[en] Proteoglycans play a key role in cancer development and progression by participating in the constitution of a specific fertile tumor microenvironment. As they are largely overexpressed in the malignant stroma, proteoglycans provide a reservoir of potential new targets for anticancer therapies, because they can serve to convey toxic payloads in the close proximity of cancer cells and subsequently destroy them. In this context, versican, a proteoglycan largely overexpressed in several solid cancers, bears the potential to be such an ideal target. As 4 main versican isoforms have been characterized, we sought to determine which isoform could represent the best target in human breast cancer. We used a series of 10 primary breast cancer lesions that were characterized as overexpressing the versican protein, when compared with matched normal breast tissues, using shotgun mass spectrometry and immunohistochemistry experiments. Quantitative polymerase chain reaction and western-blotting experiments were used to evaluate versican isoform expression in breast cancer/normal tissue pairs for which ARN quality was excellent. All known isoforms were significantly overexpressed in the malignant lesions, both at the mRNA and at the protein levels. In the course of this study, we also identified and cloned a new alternatively spliced versican isoform, referred to as V4, which was also found to be upregulated in human breast cancer. This study provides for the first time a comprehensive mRNA and protein analysis of versican isoforms expression in human breast tissues, and offers insights into which therapeutic strategy would be best suited to target versican in human breast cancer lesions.
Kischel, Philippe ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > GIGA-R : Labo de recherche sur les métastases
Waltregny, David ; Université de Liège - ULiège > Département des sciences cliniques > Urologie - GIGA-R : Labo de recherche sur les métastases
Dumont, Bruno ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > GIGA-R : Labo de recherche sur les métastases
Turtoi, Andrei ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > GIGA-R : Labo de recherche sur les métastases
Greffe, Yannick ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > GIGA-R : Labo de recherche sur les métastases
Kirsch, Stéphanie ; Université de Liège - ULiège > Département de chimie (sciences) > GIGA-R : Laboratoire de spectrométrie de masse (L.S.M.)
De Pauw, Edwin ; Université de Liège - ULiège > Département de chimie (sciences) > GIGA-R : Laboratoire de spectrométrie de masse (L.S.M.)
Castronovo, Vincenzo ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biologie générale et cellulaire - GIGA-R : Labo de recherche sur les métastases
Language :
English
Title :
Versican overexpression in human breast cancer lesions: Known and new isoforms for stromal tumor targeting.
Publication date :
2010
Journal title :
International Journal of Cancer
ISSN :
0020-7136
eISSN :
1097-0215
Publisher :
Wiley Liss, Inc., New York, United States - New York
Volume :
126
Issue :
3
Pages :
640-50
Peer reviewed :
Peer Reviewed verified by ORBi
Commentary :
P. Kischel and D. Waltregny share first authorship.
Proia DA, Kuperwasser C. Stroma: tumor agonist or antagonist. Cell Cycle 2005;4: 1022-5.
Liotta LA, Kohn EC. The microenvironment of the tumour-host interface. Nature 2001;411:375-9.
Ruoslahti E. Proteoglycans in cell regulation. J Biol Chem 1989;264:13369-72.
Iozzo RV. Proteoglycans: structure, function, and role in neoplasia. Lab Invest 1985;53:373-96.
Ricciardelli C, Mayne K, Sykes PJ, Raymond WA, McCaul K, Marshall VR, Tilley WD, Skinner JM, Horsfall DJ. Elevated stromal chondroitin sulfate glycosaminoglycan predicts progression in early-stage prostate cancer. Clin Cancer Res 1997;3:983-92.
Alini M, Losa GA. Partial characterization of proteoglycans isolated from neoplastic and nonneoplastic human breast tissues. Cancer Res 1991;51:1443-7.
Neri D, Bicknell R. Tumour vascular targeting. Nat Rev Cancer 2005;5:436-46.
Castronovo V, Kischel P, Guillonneau F, de Leval L, Defechereux T, De Pauw E, Neri D, Waltregny D. Identification of specific reachable molecular targets in human breast cancer using a versatile ex vivo proteomic method. Proteomics 2007;7: 1188-96.
Zimmermann DR, Ruoslahti E. Multiple domains of the large fibroblast proteoglycan, versican. Embo J 1989;8: 2975-81.
Kimata K, Oike Y, Tani K, Shinomura T, Yamagata M, Uritani M, Suzuki S. A large chondroitin sulfate proteoglycan (PG-M) synthesized before chondrogenesis in the limb bud of chick embryo. J Biol Chem 1986;261:13517-25.
Naso MF, Zimmermann DR, Iozzo RV. Characterization of the complete genomic structure of the human versican gene and functional analysis of its promoter. J Biol Chem 1994;269: 32999-3008.
Dours-Zimmermann MT, Zimmermann DR. A novel glycosaminoglycan attachment domain identified in two alternative splice variants of human versican. J Biol Chem 1994;269:32992-8.
Zako M, Shinomura T, Ujita M, Ito K, Kimata K. Expression of PG-M(V3), an alternatively spliced form of PG-M without a chondroitin sulfate attachment in region in mouse and human tissues. J Biol Chem 1995;270:3914-8.
Cattaruzza S, Schiappacassi M, Ljungberg-Rose A, Spessotto P, Perissinotto D, Morgelin M, Mucignat MT, Colombatti A, Perris R. Distribution of PG-M/versican variants in human tissues and de novo expression of isoform V3 upon endothelial cell activation, migration, and neoangiogenesis in vitro. J Biol Chem 2002; 277:47626-35.
Paulus W, Baur I, Dours-Zimmermann MT, Zimmermann DR. Differential expression of versican isoforms in brain tumors. J Neuropathol Exp Neurol 1996;55: 528-33.
Schmalfeldt M, Dours-Zimmermann MT, Winterhalter KH, Zimmermann DR. Versican V2 is a major extracellular matrix component of the mature bovine brain. J Biol Chem 1998;273:15758-64.
Ricciardelli C, Brooks JH, Suwiwat S, Sakko AJ, Mayne K, Raymond WA, Seshadri R, LeBaron RG, Horsfall DJ. Regulation of stromal versican expression by breast cancer cells and importance to relapse-free survival in patients with nodenegative primary breast cancer. Clin Cancer Res 2002;8:1054-60.
Zhao X, Russell P. Versican splice variants in human trabecular meshwork and ciliary muscle. Mol Vis 2005;11:603-8.
Glenisson W, Castronovo V, Waltregny D. Histone deacetylase 4 is required for TGFbeta1-induced myofibroblastic differentiation. Biochim Biophys Acta 2007; 1773:1572-82.
Deepa SS, Carulli D, Galtrey C, Rhodes K, Fukuda J, Mikami T, Sugahara K, Fawcett JW. Composition of perineuronal net extracellular matrix in rat brain: a different disaccharide composition for the netassociated proteoglycans. J Biol Chem 2006; 281: 17789-800.
Isogai Z, Shinomura T, Yamakawa N, Takeuchi J, Tsuji T, Heinegard D, Kimata K. 2B1 antigen characteristically expressed on extracellular matrices of human malignant tumors is a large chondroitin sulfate proteoglycan. PG-M/versican. Cancer Res 1996;56:3902-8.
Anderson L, Hunter CL. Quantitative mass spectrometric multiple reaction monitoring assays for major plasma proteins. Mol Cell Proteomics 2006;5:573-88.
Barnidge DR, Dratz EA, Martin T, Bonilla LE, Moran LB, Lindall A. Absolute quantification of the G protein-coupled receptor rhodopsin by LC/MS/MS using proteolysis product peptides and synthetic peptide standards. Anal Chem 2003;75: 445-51.
Barnidge DR, Goodmanson MK, Klee GG, Muddiman DC. Absolute quantification of the model biomarker prostate-specific antigen in serum by LC-Ms/MS using protein cleavage and isotope dilution mass spectrometry. J Proteome Res 2004;3: 644-52.
Barnidge DR, Hall GD, Stocker JL, Muddiman DC. Evaluation of a cleavable stable isotope labeled synthetic peptide for absolute protein quantification using LC-MS/MS. J Proteome Res 2004;3: 658-61.
van Roozendaal CE, van Ooijen B, Klijn JG, Claassen C, Eggermont AM, Henzen-Logmans SC, Foekens JA. Stromal influences on breast cancer cell growth. Br. J Cancer. 1992;65:77-81.
Revillion F, Pawlowski V, Hornez L, Peyrat JP. Glyceraldehyde-3-phosphate dehydrogenase gene expression in human breast cancer. Eur J Cancer 2000;36: 1038-42.
Tricarico C, Pinzani P, Bianchi S, Paglierani M, Distante V, Pazzagli M, Bustin SA, Orlando C. Quantitative realtime reverse transcription polymerase chain reaction: normalization to rRNA or single housekeeping genes is inappropriate for human tissue biopsies. Anal Biochem 2002;309:293-300.
Sandy JD, Westling J, Kenagy RD, Iruela-Arispe ML, Verscharen C, Rodriguez-Mazaneque JC, Zimmermann DR, Lemire JM, Fischer JW, Wight TN, Clowes AW. Versican V1 proteolysis in human aorta in vivo occurs at the Glu441-Ala442 bond, a site that is cleaved by recombinant ADAMTS-1 and ADAMTS-4. J Biol Chem 2001;276: 13372-8.
Emanuelsson O, Brunak S, von Heijne G, Nielsen H. Locating proteins in the cell using TargetP, SignalP and related tools. Nat Protoc 2007;2:953-71.
Westling J, Gottschall PE, Thompson VP, Cockburn A, Perides G, Zimmermann DR, Sandy JD. ADAMTS4 (aggrecanase-1) cleaves human brain versican V2 at Glu405-Gln406 to generate glial hyaluronate binding protein. Biochem J 2004;377:787-95.
Suwiwat S, Ricciardelli C, Tammi R, Tammi M, Auvinen P, Kosma VM, LeBaron RG, Raymond WA, Tilley WD, Horsfall DJ. Expression of extracellular matrix components versican, chondroitin sulfate, tenascin, and hyaluronan, and their association with disease outcome in nodenegative breast cancer. Clin Cancer Res 2004;10:2491-8.
Koninger J, Giese T, di Mola FF, Wente MN, Esposito I, Bachem MG, Giese NA, Buchler MW, Friess H. Pancreatic tumor cells influence the composition of the extracellular matrix. Biochem Biophys Res Commun 2004;322:943-9.
Ricciardelli C, Mayne K, Sykes PJ, Raymond WA, McCaul K, Marshall VR, Horsfall DJ. Elevated levels of versican but not decorin predict disease progression in early-stage prostate cancer. Clin Cancer Res 1998;4:963-71.
Voutilainen K, Anttila M, Sillanpaa S, Tammi R, Tammi M, Saarikoski S, Kosma VM. Versican in epithelial ovarian cancer: relation to hyaluronan, clinicopathologic factors and prognosis. Int J Cancer 2003; 107:359-64.
Nara Y, Kato Y, Torii Y, Tsuji Y, Nakagaki S, Goto S, Isobe H, Nakashima N, Takeuchi J. Immunohistochemical localization of extracellular matrix components in human breast tumours with special reference to PG-M/versican. Histochem J 1997;29: 21-30.
Touab M, Villena J, Barranco C, Arumi-Uria M, Bassols A. Versican is differentially expressed in human melanoma and may play a role in tumor development. Am J Pathol 2002;160: 549-57.
Breathnach R, Chambon P. Organization and expression of eucaryotic split genes coding for proteins. Annu Rev Biochem 1981;50: 349-83.
Boyd CD, Pierce RA, Schwarzbauer JE, Doege K, Sandell LJ. Alternate exon usage is a commonly used mechanism for increasing coding diversity within genes coding for extracellular matrix proteins. Matrix 1993;13:457-69.
Sakko AJ, Ricciardelli C, Mayne K, Suwiwat S, LeBaron RG, Marshall VR, Tilley WD, Horsfall DJ. Modulation of prostate cancer cell attachment to matrix by versican. Cancer Res 2003;63: 4786-91.
Gulyas M, Hjerpe A. Proteoglycans and WT1 as markers for distinguishing adenocarcinoma, epithelioid mesothelioma, and benign mesothelium. J Pathol 2003; 199:479-87.
Anderson L, Seilhamer J. A comparison of selected mRNA and protein abundances in human liver. Electrophoresis 1997;18:533-7.
Gygi SP, Rochon Y, Franza BR, Aebersold R. Correlation between protein and mRNA abundance in yeast. Mol Cell Biol 1999;19: 1720-30.
Rahmani M, Wong BW, Ang L, Cheung CC, Carthy JM, Walinski H, McManus BM. Versican: signaling to transcriptional control pathways. Can J Physiol Pharmacol 2006;84:77-92.
Hakomori S. Aberrant glycosylation in tumors and tumor-associated carbohydrate antigens. Adv Cancer Res 1989;52:257-331.
Yang BL, Cao L, Kiani C, Lee V, Zhang Y, Adams ME, Yang BB. Tandem repeats are involved in G1 domain inhibition of versican expression and secretion and the G3 domain enhances glycosaminoglycan modification and product secretion via the complement-binding protein-like motif. J Biol Chem 2000;275:21255-61.
Chen L, Wu Y, Lee V, Kiani C, Adams ME, Yao Y, Yang BB. The folded modules of aggrecan G3 domain exert two separable functions in glycosaminoglycan modification and product secretion. J Biol Chem 2002;277:2657-65.
Brinkmann T, Weilke C, Kleesiek K. Recognition of acceptor proteins by UDP-D-xylose proteoglycan core protein beta-D-xylosyltransferase. J Biol Chem 1997;272:11171-5.
Derynck R, Goeddel DV, Ullrich A, Gutterman JU, Williams RD, Bringman TS, Berger WH. Synthesis of messenger RNAs for transforming growth factors alpha and beta and the epidermal growth factor receptor by human tumors. Cancer Res 1987; 47:707-12.
Zardi L, Neri D. Affinity reagents against tumour-associated extracellular molecules and new forming vessels. Adv Drug Deliv Rev 1998; 31:43-52.
Castronovo V, Waltregny D, Kischel P, Roesli C, Elia G, Rybak JN, Neri D. A chemical proteomics approach for the identification of accessible antigens expressed in human kidney cancer. Mol Cell Proteomics 2006;5: 2083-91.
Conrotto P, Roesli C, Rybak JN, Kischel P, Waltregny D, Neri D, Castronovo V. Identification of new accessible tumor antigens in human colon cancer by ex vivo protein biotinylation and comparative mass spectrometry analysis. Int J Cancer 2008; 123:2856-64.
Kaspar M, Zardi L, Neri D. Fibronectin as target for tumor therapy. Int J Cancer 2006;118:1331-9.
Silacci M, Brack SS, Spath N, Buck A, Hillinger S, Arni S, Weder W, Zardi L, Neri D. Human monoclonal antibodies to domain C of tenascin-C selectively target solid tumors in vivo. Protein Eng Des Sel 2006;19:471-8.
