyano A Garcia-Pardo and G Orend ldquoInterference of tenascin-C withsyndecan-4 binding to fibronectin blocks cell adhesion andstimulates tumor cell proliferationrdquoCancer Research vol 61 no23 pp 8586ndash8594 2001

[120] GVollmerM I TanWWunsche andK Frank ldquoExpression oftenascin-C by human endometrial adenocarcinoma and stromacells heterogeneity of splice variants and induction by TGF-120573rdquoBiochemistry and Cell Biology vol 75 no 6 pp 759ndash769 1997

[121] M Kato S Saunders H Nguyen and M Bernfield ldquoLossof cell surface syndecan-1 causes epithelia to transforminto anchorage-independentmesenchyme-like cellsrdquoMolecularBiology of the Cell vol 6 no 5 pp 559ndash576 1995

[122] A J McFall and A C Rapraeger ldquoIdentification of an adhesionsite within the syndecan-4 extracellular protein domainrdquo TheJournal of Biological Chemistry vol 272 no 20 pp 12901ndash129041997

[123] A J McFall and A C Rapraeger ldquoCharacterization of the highaffinity cell-binding domain in the cell surface proteoglycansyndecan-4rdquo Journal of Biological Chemistry vol 273 no 43 pp28270ndash28276 1998

[124] V Nikolova C Koo S A Ibrahim et al ldquoDifferential rolesformembrane-bound and soluble syndecan-1 (CD138) in breastcancer progressionrdquo Carcinogenesis vol 30 no 3 pp 397ndash4072009

[125] I Vlodavsky M Elkin and N Ilan ldquoImpact of heparanaseand the tumor microenvironment on cancer metastasis andangiogenesis basic aspects and clinical applicationsrdquo RambamMaimonides Medical Journal vol 2 no 1 Article ID e0019 2011

[126] M G Peters E Farıas L Colombo J Filmus L Puricelli andE Bal de Kier Joffe ldquoInhibition of invasion and metastasis byglypican-3 in a syngeneic breast cancer modelrdquo Breast CancerResearch and Treatment vol 80 no 2 pp 221ndash232 2003

[127] I Stigliano L Puricelli J Filmus M C Sogayar E B deKier Joffe and M G Peters ldquoGlypican-3 regulates migrationadhesion and actin cytoskeleton organization in mammarytumor cells through Wnt signaling modulationrdquo Breast CancerResearch and Treatment vol 114 no 2 pp 251ndash262 2009

[128] G K Yiu A Kaunisto Y R Chin and A Toker ldquoNFATpromotes carcinoma invasive migration through glypican-6rdquoBiochemical Journal vol 440 no 1 pp 157ndash166 2011

[129] Y J Wu D P La Pierre J Wu A J Yee and B B Yang ldquoTheinteraction of versican with its binding partnersrdquo Cell Researchvol 15 no 7 pp 483ndash494 2005

[130] A D Theocharis ldquoVersican in health and diseaserdquo ConnectiveTissue Research vol 49 no 3-4 pp 230ndash234 2008

[131] S S Skandalis V T Labropoulou P Ravazoula et al ldquoVersicanbut not decorin accumulation is related to malignancy in mam-mographically detected high density and malignant-appearingmicrocalcifications in non-palpable breast carcinomasrdquo BMCCancer vol 11 article 314 2011

[132] W W Du L Fang W Yang et al ldquoThe role of versicanG3 domain in regulating breast cancer cell motility includingeffects on osteoblast cell growth and differentiation in vitromdashevaluation towards understanding breast cancer cell bonemetastasisrdquo BMC Cancer vol 12 article 341 2012

[133] S S Skandalis N Afratis G Smirlaki D Nikitovic A DTheocharis and G N Tzanakakis ldquoCross-talk between estra-diol receptor andEGFRIGF-IR signaling pathways in estrogen-responsive breast cancers focus on the role and impact ofproteoglycansrdquoMatrix Biology vol 35 pp 182ndash193 2014

[134] J Zhu S Goldoni G Bix et al ldquoDecorin evokes protractedinternalization and degradation of the epidermal growth factorreceptor via caveolar endocytosisrdquo Journal of Biological Chem-istry vol 280 no 37 pp 32468ndash32479 2005

[135] R V Iozzo S Buraschi M Genua et al ldquoDecorin antagonizesIGF receptor I (IGF-IR) function by interfering with IGF-IRactivity and attenuating downstream signalingrdquo The Journal ofBiological Chemistry vol 286 no 40 pp 34712ndash34721 2011

[136] B Vuillermoz A Khoruzhenko M DrsquoOnofrio et al ldquoThesmall leucine-rich proteoglycan lumican inhibits melanomaprogressionrdquo Experimental Cell Research vol 296 no 2 pp294ndash306 2004

[137] S Brezillon C Zeltz L Schneider et al ldquoLumican inhibitsB16F1 melanoma cell lungmetastasisrdquo Journal of Physiology andPharmacology vol 60 pp 15ndash22 2009

[138] C Zeltz S Brezillon J Kapyla et al ldquoLumican inhibits cellmigration through 1205722Β1 integrinrdquo Experimental Cell Researchvol 316 no 17 pp 2922ndash2931 2010

[139] A Korpetinou S S Skandalis A Moustakas et al ldquoSerglycin isimplicated in the promotion of aggressive phenotype of breastcancer cellsrdquo PLoS ONE vol 8 Article ID e78157 2013

[140] N Montgomery A Hill S McFarlane et al ldquoCD44 enhancesinvasion of basal-like breast cancer cells by upregulating serineprotease and collagen-degrading enzymatic expression andactivityrdquo Breast Cancer Research vol 14 no 3 article R84 2012

[141] L E Dickinson C C Ho G M Wang K J Stebe andS Gerecht ldquoFunctional surfaces for high-resolution analysisof cancer cell interactions on exogenous hyaluronic acidrdquoBiomaterials vol 31 no 20 pp 5472ndash5478 2010

[142] C Yang M Cao H Liu et al ldquoThe high and low molecularweight forms of hyaluronan have distinct effects on CD44clusteringrdquoThe Journal of Biological Chemistry vol 287 no 51pp 43094ndash43107 2012

[143] L Y W Bourguignon G Wong C A Earle and W XialdquoInteraction of low molecular weight hyaluronan with CD44and toll-like receptors promotes the actin filament-associatedprotein 110-actin binding and MyD88-NF120581B signaling leading

BioMed Research International 13

to proinflammatory cytokinechemokine production andbreasttumor invasionrdquo Cytoskeleton vol 68 no 12 pp 671ndash693 2011

[144] P G Dedes C Gialeli A I Tsonis et al ldquoExpression of matrixmacromolecules and functional properties of breast cancercells are modulated by the bisphosphonate zoledronic acidrdquoBiochimica et Biophysica Acta vol 1820 no 12 pp 1926ndash19392012

[145] A C Rapraeger ldquoSynstatin A selective inhibitor of thesyndecan-1-coupled IGF1R-120572v1205733 integrin complex in tumori-genesis and angiogenesisrdquo The FEBS Journal vol 280 no 10pp 2207ndash2215 2013

[146] D Liu Z Shriver G Venkataraman Y El Shabrawi and RSasisekharan ldquoTumor cell surface heparan sulfate as crypticpromoters or inhibitors of tumor growth and metastasisrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 99 no 2 pp 568ndash573 2002

[147] C Y Pumphrey A M Theus S Li R S Parrish and R DSanderson ldquoNeoglycans carbodiimide-modified glycosamino-glycans a new class of anticancer agents that inhibit cancer cellproliferation and induce apoptosisrdquoCancer Research vol 62 no13 pp 3722ndash3728 2002

10 BioMed Research International

[50] P Kischel DWaltregny BDumont et al ldquoVersican overexpres-sion in human breast cancer lesions known and new isoformsfor stromal tumor targetingrdquo International Journal of Cancervol 126 no 3 pp 640ndash650 2010

[51] P A McEwan P G Scott P N Bishop and J Bella ldquoStructuralcorrelations in the family of small leucine-rich repeat proteinsand proteoglycansrdquo Journal of Structural Biology vol 155 no 2pp 294ndash305 2006

[52] L Schaefer and R V Iozzo ldquoBiological functions of the smallleucine-rich proteoglycans from genetics to signal transduc-tionrdquo Journal of Biological Chemistry vol 283 no 31 pp 21305ndash21309 2008

[53] E Leygue L Snell H Dotzlaw et al ldquoLumican and decorinare differentially expressed in human breast carcinomardquo TheJournal of Pathology vol 192 pp 313ndash320 2000

[54] P Bostrom A Sainio T Kakko M Savontaus M Soderstromand H Jarvelainen ldquoLocalization of decorin gene expressionin normal human breast tissue and in benign and malignanttumors of the human breastrdquo Histochemistry and Cell Biologyvol 139 no 1 pp 161ndash171 2013

[55] S Troup C Njue E V Kliewer et al ldquoReduced expression ofthe small leucine-rich proteoglycans lumican and decorin isassociated with poor outcome in node-negative invasive breastcancerrdquoClinical Cancer Research vol 9 no 1 pp 207ndash214 2003

[56] C C Reed A Waterhouse S Kirby et al ldquoDecorin preventsmetastatic spreading of breast cancerrdquo Oncogene vol 24 no 6pp 1104ndash1110 2005

[57] M Santra I Eichstetter and R V Iozzo ldquoAn anti-oncogenicrole for decorin down-regulation of ErbB2 leads to growthsuppression and cytodifferentiation of mammary carcinomacellsrdquo The Journal of Biological Chemistry vol 275 no 45 pp35153ndash35161 2000

[58] E Leygue L Snell H Dotzlaw et al ldquoExpression of lumicanin human breast carcinomardquo Cancer Research vol 58 no 7 pp1348ndash1352 1998

[59] R H Tammi A Kultti V Kosma R Pirinen P Auvinen andM I Tammi ldquoHyaluronan in human tumors pathobiologicaland prognostic messages from cell-associated and stromalhyaluronanrdquo Seminars in Cancer Biology vol 18 no 4 pp 288ndash295 2008

[60] B P Toole T N Wight and M I Tammi ldquoHyaluronan-cellinteractions in cancer and vascular diseaserdquo Journal of BiologicalChemistry vol 277 no 7 pp 4593ndash4596 2002

[61] M Jojovic B Delpech P Prehm and U Schumacher ldquoExpres-sion of hyaluronate andhyaluronate synthase in humanprimarytumours and their metastases in scid micerdquo Cancer Letters vol188 no 1-2 pp 181ndash189 2002

[62] P Auvinen R Tammi J Parkkinen et al ldquoHyaluronan inperitumoral stroma and malignant cells associates with breastcancer spreading and predicts survivalrdquo The American Journalof Pathology vol 156 no 2 pp 529ndash536 2000

[63] J X Tan X Y Wang H Y Li et al ldquoHYAL1 overexpression iscorrelatedwith themalignant behavior of human breast cancerrdquoInternational Journal of Cancer vol 128 no 6 pp 1303ndash13152011

[64] A Wells J Grahovac S Wheeler B Ma and D LauffenburgerldquoTargeting tumor cell motility as a strategy against invasion andmetastasisrdquo Trends in Pharmacological Sciences vol 34 no 5pp 283ndash289 2013

[65] A J Ridley ldquoRho GTPases and actin dynamics in membraneprotrusions and vesicle traffickingrdquo Trends in Cell Biology vol16 no 10 pp 522ndash529 2006

[66] A K Howe ldquoRegulation of actin-based cell migration bycAMPPKArdquo Biochimica et Biophysica Acta vol 1692 no 2-3pp 159ndash174 2004

[67] S Gehler S M Ponik K M Riching and P J Keely ldquoBi-Directional signaling Extracellular matrix and integrin regula-tion of breast tumor progressionrdquoCritical Reviews in EukaryoticGene Expression vol 23 no 2 pp 139ndash157 2013

[68] J Zhao and J Guan ldquoSignal transduction by focal adhesionkinase in cancerrdquo Cancer and Metastasis Reviews vol 28 no1-2 pp 35ndash49 2009

[69] G Hannigan A A Troussard and S Dedhar ldquoIntegrin-linkedkinase a cancer therapeutic target unique among its ILKrdquoNature Reviews Cancer vol 5 no 1 pp 51ndash63 2005

[70] P Savagner ldquoThe epithelial-mesenchymal transition (EMT)phenomenonrdquo Annals of Oncology vol 21 supplement 7 ppvii89ndashvii92 2010

[71] M J C Hendrix E A Seftor Y Chu K T Trevor and R EB Seftor ldquoRole of intermediate filaments in migration invasionand metastasisrdquo Cancer and Metastasis Reviews vol 15 no 4pp 507ndash525 1996

[72] V Quaranta ldquoMotility cues in the tumor microenvironmentrdquoDifferentiation vol 70 no 9-10 pp 590ndash598 2002

[73] DHanahan andRAWeinberg ldquoThehallmarks of cancerrdquoCellvol 100 no 1 pp 57ndash70 2000

[74] A V Marusyk A Almendro and K Polyak ldquoIntra-tumourheterogeneity a looking glass for cancerrdquo Nature ReviewsCancer vol 12 no 5 pp 323ndash334 2013

[75] F Marcucci M Bellone C A Caserta and A Corti ldquoPushingtumor cells towards a malignant phenotype stimuli from themicroenvironment intercellular communications and alterna-tive roadsrdquo International Journal of Cancer vol 135 no 6 pp1265ndash1276 2014

[76] J P Thiery H Acloque R Y J Huang and M A NietoldquoEpithelial-mesenchymal transitions in development and dis-easerdquo Cell vol 139 no 5 pp 871ndash890 2009

[77] A Morel M Lievre C Thomas G Hinkal S Ansieau andA Puisieux ldquoGeneration of breast cancer stem cells throughepithelial-mesenchymal transitionrdquo PLoS ONE vol 3 no 8Article ID e2888 2008

[78] M L Ackland D F Newgreen M Fridman et al ldquoEpidermalgrowth factor-induced epithelio-mesenchymal transition inhuman breast carcinoma cellsrdquo Laboratory Investigation vol 83no 3 pp 435ndash448 2003

[79] S Giampieri C Manning S Hooper L Jones C S Hill andE Sahai ldquoLocalized and reversible TGF120573 signalling switchesbreast cancer cells from cohesive to single cell motilityrdquo NatureCell Biology vol 11 no 11 pp 1287ndash1296 2009

[80] AWicki F LehembreNWick BHantuschDKerjaschki andG Christofori ldquoTumor invasion in the absence of epithelial-mesenchymal transition podoplanin-mediated remodeling ofthe actin cytoskeletonrdquo Cancer Cell vol 9 no 4 pp 261ndash2722006

[81] M Marsan G van den Eynden R Limame et al ldquoA coreinvasiveness gene signature reflects epithelial-to-mesenchymaltransition but not metastatic potential in breast cancer cell linesand tissue samplesrdquo PLoS ONE vol 21 Article ID e89262 2014

BioMed Research International 11

[82] D Gao L T Vahdat S Wong J C Chang and V Mit-tal ldquoMicroenvironmental regulation of epithelial-mesenchymaltransitionsin cancerrdquo Cancer Research vol 72 no 19 pp 4883ndash4889 2012

[83] Q Zheng A Safina and A V Bakin ldquoRole of high-molecularweight tropomyosins in TGF-120573-mediated control of cell motil-ityrdquo International Journal of Cancer vol 122 no 1 pp 78ndash902008

[84] H Kim B C Litzenburger X Cui et al ldquoConstitutively activetype I insulin-like growth factor receptor causes transformationand xenograft growth of immortalized mammary epithelialcells and is accompanied by an epithelial-to-mesenchymaltransitionmediated byNF-120581B and snailrdquoMolecular andCellularBiology vol 27 no 8 pp 3165ndash3175 2007

[85] H Porsch B Bernert M Mehic A D Theocharis CHeldin and P Heldin ldquoEfficient TGF120573-induced epithelial-mesenchymal transition depends on hyaluronan synthaseHAS2rdquo Oncogene vol 32 pp 4355ndash4365 2013

[86] H C Lien Y H Lee Y M Jeng C H Lin Y S Lu and Y TYao ldquoDifferential expression of hyaluronan synthase 2 in breastcarcinoma and its biological significancerdquoHistopathology 2014

[87] A K Kiemer K Takeuchi andM P Quinlan ldquoIdentification ofgenes involved in epithelial-mesenchymal transition and tumorprogressionrdquo Oncogene vol 20 no 46 pp 6679ndash6688 2001

[88] C Thomas and A E Karnoub ldquoLysyl oxidase at the crossroadsof mesenchymal stem cells and epithelial-mesenchymal transi-tionrdquo Oncotarget vol 4 no 3 pp 376ndash377 2013

[89] S Maschler S Grunert A Danielopol H Beug and G WirlldquoEnhanced tenascin-C expression andmatrix deposition duringRasTGF-120573-induced progression of mammary tumor cellsrdquoOncogene vol 23 no 20 pp 3622ndash3633 2004

[90] D Loussouarn L Campion C Sagan et al ldquoPrognostic impactof syndecan-1 expression in invasive ductal breast carcinomasrdquoBritish Journal of Cancer vol 98 no 12 pp 1993ndash1998 2008

[91] M Gotte C Kersting I Radke L Kiesel and P Wulfing ldquoAnexpression signature of syndecan-1 (CD138) E-cadherin and c-met is associated with factors of angiogenesis and lymphan-giogenesis in ductal breast carcinoma in siturdquo Breast CancerResearch vol 9 no 1 article R8 2007

[92] D Gao N Joshi H Choi et al ldquoMyeloid progenitor cellsin the premetastatic lung promote metastases by inducingmesenchymal to epithelial transitionrdquo Cancer Research vol 72no 6 pp 1384ndash1394 2012

[93] C Gialeli A D Theocharis and N K Karamanos ldquoRolesof matrix metalloproteinases in cancer progression and theirpharmacological targetingrdquo The FEBS Journal vol 278 no 1pp 16ndash27 2011

[94] R V Iozzo ldquoThe family of the small leucine-rich proteoglycanskey regulators of matrix assembly and cellular growthrdquo CriticalReviews in Biochemistry andMolecular Biology vol 32 no 2 pp141ndash174 1997

[95] S Sarrazin W C Lamanna and J D Esko ldquoHeparan sulfateproteoglycansrdquo Cold Spring Harbor Perspectives in Biology vol3 no 7 Article ID a004952 2011

[96] D M Beauvais and A C Rapraeger ldquoSyndecans in tumor celladhesion and signalingrdquo Reproductive Biology and Endocrinol-ogy vol 2 article 3 2004

[97] J R Couchman ldquoSyndecans proteoglycan regulators of cell-surfacemicrodomainsrdquoNature ReviewsMolecular Cell Biologyvol 4 no 12 pp 926ndash937 2003

[98] J R Couchman ldquoTransmembrane signaling proteoglycansrdquoAnnual Review of Cell and Developmental Biology vol 26 pp89ndash114 2010

[99] T Manon-Jensen Y Itoh and J R Couchman ldquoProteoglycansin health and disease the multiple roles of syndecan sheddingrdquoFEBS Journal vol 277 no 19 pp 3876ndash3889 2010

[100] X Xian S Gopal and J R Couchman ldquoSyndecans as receptorsand organizers of the extracellular matrixrdquo Cell and TissueResearch vol 339 no 1 pp 31ndash46 2010

[101] A I Tsonis N Afratis C Gialeli et al ldquoEvaluation of the coor-dinated actions of estrogen receptors with epidermal growthfactor receptor and insulin-like growth factor receptor in theexpression of cell surface heparan sulfate proteoglycans and cellmotility in breast cancer cellsrdquo FEBS Journal vol 280 no 10 pp2248ndash2259 2013

[102] G W Yip M Smollich and M Gotte ldquoTherapeutic value ofglycosaminoglycans in cancerrdquo Molecular Cancer Therapeuticsvol 5 no 9 pp 2139ndash2148 2006

[103] C Y Fears and A Woods ldquoThe role of syndecans in diseaseand wound healingrdquoMatrix Biology vol 25 no 7 pp 443ndash4562006

[104] K Lambaerts S A Wilcox-Adelman and P ZimmermannldquoThe signaling mechanisms of syndecan heparan sulfate pro-teoglycansrdquo Current Opinion in Cell Biology vol 21 no 5 pp662ndash669 2009

[105] S A Ibrahim GW Yip C Stock et al ldquoTargeting of syndecan-1 by microRNA miR-10b promotes breast cancer cell motilityand invasiveness via aRho-GTPase- andE-cadherin-dependentmechanismrdquo International Journal of Cancer vol 131 no 6 ppE884ndashE896 2012

[106] D M Beauvais and A C Rapraeger ldquoSyndecan-1-mediated cellspreading requires signaling by 120572v1205733 integrins in human breastcarcinoma cellsrdquo Experimental Cell Research vol 286 no 2 pp219ndash232 2003

[107] D M Beauvais and A C Rapraeger ldquoSyndecan-1 couplesthe insulin-like growth factor-1 receptor to inside-out integrinactivationrdquo Journal of Cell Science vol 123 no 21 pp 3796ndash3807 2010

[108] HHassan B GreveM S G Pavao L Kiesel S A Ibrahim andM Gotte ldquoSyndecan-1 modulates 120573-integrin-dependent andinterleukin-6-dependent functions in breast cancer cell adhe-sion migration and resistance to irradiationrdquo FEBS Journalvol 280 no 10 pp 2216ndash2227 2013

[109] E Tkachenko J M Rhodes and M Simons ldquoSyndecans newkids on the signaling blockrdquo Circulation Research vol 96 no 5pp 488ndash500 2005

[110] O C Kousidou A Berdiaki D Kletsas et al ldquoEstradiol-estrogen receptor a key interplay of the expression of syndecan-2 and metalloproteinase-9 in breast cancer cellsrdquo MolecularOncology vol 2 no 3 pp 223ndash232 2008

[111] A Yoneda M E Lendorf J R Couchman and H A BMulthaupt ldquoBreast and ovarian cancers a survey and possibleroles for the cell surface heparan sulfate proteoglycansrdquo Journalof Histochemistry and Cytochemistry vol 60 no 1 pp 9ndash212012

[112] E J Davies F H Blackhall J H Shanks et al ldquoDistribution andclinical significance of heparan sulfate proteoglycans in ovariancancerrdquo Clinical Cancer Research vol 10 no 15 pp 5178ndash51862004

12 BioMed Research International

[113] A Woods and J R Couchman ldquoSyndecan 4 heparan sulfateproteoglycan is a selectively enriched and widespread focaladhesion componentrdquo Molecular Biology of the Cell vol 5 no2 pp 183ndash192 1994

[114] A Woods R L Longley S Tumova and J R CouchmanldquoSyndecan-4 binding to the high affinity heparin-bindingdomain of fibronectin drives focal adhesion formation infibroblastsrdquoArchives of Biochemistry and Biophysics vol 374 no1 pp 66ndash72 2000

[115] A C Rapraeger ldquoSyndecan-regulated receptor signalingrdquo Jour-nal of Cell Biology vol 149 no 5 pp 995ndash997 2000

[116] AWoods ldquoSyndecans transmembranemodulators of adhesionand matrix assemblyrdquo Journal of Clinical Investigation vol 107no 8 pp 935ndash941 2001

[117] L A Cary J F Chang and J Guan ldquoStimulation of cellmigration by overexpression of focal adhesion kinase and itsassociation with Src and Fynrdquo Journal of Cell Science vol 109no 7 pp 1787ndash1794 1996

[118] R L Longley A Woods A Fleetwood G J Cowling JT Gallagher and J R Couchman ldquoControl of morphologycytoskeleton and migration by syndecan-4rdquo Journal of CellScience vol 112 no 20 pp 3421ndash3431 1999

[119] W Huang R Chiquet-Ehrismann J V Moyano A Garcia-Pardo and G Orend ldquoInterference of tenascin-C withsyndecan-4 binding to fibronectin blocks cell adhesion andstimulates tumor cell proliferationrdquoCancer Research vol 61 no23 pp 8586ndash8594 2001

[120] GVollmerM I TanWWunsche andK Frank ldquoExpression oftenascin-C by human endometrial adenocarcinoma and stromacells heterogeneity of splice variants and induction by TGF-120573rdquoBiochemistry and Cell Biology vol 75 no 6 pp 759ndash769 1997

[121] M Kato S Saunders H Nguyen and M Bernfield ldquoLossof cell surface syndecan-1 causes epithelia to transforminto anchorage-independentmesenchyme-like cellsrdquoMolecularBiology of the Cell vol 6 no 5 pp 559ndash576 1995

[122] A J McFall and A C Rapraeger ldquoIdentification of an adhesionsite within the syndecan-4 extracellular protein domainrdquo TheJournal of Biological Chemistry vol 272 no 20 pp 12901ndash129041997

[123] A J McFall and A C Rapraeger ldquoCharacterization of the highaffinity cell-binding domain in the cell surface proteoglycansyndecan-4rdquo Journal of Biological Chemistry vol 273 no 43 pp28270ndash28276 1998

[124] V Nikolova C Koo S A Ibrahim et al ldquoDifferential rolesformembrane-bound and soluble syndecan-1 (CD138) in breastcancer progressionrdquo Carcinogenesis vol 30 no 3 pp 397ndash4072009

[125] I Vlodavsky M Elkin and N Ilan ldquoImpact of heparanaseand the tumor microenvironment on cancer metastasis andangiogenesis basic aspects and clinical applicationsrdquo RambamMaimonides Medical Journal vol 2 no 1 Article ID e0019 2011

[126] M G Peters E Farıas L Colombo J Filmus L Puricelli andE Bal de Kier Joffe ldquoInhibition of invasion and metastasis byglypican-3 in a syngeneic breast cancer modelrdquo Breast CancerResearch and Treatment vol 80 no 2 pp 221ndash232 2003

[127] I Stigliano L Puricelli J Filmus M C Sogayar E B deKier Joffe and M G Peters ldquoGlypican-3 regulates migrationadhesion and actin cytoskeleton organization in mammarytumor cells through Wnt signaling modulationrdquo Breast CancerResearch and Treatment vol 114 no 2 pp 251ndash262 2009

[128] G K Yiu A Kaunisto Y R Chin and A Toker ldquoNFATpromotes carcinoma invasive migration through glypican-6rdquoBiochemical Journal vol 440 no 1 pp 157ndash166 2011

[129] Y J Wu D P La Pierre J Wu A J Yee and B B Yang ldquoTheinteraction of versican with its binding partnersrdquo Cell Researchvol 15 no 7 pp 483ndash494 2005

[130] A D Theocharis ldquoVersican in health and diseaserdquo ConnectiveTissue Research vol 49 no 3-4 pp 230ndash234 2008

[131] S S Skandalis V T Labropoulou P Ravazoula et al ldquoVersicanbut not decorin accumulation is related to malignancy in mam-mographically detected high density and malignant-appearingmicrocalcifications in non-palpable breast carcinomasrdquo BMCCancer vol 11 article 314 2011

[132] W W Du L Fang W Yang et al ldquoThe role of versicanG3 domain in regulating breast cancer cell motility includingeffects on osteoblast cell growth and differentiation in vitromdashevaluation towards understanding breast cancer cell bonemetastasisrdquo BMC Cancer vol 12 article 341 2012

[133] S S Skandalis N Afratis G Smirlaki D Nikitovic A DTheocharis and G N Tzanakakis ldquoCross-talk between estra-diol receptor andEGFRIGF-IR signaling pathways in estrogen-responsive breast cancers focus on the role and impact ofproteoglycansrdquoMatrix Biology vol 35 pp 182ndash193 2014

[134] J Zhu S Goldoni G Bix et al ldquoDecorin evokes protractedinternalization and degradation of the epidermal growth factorreceptor via caveolar endocytosisrdquo Journal of Biological Chem-istry vol 280 no 37 pp 32468ndash32479 2005

[135] R V Iozzo S Buraschi M Genua et al ldquoDecorin antagonizesIGF receptor I (IGF-IR) function by interfering with IGF-IRactivity and attenuating downstream signalingrdquo The Journal ofBiological Chemistry vol 286 no 40 pp 34712ndash34721 2011

[136] B Vuillermoz A Khoruzhenko M DrsquoOnofrio et al ldquoThesmall leucine-rich proteoglycan lumican inhibits melanomaprogressionrdquo Experimental Cell Research vol 296 no 2 pp294ndash306 2004

[137] S Brezillon C Zeltz L Schneider et al ldquoLumican inhibitsB16F1 melanoma cell lungmetastasisrdquo Journal of Physiology andPharmacology vol 60 pp 15ndash22 2009

[138] C Zeltz S Brezillon J Kapyla et al ldquoLumican inhibits cellmigration through 1205722Β1 integrinrdquo Experimental Cell Researchvol 316 no 17 pp 2922ndash2931 2010

[139] A Korpetinou S S Skandalis A Moustakas et al ldquoSerglycin isimplicated in the promotion of aggressive phenotype of breastcancer cellsrdquo PLoS ONE vol 8 Article ID e78157 2013

[140] N Montgomery A Hill S McFarlane et al ldquoCD44 enhancesinvasion of basal-like breast cancer cells by upregulating serineprotease and collagen-degrading enzymatic expression andactivityrdquo Breast Cancer Research vol 14 no 3 article R84 2012

[141] L E Dickinson C C Ho G M Wang K J Stebe andS Gerecht ldquoFunctional surfaces for high-resolution analysisof cancer cell interactions on exogenous hyaluronic acidrdquoBiomaterials vol 31 no 20 pp 5472ndash5478 2010

[142] C Yang M Cao H Liu et al ldquoThe high and low molecularweight forms of hyaluronan have distinct effects on CD44clusteringrdquoThe Journal of Biological Chemistry vol 287 no 51pp 43094ndash43107 2012

[143] L Y W Bourguignon G Wong C A Earle and W XialdquoInteraction of low molecular weight hyaluronan with CD44and toll-like receptors promotes the actin filament-associatedprotein 110-actin binding and MyD88-NF120581B signaling leading

BioMed Research International 13

to proinflammatory cytokinechemokine production andbreasttumor invasionrdquo Cytoskeleton vol 68 no 12 pp 671ndash693 2011

[144] P G Dedes C Gialeli A I Tsonis et al ldquoExpression of matrixmacromolecules and functional properties of breast cancercells are modulated by the bisphosphonate zoledronic acidrdquoBiochimica et Biophysica Acta vol 1820 no 12 pp 1926ndash19392012

[145] A C Rapraeger ldquoSynstatin A selective inhibitor of thesyndecan-1-coupled IGF1R-120572v1205733 integrin complex in tumori-genesis and angiogenesisrdquo The FEBS Journal vol 280 no 10pp 2207ndash2215 2013

[146] D Liu Z Shriver G Venkataraman Y El Shabrawi and RSasisekharan ldquoTumor cell surface heparan sulfate as crypticpromoters or inhibitors of tumor growth and metastasisrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 99 no 2 pp 568ndash573 2002

[147] C Y Pumphrey A M Theus S Li R S Parrish and R DSanderson ldquoNeoglycans carbodiimide-modified glycosamino-glycans a new class of anticancer agents that inhibit cancer cellproliferation and induce apoptosisrdquoCancer Research vol 62 no13 pp 3722ndash3728 2002

BioMed Research International 11

[82] D Gao L T Vahdat S Wong J C Chang and V Mit-tal ldquoMicroenvironmental regulation of epithelial-mesenchymaltransitionsin cancerrdquo Cancer Research vol 72 no 19 pp 4883ndash4889 2012

[83] Q Zheng A Safina and A V Bakin ldquoRole of high-molecularweight tropomyosins in TGF-120573-mediated control of cell motil-ityrdquo International Journal of Cancer vol 122 no 1 pp 78ndash902008

[84] H Kim B C Litzenburger X Cui et al ldquoConstitutively activetype I insulin-like growth factor receptor causes transformationand xenograft growth of immortalized mammary epithelialcells and is accompanied by an epithelial-to-mesenchymaltransitionmediated byNF-120581B and snailrdquoMolecular andCellularBiology vol 27 no 8 pp 3165ndash3175 2007

[85] H Porsch B Bernert M Mehic A D Theocharis CHeldin and P Heldin ldquoEfficient TGF120573-induced epithelial-mesenchymal transition depends on hyaluronan synthaseHAS2rdquo Oncogene vol 32 pp 4355ndash4365 2013

[86] H C Lien Y H Lee Y M Jeng C H Lin Y S Lu and Y TYao ldquoDifferential expression of hyaluronan synthase 2 in breastcarcinoma and its biological significancerdquoHistopathology 2014

[87] A K Kiemer K Takeuchi andM P Quinlan ldquoIdentification ofgenes involved in epithelial-mesenchymal transition and tumorprogressionrdquo Oncogene vol 20 no 46 pp 6679ndash6688 2001

[88] C Thomas and A E Karnoub ldquoLysyl oxidase at the crossroadsof mesenchymal stem cells and epithelial-mesenchymal transi-tionrdquo Oncotarget vol 4 no 3 pp 376ndash377 2013

[89] S Maschler S Grunert A Danielopol H Beug and G WirlldquoEnhanced tenascin-C expression andmatrix deposition duringRasTGF-120573-induced progression of mammary tumor cellsrdquoOncogene vol 23 no 20 pp 3622ndash3633 2004

[90] D Loussouarn L Campion C Sagan et al ldquoPrognostic impactof syndecan-1 expression in invasive ductal breast carcinomasrdquoBritish Journal of Cancer vol 98 no 12 pp 1993ndash1998 2008

[91] M Gotte C Kersting I Radke L Kiesel and P Wulfing ldquoAnexpression signature of syndecan-1 (CD138) E-cadherin and c-met is associated with factors of angiogenesis and lymphan-giogenesis in ductal breast carcinoma in siturdquo Breast CancerResearch vol 9 no 1 article R8 2007

[92] D Gao N Joshi H Choi et al ldquoMyeloid progenitor cellsin the premetastatic lung promote metastases by inducingmesenchymal to epithelial transitionrdquo Cancer Research vol 72no 6 pp 1384ndash1394 2012

[93] C Gialeli A D Theocharis and N K Karamanos ldquoRolesof matrix metalloproteinases in cancer progression and theirpharmacological targetingrdquo The FEBS Journal vol 278 no 1pp 16ndash27 2011

[94] R V Iozzo ldquoThe family of the small leucine-rich proteoglycanskey regulators of matrix assembly and cellular growthrdquo CriticalReviews in Biochemistry andMolecular Biology vol 32 no 2 pp141ndash174 1997

[95] S Sarrazin W C Lamanna and J D Esko ldquoHeparan sulfateproteoglycansrdquo Cold Spring Harbor Perspectives in Biology vol3 no 7 Article ID a004952 2011

[96] D M Beauvais and A C Rapraeger ldquoSyndecans in tumor celladhesion and signalingrdquo Reproductive Biology and Endocrinol-ogy vol 2 article 3 2004

[97] J R Couchman ldquoSyndecans proteoglycan regulators of cell-surfacemicrodomainsrdquoNature ReviewsMolecular Cell Biologyvol 4 no 12 pp 926ndash937 2003

[98] J R Couchman ldquoTransmembrane signaling proteoglycansrdquoAnnual Review of Cell and Developmental Biology vol 26 pp89ndash114 2010

[99] T Manon-Jensen Y Itoh and J R Couchman ldquoProteoglycansin health and disease the multiple roles of syndecan sheddingrdquoFEBS Journal vol 277 no 19 pp 3876ndash3889 2010

[100] X Xian S Gopal and J R Couchman ldquoSyndecans as receptorsand organizers of the extracellular matrixrdquo Cell and TissueResearch vol 339 no 1 pp 31ndash46 2010

[101] A I Tsonis N Afratis C Gialeli et al ldquoEvaluation of the coor-dinated actions of estrogen receptors with epidermal growthfactor receptor and insulin-like growth factor receptor in theexpression of cell surface heparan sulfate proteoglycans and cellmotility in breast cancer cellsrdquo FEBS Journal vol 280 no 10 pp2248ndash2259 2013

[102] G W Yip M Smollich and M Gotte ldquoTherapeutic value ofglycosaminoglycans in cancerrdquo Molecular Cancer Therapeuticsvol 5 no 9 pp 2139ndash2148 2006

[103] C Y Fears and A Woods ldquoThe role of syndecans in diseaseand wound healingrdquoMatrix Biology vol 25 no 7 pp 443ndash4562006

[104] K Lambaerts S A Wilcox-Adelman and P ZimmermannldquoThe signaling mechanisms of syndecan heparan sulfate pro-teoglycansrdquo Current Opinion in Cell Biology vol 21 no 5 pp662ndash669 2009

[105] S A Ibrahim GW Yip C Stock et al ldquoTargeting of syndecan-1 by microRNA miR-10b promotes breast cancer cell motilityand invasiveness via aRho-GTPase- andE-cadherin-dependentmechanismrdquo International Journal of Cancer vol 131 no 6 ppE884ndashE896 2012

[106] D M Beauvais and A C Rapraeger ldquoSyndecan-1-mediated cellspreading requires signaling by 120572v1205733 integrins in human breastcarcinoma cellsrdquo Experimental Cell Research vol 286 no 2 pp219ndash232 2003

[107] D M Beauvais and A C Rapraeger ldquoSyndecan-1 couplesthe insulin-like growth factor-1 receptor to inside-out integrinactivationrdquo Journal of Cell Science vol 123 no 21 pp 3796ndash3807 2010

[108] HHassan B GreveM S G Pavao L Kiesel S A Ibrahim andM Gotte ldquoSyndecan-1 modulates 120573-integrin-dependent andinterleukin-6-dependent functions in breast cancer cell adhe-sion migration and resistance to irradiationrdquo FEBS Journalvol 280 no 10 pp 2216ndash2227 2013

[109] E Tkachenko J M Rhodes and M Simons ldquoSyndecans newkids on the signaling blockrdquo Circulation Research vol 96 no 5pp 488ndash500 2005

[110] O C Kousidou A Berdiaki D Kletsas et al ldquoEstradiol-estrogen receptor a key interplay of the expression of syndecan-2 and metalloproteinase-9 in breast cancer cellsrdquo MolecularOncology vol 2 no 3 pp 223ndash232 2008

[111] A Yoneda M E Lendorf J R Couchman and H A BMulthaupt ldquoBreast and ovarian cancers a survey and possibleroles for the cell surface heparan sulfate proteoglycansrdquo Journalof Histochemistry and Cytochemistry vol 60 no 1 pp 9ndash212012

[112] E J Davies F H Blackhall J H Shanks et al ldquoDistribution andclinical significance of heparan sulfate proteoglycans in ovariancancerrdquo Clinical Cancer Research vol 10 no 15 pp 5178ndash51862004

12 BioMed Research International

[113] A Woods and J R Couchman ldquoSyndecan 4 heparan sulfateproteoglycan is a selectively enriched and widespread focaladhesion componentrdquo Molecular Biology of the Cell vol 5 no2 pp 183ndash192 1994

[114] A Woods R L Longley S Tumova and J R CouchmanldquoSyndecan-4 binding to the high affinity heparin-bindingdomain of fibronectin drives focal adhesion formation infibroblastsrdquoArchives of Biochemistry and Biophysics vol 374 no1 pp 66ndash72 2000

[115] A C Rapraeger ldquoSyndecan-regulated receptor signalingrdquo Jour-nal of Cell Biology vol 149 no 5 pp 995ndash997 2000

[116] AWoods ldquoSyndecans transmembranemodulators of adhesionand matrix assemblyrdquo Journal of Clinical Investigation vol 107no 8 pp 935ndash941 2001

[117] L A Cary J F Chang and J Guan ldquoStimulation of cellmigration by overexpression of focal adhesion kinase and itsassociation with Src and Fynrdquo Journal of Cell Science vol 109no 7 pp 1787ndash1794 1996

[118] R L Longley A Woods A Fleetwood G J Cowling JT Gallagher and J R Couchman ldquoControl of morphologycytoskeleton and migration by syndecan-4rdquo Journal of CellScience vol 112 no 20 pp 3421ndash3431 1999

[119] W Huang R Chiquet-Ehrismann J V Moyano A Garcia-Pardo and G Orend ldquoInterference of tenascin-C withsyndecan-4 binding to fibronectin blocks cell adhesion andstimulates tumor cell proliferationrdquoCancer Research vol 61 no23 pp 8586ndash8594 2001

[120] GVollmerM I TanWWunsche andK Frank ldquoExpression oftenascin-C by human endometrial adenocarcinoma and stromacells heterogeneity of splice variants and induction by TGF-120573rdquoBiochemistry and Cell Biology vol 75 no 6 pp 759ndash769 1997

[121] M Kato S Saunders H Nguyen and M Bernfield ldquoLossof cell surface syndecan-1 causes epithelia to transforminto anchorage-independentmesenchyme-like cellsrdquoMolecularBiology of the Cell vol 6 no 5 pp 559ndash576 1995

[122] A J McFall and A C Rapraeger ldquoIdentification of an adhesionsite within the syndecan-4 extracellular protein domainrdquo TheJournal of Biological Chemistry vol 272 no 20 pp 12901ndash129041997

[123] A J McFall and A C Rapraeger ldquoCharacterization of the highaffinity cell-binding domain in the cell surface proteoglycansyndecan-4rdquo Journal of Biological Chemistry vol 273 no 43 pp28270ndash28276 1998

[124] V Nikolova C Koo S A Ibrahim et al ldquoDifferential rolesformembrane-bound and soluble syndecan-1 (CD138) in breastcancer progressionrdquo Carcinogenesis vol 30 no 3 pp 397ndash4072009

[125] I Vlodavsky M Elkin and N Ilan ldquoImpact of heparanaseand the tumor microenvironment on cancer metastasis andangiogenesis basic aspects and clinical applicationsrdquo RambamMaimonides Medical Journal vol 2 no 1 Article ID e0019 2011

[126] M G Peters E Farıas L Colombo J Filmus L Puricelli andE Bal de Kier Joffe ldquoInhibition of invasion and metastasis byglypican-3 in a syngeneic breast cancer modelrdquo Breast CancerResearch and Treatment vol 80 no 2 pp 221ndash232 2003

[127] I Stigliano L Puricelli J Filmus M C Sogayar E B deKier Joffe and M G Peters ldquoGlypican-3 regulates migrationadhesion and actin cytoskeleton organization in mammarytumor cells through Wnt signaling modulationrdquo Breast CancerResearch and Treatment vol 114 no 2 pp 251ndash262 2009

[128] G K Yiu A Kaunisto Y R Chin and A Toker ldquoNFATpromotes carcinoma invasive migration through glypican-6rdquoBiochemical Journal vol 440 no 1 pp 157ndash166 2011

[129] Y J Wu D P La Pierre J Wu A J Yee and B B Yang ldquoTheinteraction of versican with its binding partnersrdquo Cell Researchvol 15 no 7 pp 483ndash494 2005

[130] A D Theocharis ldquoVersican in health and diseaserdquo ConnectiveTissue Research vol 49 no 3-4 pp 230ndash234 2008

[131] S S Skandalis V T Labropoulou P Ravazoula et al ldquoVersicanbut not decorin accumulation is related to malignancy in mam-mographically detected high density and malignant-appearingmicrocalcifications in non-palpable breast carcinomasrdquo BMCCancer vol 11 article 314 2011

[132] W W Du L Fang W Yang et al ldquoThe role of versicanG3 domain in regulating breast cancer cell motility includingeffects on osteoblast cell growth and differentiation in vitromdashevaluation towards understanding breast cancer cell bonemetastasisrdquo BMC Cancer vol 12 article 341 2012

[133] S S Skandalis N Afratis G Smirlaki D Nikitovic A DTheocharis and G N Tzanakakis ldquoCross-talk between estra-diol receptor andEGFRIGF-IR signaling pathways in estrogen-responsive breast cancers focus on the role and impact ofproteoglycansrdquoMatrix Biology vol 35 pp 182ndash193 2014

[134] J Zhu S Goldoni G Bix et al ldquoDecorin evokes protractedinternalization and degradation of the epidermal growth factorreceptor via caveolar endocytosisrdquo Journal of Biological Chem-istry vol 280 no 37 pp 32468ndash32479 2005

[135] R V Iozzo S Buraschi M Genua et al ldquoDecorin antagonizesIGF receptor I (IGF-IR) function by interfering with IGF-IRactivity and attenuating downstream signalingrdquo The Journal ofBiological Chemistry vol 286 no 40 pp 34712ndash34721 2011

[136] B Vuillermoz A Khoruzhenko M DrsquoOnofrio et al ldquoThesmall leucine-rich proteoglycan lumican inhibits melanomaprogressionrdquo Experimental Cell Research vol 296 no 2 pp294ndash306 2004

[137] S Brezillon C Zeltz L Schneider et al ldquoLumican inhibitsB16F1 melanoma cell lungmetastasisrdquo Journal of Physiology andPharmacology vol 60 pp 15ndash22 2009

[138] C Zeltz S Brezillon J Kapyla et al ldquoLumican inhibits cellmigration through 1205722Β1 integrinrdquo Experimental Cell Researchvol 316 no 17 pp 2922ndash2931 2010

[139] A Korpetinou S S Skandalis A Moustakas et al ldquoSerglycin isimplicated in the promotion of aggressive phenotype of breastcancer cellsrdquo PLoS ONE vol 8 Article ID e78157 2013

[140] N Montgomery A Hill S McFarlane et al ldquoCD44 enhancesinvasion of basal-like breast cancer cells by upregulating serineprotease and collagen-degrading enzymatic expression andactivityrdquo Breast Cancer Research vol 14 no 3 article R84 2012

[141] L E Dickinson C C Ho G M Wang K J Stebe andS Gerecht ldquoFunctional surfaces for high-resolution analysisof cancer cell interactions on exogenous hyaluronic acidrdquoBiomaterials vol 31 no 20 pp 5472ndash5478 2010

[142] C Yang M Cao H Liu et al ldquoThe high and low molecularweight forms of hyaluronan have distinct effects on CD44clusteringrdquoThe Journal of Biological Chemistry vol 287 no 51pp 43094ndash43107 2012

[143] L Y W Bourguignon G Wong C A Earle and W XialdquoInteraction of low molecular weight hyaluronan with CD44and toll-like receptors promotes the actin filament-associatedprotein 110-actin binding and MyD88-NF120581B signaling leading

BioMed Research International 13

to proinflammatory cytokinechemokine production andbreasttumor invasionrdquo Cytoskeleton vol 68 no 12 pp 671ndash693 2011

[144] P G Dedes C Gialeli A I Tsonis et al ldquoExpression of matrixmacromolecules and functional properties of breast cancercells are modulated by the bisphosphonate zoledronic acidrdquoBiochimica et Biophysica Acta vol 1820 no 12 pp 1926ndash19392012

[145] A C Rapraeger ldquoSynstatin A selective inhibitor of thesyndecan-1-coupled IGF1R-120572v1205733 integrin complex in tumori-genesis and angiogenesisrdquo The FEBS Journal vol 280 no 10pp 2207ndash2215 2013

[146] D Liu Z Shriver G Venkataraman Y El Shabrawi and RSasisekharan ldquoTumor cell surface heparan sulfate as crypticpromoters or inhibitors of tumor growth and metastasisrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 99 no 2 pp 568ndash573 2002

[147] C Y Pumphrey A M Theus S Li R S Parrish and R DSanderson ldquoNeoglycans carbodiimide-modified glycosamino-glycans a new class of anticancer agents that inhibit cancer cellproliferation and induce apoptosisrdquoCancer Research vol 62 no13 pp 3722ndash3728 2002

12 BioMed Research International

[113] A Woods and J R Couchman ldquoSyndecan 4 heparan sulfateproteoglycan is a selectively enriched and widespread focaladhesion componentrdquo Molecular Biology of the Cell vol 5 no2 pp 183ndash192 1994

[114] A Woods R L Longley S Tumova and J R CouchmanldquoSyndecan-4 binding to the high affinity heparin-bindingdomain of fibronectin drives focal adhesion formation infibroblastsrdquoArchives of Biochemistry and Biophysics vol 374 no1 pp 66ndash72 2000

[115] A C Rapraeger ldquoSyndecan-regulated receptor signalingrdquo Jour-nal of Cell Biology vol 149 no 5 pp 995ndash997 2000

[116] AWoods ldquoSyndecans transmembranemodulators of adhesionand matrix assemblyrdquo Journal of Clinical Investigation vol 107no 8 pp 935ndash941 2001

[117] L A Cary J F Chang and J Guan ldquoStimulation of cellmigration by overexpression of focal adhesion kinase and itsassociation with Src and Fynrdquo Journal of Cell Science vol 109no 7 pp 1787ndash1794 1996

[118] R L Longley A Woods A Fleetwood G J Cowling JT Gallagher and J R Couchman ldquoControl of morphologycytoskeleton and migration by syndecan-4rdquo Journal of CellScience vol 112 no 20 pp 3421ndash3431 1999

[119] W Huang R Chiquet-Ehrismann J V Moyano A Garcia-Pardo and G Orend ldquoInterference of tenascin-C withsyndecan-4 binding to fibronectin blocks cell adhesion andstimulates tumor cell proliferationrdquoCancer Research vol 61 no23 pp 8586ndash8594 2001

[120] GVollmerM I TanWWunsche andK Frank ldquoExpression oftenascin-C by human endometrial adenocarcinoma and stromacells heterogeneity of splice variants and induction by TGF-120573rdquoBiochemistry and Cell Biology vol 75 no 6 pp 759ndash769 1997

[121] M Kato S Saunders H Nguyen and M Bernfield ldquoLossof cell surface syndecan-1 causes epithelia to transforminto anchorage-independentmesenchyme-like cellsrdquoMolecularBiology of the Cell vol 6 no 5 pp 559ndash576 1995

[122] A J McFall and A C Rapraeger ldquoIdentification of an adhesionsite within the syndecan-4 extracellular protein domainrdquo TheJournal of Biological Chemistry vol 272 no 20 pp 12901ndash129041997

[123] A J McFall and A C Rapraeger ldquoCharacterization of the highaffinity cell-binding domain in the cell surface proteoglycansyndecan-4rdquo Journal of Biological Chemistry vol 273 no 43 pp28270ndash28276 1998

[124] V Nikolova C Koo S A Ibrahim et al ldquoDifferential rolesformembrane-bound and soluble syndecan-1 (CD138) in breastcancer progressionrdquo Carcinogenesis vol 30 no 3 pp 397ndash4072009

[125] I Vlodavsky M Elkin and N Ilan ldquoImpact of heparanaseand the tumor microenvironment on cancer metastasis andangiogenesis basic aspects and clinical applicationsrdquo RambamMaimonides Medical Journal vol 2 no 1 Article ID e0019 2011

[126] M G Peters E Farıas L Colombo J Filmus L Puricelli andE Bal de Kier Joffe ldquoInhibition of invasion and metastasis byglypican-3 in a syngeneic breast cancer modelrdquo Breast CancerResearch and Treatment vol 80 no 2 pp 221ndash232 2003

[127] I Stigliano L Puricelli J Filmus M C Sogayar E B deKier Joffe and M G Peters ldquoGlypican-3 regulates migrationadhesion and actin cytoskeleton organization in mammarytumor cells through Wnt signaling modulationrdquo Breast CancerResearch and Treatment vol 114 no 2 pp 251ndash262 2009

[128] G K Yiu A Kaunisto Y R Chin and A Toker ldquoNFATpromotes carcinoma invasive migration through glypican-6rdquoBiochemical Journal vol 440 no 1 pp 157ndash166 2011

[129] Y J Wu D P La Pierre J Wu A J Yee and B B Yang ldquoTheinteraction of versican with its binding partnersrdquo Cell Researchvol 15 no 7 pp 483ndash494 2005

[130] A D Theocharis ldquoVersican in health and diseaserdquo ConnectiveTissue Research vol 49 no 3-4 pp 230ndash234 2008

[131] S S Skandalis V T Labropoulou P Ravazoula et al ldquoVersicanbut not decorin accumulation is related to malignancy in mam-mographically detected high density and malignant-appearingmicrocalcifications in non-palpable breast carcinomasrdquo BMCCancer vol 11 article 314 2011

[132] W W Du L Fang W Yang et al ldquoThe role of versicanG3 domain in regulating breast cancer cell motility includingeffects on osteoblast cell growth and differentiation in vitromdashevaluation towards understanding breast cancer cell bonemetastasisrdquo BMC Cancer vol 12 article 341 2012

[133] S S Skandalis N Afratis G Smirlaki D Nikitovic A DTheocharis and G N Tzanakakis ldquoCross-talk between estra-diol receptor andEGFRIGF-IR signaling pathways in estrogen-responsive breast cancers focus on the role and impact ofproteoglycansrdquoMatrix Biology vol 35 pp 182ndash193 2014

[134] J Zhu S Goldoni G Bix et al ldquoDecorin evokes protractedinternalization and degradation of the epidermal growth factorreceptor via caveolar endocytosisrdquo Journal of Biological Chem-istry vol 280 no 37 pp 32468ndash32479 2005

[135] R V Iozzo S Buraschi M Genua et al ldquoDecorin antagonizesIGF receptor I (IGF-IR) function by interfering with IGF-IRactivity and attenuating downstream signalingrdquo The Journal ofBiological Chemistry vol 286 no 40 pp 34712ndash34721 2011

[136] B Vuillermoz A Khoruzhenko M DrsquoOnofrio et al ldquoThesmall leucine-rich proteoglycan lumican inhibits melanomaprogressionrdquo Experimental Cell Research vol 296 no 2 pp294ndash306 2004

[137] S Brezillon C Zeltz L Schneider et al ldquoLumican inhibitsB16F1 melanoma cell lungmetastasisrdquo Journal of Physiology andPharmacology vol 60 pp 15ndash22 2009

[138] C Zeltz S Brezillon J Kapyla et al ldquoLumican inhibits cellmigration through 1205722Β1 integrinrdquo Experimental Cell Researchvol 316 no 17 pp 2922ndash2931 2010

[139] A Korpetinou S S Skandalis A Moustakas et al ldquoSerglycin isimplicated in the promotion of aggressive phenotype of breastcancer cellsrdquo PLoS ONE vol 8 Article ID e78157 2013

[140] N Montgomery A Hill S McFarlane et al ldquoCD44 enhancesinvasion of basal-like breast cancer cells by upregulating serineprotease and collagen-degrading enzymatic expression andactivityrdquo Breast Cancer Research vol 14 no 3 article R84 2012

[141] L E Dickinson C C Ho G M Wang K J Stebe andS Gerecht ldquoFunctional surfaces for high-resolution analysisof cancer cell interactions on exogenous hyaluronic acidrdquoBiomaterials vol 31 no 20 pp 5472ndash5478 2010

[142] C Yang M Cao H Liu et al ldquoThe high and low molecularweight forms of hyaluronan have distinct effects on CD44clusteringrdquoThe Journal of Biological Chemistry vol 287 no 51pp 43094ndash43107 2012

[143] L Y W Bourguignon G Wong C A Earle and W XialdquoInteraction of low molecular weight hyaluronan with CD44and toll-like receptors promotes the actin filament-associatedprotein 110-actin binding and MyD88-NF120581B signaling leading

BioMed Research International 13

to proinflammatory cytokinechemokine production andbreasttumor invasionrdquo Cytoskeleton vol 68 no 12 pp 671ndash693 2011

[144] P G Dedes C Gialeli A I Tsonis et al ldquoExpression of matrixmacromolecules and functional properties of breast cancercells are modulated by the bisphosphonate zoledronic acidrdquoBiochimica et Biophysica Acta vol 1820 no 12 pp 1926ndash19392012

[145] A C Rapraeger ldquoSynstatin A selective inhibitor of thesyndecan-1-coupled IGF1R-120572v1205733 integrin complex in tumori-genesis and angiogenesisrdquo The FEBS Journal vol 280 no 10pp 2207ndash2215 2013

[146] D Liu Z Shriver G Venkataraman Y El Shabrawi and RSasisekharan ldquoTumor cell surface heparan sulfate as crypticpromoters or inhibitors of tumor growth and metastasisrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 99 no 2 pp 568ndash573 2002

[147] C Y Pumphrey A M Theus S Li R S Parrish and R DSanderson ldquoNeoglycans carbodiimide-modified glycosamino-glycans a new class of anticancer agents that inhibit cancer cellproliferation and induce apoptosisrdquoCancer Research vol 62 no13 pp 3722ndash3728 2002

BioMed Research International 13

to proinflammatory cytokinechemokine production andbreasttumor invasionrdquo Cytoskeleton vol 68 no 12 pp 671ndash693 2011

[144] P G Dedes C Gialeli A I Tsonis et al ldquoExpression of matrixmacromolecules and functional properties of breast cancercells are modulated by the bisphosphonate zoledronic acidrdquoBiochimica et Biophysica Acta vol 1820 no 12 pp 1926ndash19392012

[145] A C Rapraeger ldquoSynstatin A selective inhibitor of thesyndecan-1-coupled IGF1R-120572v1205733 integrin complex in tumori-genesis and angiogenesisrdquo The FEBS Journal vol 280 no 10pp 2207ndash2215 2013

[146] D Liu Z Shriver G Venkataraman Y El Shabrawi and RSasisekharan ldquoTumor cell surface heparan sulfate as crypticpromoters or inhibitors of tumor growth and metastasisrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 99 no 2 pp 568ndash573 2002

[147] C Y Pumphrey A M Theus S Li R S Parrish and R DSanderson ldquoNeoglycans carbodiimide-modified glycosamino-glycans a new class of anticancer agents that inhibit cancer cellproliferation and induce apoptosisrdquoCancer Research vol 62 no13 pp 3722ndash3728 2002