Skip to main content

Advertisement

SpringerLink
Log in

Shed proteoglycans in tumor stroma

  • Review
  • Published:
Cell and Tissue Research Aims and scope Submit manuscript

Abstract

Cancer cell behavior is not only governed by tumor cell-autonomous properties but also by the surrounding tumor stroma. Cancer-associated fibroblasts, blood vessels, immune cells and the extracellular matrix of the tumor microenvironment have a profound influence on tumor progression. Proteoglycans control various normal and pathological processes, modulating cell proliferation and motility, cell-matrix interactions, immune cell recruitment and angiogenesis. They are major mediators of cancer cell behavior though a dynamic interplay with extracellular matrix components. During cancer progression, their altered expression can promote the activation of several signaling cascades regulating crucial functional properties of cancer cells. Notably, the function of cell surface proteoglycans can be altered by ectodomain shedding, which converts membrane-bound coreceptors into soluble paracrine effector molecules. In this review, we highlight the importance of proteoglycans and their soluble counterparts in cancer progression and the consequences of their interactions with the adjacent stroma. The dynamic interplay among shed proteoglycans and proteolytic enzymes has a significant impact both on tumor cells and their surrounding stroma, with important implications for the diagnosis of this disease and for novel therapeutic approaches.

Syndecan shedding. The mechanism of shedding involves the proteolytic cleavage of their ectodomain near the plasma membrane by metzincin enzymes, such as metalloproteinases. N-acetylglucosamine-alpha-L-iduronic acid/beta-D-glucuronic acid (HS) chains can be additionally cleaved by heparanase. Syndecan core protein can be further processed by intramembrane enzymatic cleavage. Syndecans are in a dynamic interplay with the extracellular matrix and several receptor-tyrosine-kinases (RTKs) and various growth factors, for which they act as co-receptors, thus mediating numerous signaling pathways

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Ahmed Haji Omar A, Haglund C, Virolainen S, Hayry V, Atula T, Kontio R, Rihtniemi J, Pihakari A, Salo T, Hagstrom J, Sorsa T (2013) Epithelial and stromal syndecan-1 and -2 are distinctly expressed in oral- and cutaneous squamous cell carcinomas. J Oral Pathol Med 42:389–395

    Article  PubMed  Google Scholar 

  • Asuthkar S, Velpula KK, Nalla AK, Gogineni VR, Gondi CS, Rao JS (2014) Irradiation-induced angiogenesis is associated with an MMP-9-miR-494-syndecan-1 regulatory loop in medulloblastoma cells. Oncogene 33:1922–1933

    Article  CAS  PubMed  Google Scholar 

  • Balzarini P, Benetti A, Invernici G, Cristini S, Zicari S, Caruso A, Gatta LB, Berenzi A, Imberti L, Zanotti C, Portolani N, Giulini SM, Ferrari M, Ciusani E, Navone SE, Canazza A, Parati EA, Alessandri G (2012) Transforming growth factor-beta1 induces microvascular abnormalities through a down-modulation of neural cell adhesion molecule in human hepatocellular carcinoma. Lab Invest 92:1297–1309

    Article  CAS  PubMed  Google Scholar 

  • Barbouri D, Afratis N, Gialeli C, Vynios DH, Theocharis AD, Karamanos NK (2014) Syndecans as modulators and potential pharmacological targets in cancer progression. Front Oncol 4:4

    Article  PubMed  PubMed Central  Google Scholar 

  • Benassi MS, Pazzaglia L, Chiechi A, Alberghini M, Conti A, Cattaruzza S, Wassermann B, Picci P, Perris R (2009) NG2 expression predicts the metastasis formation in soft-tissue sarcoma patients. J Orthop Res 27:135–140

    Article  PubMed  Google Scholar 

  • Bernabeu C, Lopez-Novoa JM, Quintanilla M (2009) The emerging role of TGF-beta superfamily coreceptors in cancer. Biochim Biophys Acta 1792:954–973

    Article  CAS  PubMed  Google Scholar 

  • Bernfield M, Gotte M, Park PW, Reizes O, Fitzgerald ML, Lincecum J, Zako M (1999) Functions of cell surface heparan sulfate proteoglycans. Annu Rev Biochem 68:729–777

    Article  CAS  PubMed  Google Scholar 

  • Bilandzic M, Stenvers KL (2011) Betaglycan: a multifunctional accessory. Mol Cell Endocrinol 339:180–189

    Article  CAS  PubMed  Google Scholar 

  • Bilandzic M, Wang Y, Ahmed N, Luwor RB, Zhu HJ, Findlay JK, Stenvers KL (2014) Betaglycan blocks metastatic behaviors in human granulosa cell tumors by suppressing NFkappaB-mediated induction of MMP2. Cancer Lett 354:107–114

    Article  CAS  PubMed  Google Scholar 

  • Bloushtain N, Qimron U, Bar-Ilan A, Hershkovitz O, Gazit R, Fima E, Korc M, Vlodavsky I, Bovin NV, Porgador A (2004) Membrane-associated heparan sulfate proteoglycans are involved in the recognition of cellular targets by NKp30 and NKp46. J Immunol 173:2392–2401

    Article  CAS  PubMed  Google Scholar 

  • Bourguignon LY, Wong G, Shiina M (2016) Upregulation of histone methyltransferase, DOT1L by matrix hyaluronan promotes microRNA-10 expression leading to tumor cell invasion and chemoresistance in cancer stem cells from head and neck squamous cell carcinoma. J Biol Chem 291:10571-10585

    Article  CAS  PubMed  Google Scholar 

  • Bouris P, Skandalis SS, Piperigkou Z, Afratis N, Karamanou K, Aletras AJ, Moustakas A, Theocharis AD, Karamanos NK (2015) Estrogen receptor alpha mediates epithelial to mesenchymal transition, expression of specific matrix effectors and functional properties of breast cancer cells. Matrix Biol 43:42–60

    Article  CAS  PubMed  Google Scholar 

  • Brand C, Schliemann C, Ring J, Kessler T, Bäumer S, Angenendt L, Mantke V, Ross R, Hintelmann H, Spieker T, Wardelmann E, Mesters RM, Berdel WE, Schwöppe C (2016) NG2 proteoglycan as a pericyte target for anticancer therapy by tumor vessel infarction with retargeted tissue factor. Oncotarget 7:6774–6789

    PubMed  PubMed Central  Google Scholar 

  • Brule S, Charnaux N, Sutton A, Ledoux D, Chaigneau T, Saffar L, Gattegno L (2006) The shedding of syndecan-4 and syndecan-1 from HeLa cells and human primary macrophages is accelerated by SDF-1/CXCL12 and mediated by the matrix metalloproteinase-9. Glycobiology 16:488–501

    Article  CAS  PubMed  Google Scholar 

  • Carmeliet P, Jain RK (2000) Angiogenesis in cancer and other diseases. Nature 407:249–257

    Article  CAS  PubMed  Google Scholar 

  • Cattaruzza S, Nicolosi PA, Braghetta P, Pazzaglia L, Benassi MS, Picci P, Lacrima K, Zanocco D, Rizzo E, Stallcup WB, Colombatti A, Perris R (2013a) NG2/CSPG4-collagen type VI interplays putatively involved in the microenvironmental control of tumour engraftment and local expansion. J Mol Cell Biol 5:176–193

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cattaruzza S, Ozerdem U, Denzel M, Ranscht B, Bulian P, Cavallaro U, Zanocco D, Colombatti A, Stallcup WB, Perris R (2013b) Multivalent proteoglycan modulation of FGF mitogenic responses in perivascular cells. Angiogenesis 16:309–327

    Article  CAS  PubMed  Google Scholar 

  • Choi S, Kang DH, Oh ES (2013) Targeting syndecans: a promising strategy for the treatment of cancer. Expert Opin Ther Targets 17:695–705

    Article  CAS  PubMed  Google Scholar 

  • Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420:860–867

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Criswell TL, Dumont N, Barnett JV, Arteaga CL (2008) Knockdown of the transforming growth factor-beta type III receptor impairs motility and invasion of metastatic cancer cells. Cancer Res 68:7304–7312

    Article  CAS  PubMed  Google Scholar 

  • Csordas G, Santra M, Reed CC, Eichstetter I, McQuillan DJ, Gross D, Nugent MA, Hajnoczky G, Iozzo RV (2000) Sustained down-regulation of the epidermal growth factor receptor by decorin. A mechanism for controlling tumor growth in vivo. J Biol Chem 275:32879–32887

    Article  CAS  PubMed  Google Scholar 

  • Davies EJ, Blackhall FH, Shanks JH, David G, McGown AT, Swindell R, Slade RJ, Martin-Hirsch P, Gallagher JT, Jayson GC (2004) Distribution and clinical significance of heparan sulfate proteoglycans in ovarian cancer. Clin Cancer Res 10:5178–5186

    Article  CAS  PubMed  Google Scholar 

  • De Wever O, Hendrix A, De Boeck A, Westbroek W, Braems G, Emami S, Sabbah M, Gespach C, Bracke M (2010) Modeling and quantification of cancer cell invasion through collagen type I matrices. Int J Dev Biol 54:887–896

    Article  PubMed  CAS  Google Scholar 

  • Diestel U, Resch M, Meinhardt K, Weiler S, Hellmann TV, Mueller TD, Nickel J, Eichler J, Muller YA (2013) Identification of a novel TGF-beta-binding site in the zona pellucida C-terminal (ZP-C) domain of TGF-beta-receptor-3 (TGFR-3). PLoS One 8:e67214

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dong M, How T, Kirkbride KC, Gordon KJ, Lee JD, Hempel N, Kelly P, Moeller BJ, Marks JR, Blobe GC (2007) The type III TGF-beta receptor suppresses breast cancer progression. J Clin Invest 117:206–217

    Article  CAS  PubMed  Google Scholar 

  • Dvorak HF (1986) Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med 315:1650–1659

    Article  CAS  PubMed  Google Scholar 

  • Dvorak HF (2015) Tumors: wounds that do not heal-redux. Cancer Immunol Res 3:1–11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Elderbroom JL, Huang JJ, Gatza CE, Chen J, How T, Starr M, Nixon AB, Blobe GC (2014) Ectodomain shedding of TbetaRIII is required for TbetaRIII-mediated suppression of TGF-beta signaling and breast cancer migration and invasion. Mol Biol Cell 25:2320–2332

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Elenius V, Gotte M, Reizes O, Elenius K, Bernfield M (2004) Inhibition by the soluble syndecan-1 ectodomains delays wound repair in mice overexpressing syndecan-1. J Biol Chem 279:41928–41935

    Article  CAS  PubMed  Google Scholar 

  • Endo K, Takino T, Miyamori H, Kinsen H, Yoshizaki T, Furukawa M, Sato H (2003) Cleavage of syndecan-1 by membrane type matrix metalloproteinase-1 stimulates cell migration. J Biol Chem 278:40764–40770

    Article  CAS  PubMed  Google Scholar 

  • Fanhchaksai K, Okada F, Nagai N, Pothacharoen P, Kongtawelert P, Hatano S, Makino S, Nakamura T, Watanabe H (2016) Host stromal versican is essential for cancer-associated fibroblast function to inhibit cancer growth. Int J Cancer 138:630–641

    Article  CAS  PubMed  Google Scholar 

  • Farace C, Oliver JA, Melguizo C, Alvarez P, Bandiera P, Rama AR, Malaguarnera G, Ortiz R, Madeddu R, Prados J (2015) Microenvironmental modulation of decorin and lumican in temozolomide-resistant glioblastoma and neuroblastoma cancer stem-like cells. PLoS One 10:e0134111

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Farnedi A, Rossi S, Bertani N, Gulli M, Silini EM, Mucignat MT, Poli T, Sesenna E, Lanfranco D, Montebugnoli L, Leonardi E, Marchetti C, Cocchi R, Ambrosini-Spaltro A, Foschini MP, Perris R (2015) Proteoglycan-based diversification of disease outcome in head and neck cancer patients identifies NG2/CSPG4 and syndecan-2 as unique relapse and overall survival predicting factors. BMC Cancer 15:352

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Fears CY, Gladson CL, Woods A (2006) Syndecan-2 is expressed in the microvasculature of gliomas and regulates angiogenic processes in microvascular endothelial cells. J Biol Chem 281:14533–14536

    Article  CAS  PubMed  Google Scholar 

  • Filmus J, Capurro M (2013) Glypican-3: a marker and a therapeutic target in hepatocellular carcinoma. FEBS J 280:2471–2476

    Article  CAS  PubMed  Google Scholar 

  • Fitzgerald ML, Wang Z, Park PW, Murphy G, Bernfield M (2000) Shedding of syndecan-1 and -4 ectodomains is regulated by multiple signaling pathways and mediated by a TIMP-3-sensitive metalloproteinase. J Cell Biol 148:811–824

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Frantz C, Stewart KM, Weaver VM (2010) The extracellular matrix at a glance. J Cell Sci 123:4195–4200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Garusi E, Rossi S, Perris R (2012) Antithetic roles of proteoglycans in cancer. Cell Mol Life Sci 69:553–579

    Article  CAS  PubMed  Google Scholar 

  • Gatza CE, Elderbroom JL, Oh SY, Starr MD, Nixon AB, Blobe GC (2014) The balance of cell surface and soluble type III TGF-beta receptor regulates BMP signaling in normal and cancerous mammary epithelial cells. Neoplasia 16:489–500

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Geyer MA, Krebs-Thomson K, Braff DL, Swerdlow NR (2001) Pharmacological studies of prepulse inhibition models of sensorimotor gating deficits in schizophrenia: a decade in review. Psychopharmacol (Berl) 156:117–154

    Article  CAS  Google Scholar 

  • Gialeli C, Theocharis AD, Kletsas D, Tzanakakis GN, Karamanos NK (2013) Expression of matrix macromolecules and functional properties of EGF-responsive colon cancer cells are inhibited by panitumumab. Invest New Drugs 31:516–524

    Article  CAS  PubMed  Google Scholar 

  • Gibby K, You WK, Kadoya K, Helgadottir H, Young LJ, Ellies LG, Chang Y, Cardiff RD, Stallcup WB (2012) Early vascular deficits are correlated with delayed mammary tumorigenesis in the MMTV-PyMT transgenic mouse following genetic ablation of the NG2 proteoglycan. Breast Cancer Res 14:R67

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gotte M (2003) Syndecans in inflammation. FASEB J 17:575–591

    Article  CAS  PubMed  Google Scholar 

  • Gotte M, Echtermeyer F (2003) Syndecan-1 as a regulator of chemokine function. ScientificWorldJournal 3:1327–1331

    Article  PubMed  Google Scholar 

  • Gotte M, Yip GW (2006) Heparanase, hyaluronan, and CD44 in cancers: a breast carcinoma perspective. Cancer Res 66:10233–10237

    Article  PubMed  Google Scholar 

  • Greve B, Kelsch R, Spaniol K, Eich HT, Gotte M (2012) Flow cytometry in cancer stem cell analysis and separation. Cytometry A 81:284–293

    Article  PubMed  Google Scholar 

  • Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70

    Article  CAS  PubMed  Google Scholar 

  • Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674

    Article  CAS  PubMed  Google Scholar 

  • Haruyama Y, Yorita K, Yamaguchi T, Kitajima S, Amano J, Ohtomo T, Ohno A, Kondo K, Kataoka H (2015) High preoperative levels of serum glypican-3 containing N-terminal subunit are associated with poor prognosis in patients with hepatocellular carcinoma after partial hepatectomy. Int J Cancer 137:1643–1651

    Article  CAS  PubMed  Google Scholar 

  • Hashimoto Y, Skacel M, Adams JC (2008) Association of loss of epithelial syndecan-1 with stage and local metastasis of colorectal adenocarcinomas: an immunohistochemical study of clinically annotated tumors. BMC Cancer 8:185

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Hayashida K, Chen Y, Bartlett AH, Park PW (2008) Syndecan-1 is an in vivo suppressor of Gram-positive toxic shock. J Biol Chem 283:19895–19903

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hempel N, How T, Dong M, Murphy SK, Fields TA, Blobe GC (2007) Loss of betaglycan expression in ovarian cancer: role in motility and invasion. Cancer Res 67:5231–5238

    Article  CAS  PubMed  Google Scholar 

  • Hershkovitz O, Jivov S, Bloushtain N, Zilka A, Landau G, Bar-Ilan A, Lichtenstein RG, Campbell KS, Kuppevelt TH van, Porgador A (2007) Characterization of the recognition of tumor cells by the natural cytotoxicity receptor, NKp44. Biochemistry 46:7426–7436

  • Hrabar D, Aralica G, Gomercic M, Ljubicic N, Kruslin B, Tomas D (2010) Epithelial and stromal expression of syndecan-2 in pancreatic carcinoma. Anticancer Res 30:2749–2753

    CAS  PubMed  Google Scholar 

  • Ibrahim SA, Yip GW, Stock C, Pan JW, Neubauer C, Poeter M, Pupjalis D, Koo CY, Kelsch R, Schule R, Rescher U, Kiesel L, Gotte M (2012) Targeting of syndecan-1 by microRNA miR-10b promotes breast cancer cell motility and invasiveness via a Rho-GTPase- and E-cadherin-dependent mechanism. Int J Cancer 131:E884–E896

    Article  CAS  PubMed  Google Scholar 

  • Ibrahim SA, Hassan H, Vilardo L, Kumar SK, Kumar AV, Kelsch R, Schneider C, Kiesel L, Eich HT, Zucchi I, Reinbold R, Greve B, Gotte M (2013) Syndecan-1 (CD138) modulates triple-negative breast cancer stem cell properties via regulation of LRP-6 and IL-6-mediated STAT3 signaling. PLoS One 8:e85737

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ibrahim SA, Hassan H, Gotte M (2014a) MicroRNA-dependent targeting of the extracellular matrix as a mechanism of regulating cell behavior. Biochim Biophys Acta 1840:2609–2620

    Article  CAS  PubMed  Google Scholar 

  • Ibrahim SA, Hassan H, Gotte M (2014b) MicroRNA regulation of proteoglycan function in cancer. FEBS J 281:5009–5022

    Article  CAS  PubMed  Google Scholar 

  • Iozzo RV (1998) Matrix proteoglycans: from molecular design to cellular function. Annu Rev Biochem 67:609–652

    Article  CAS  PubMed  Google Scholar 

  • Iozzo RV, Sanderson RD (2011) Proteoglycans in cancer biology, tumour microenvironment and angiogenesis. J Cell Mol Med 15:1013–1031

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Iozzo RV, Schaefer L (2015) Proteoglycan form and function: a comprehensive nomenclature of proteoglycans. Matrix Biol 42:11–55

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ishiguro T, Sugimoto M, Kinoshita Y, Miyazaki Y, Nakano K, Tsunoda H, Sugo I, Ohizumi I, Aburatani H, Hamakubo T, Kodama T, Tsuchiya M, Yamada-Okabe H (2008) Anti-glypican 3 antibody as a potential antitumor agent for human liver cancer. Cancer Res 68:9832–9838

    Article  CAS  PubMed  Google Scholar 

  • Iyengar P, Espina V, Williams TW, Lin Y, Berry D, Jelicks LA, Lee H, Temple K, Graves R, Pollard J, Chopra N, Russell RG, Sasisekharan R, Trock BJ, Lippman M, Calvert VS, Petricoin EF 3rd, Liotta L, Dadachova E, Pestell RG, Lisanti MP, Bonaldo P, Scherer PE (2005) Adipocyte-derived collagen VI affects early mammary tumor progression in vivo, demonstrating a critical interaction in the tumor/stroma microenvironment. J Clin Invest 115:1163–1176

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jachetti E, Caputo S, Mazzoleni S, Brambillasca CS, Parigi SM, Grioni M, Piras IS, Restuccia U, Calcinotto A, Freschi M, Bachi A, Galli R, Bellone M (2015) Tenascin-C protects cancer stem-like cells from immune surveillance by arresting T-cell activation. Cancer Res 75:2095–2108

    Article  CAS  PubMed  Google Scholar 

  • Joensuu H, Anttonen A, Eriksson M, Makitaro R, Alfthan H, Kinnula V, Leppa S (2002) Soluble syndecan-1 and serum basic fibroblast growth factor are new prognostic factors in lung cancer. Cancer Res 62:5210–5217

    CAS  PubMed  Google Scholar 

  • Joo NE, Miao D, Bermudez M, Stallcup WB, Kapila YL (2014) Shedding of NG2 by MMP-13 attenuates anoikis. DNA Cell Biol 33:854–862

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim CW, Goldberger OA, Gallo RL, Bernfield M (1994) Members of the syndecan family of heparan sulfate proteoglycans are expressed in distinct cell-, tissue-, and development-specific patterns. Mol Biol Cell 5:797–805

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim HM, Jung WH, Koo JS (2015) Expression of cancer-associated fibroblast related proteins in metastatic breast cancer: an immunohistochemical analysis. J Transl Med 13:222

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kliment CR, Englert JM, Gochuico BR, Yu G, Kaminski N, Rosas I, Oury TD (2009) Oxidative stress alters syndecan-1 distribution in lungs with pulmonary fibrosis. J Biol Chem 284:3537–3545

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Korpetinou A, Skandalis SS, Moustakas A, Happonen KE, Tveit H, Prydz K, Labropoulou VT, Giannopoulou E, Kalofonos HP, Blom AM, Karamanos NK, Theocharis AD (2013) Serglycin is implicated in the promotion of aggressive phenotype of breast cancer cells. PLoS One 8:e78157

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Korpetinou A, Skandalis SS, Labropoulou VT, Smirlaki G, Noulas A, Karamanos NK, Theocharis AD (2014) Serglycin: at the crossroad of inflammation and malignancy. Front Oncol 3:327

    Article  PubMed  PubMed Central  Google Scholar 

  • Korpetinou A, Papachristou DJ, Lampropoulou A, Bouris P, Labropoulou VT, Noulas A, Karamanos NK, Theocharis AD (2015) Increased expression of Serglycin in specific carcinomas and aggressive cancer cell lines. Biomed Res Int 2015:690721

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kumar AV, Katakam SK, Urbanowitz AK, Gotte M (2015) Heparan sulphate as a regulator of leukocyte recruitment in inflammation. Curr Protein Pept Sci 16:77–86

    Article  CAS  PubMed  Google Scholar 

  • Kwon MJ, Hong E, Choi Y, Kang DH, Oh ES (2014) Interleukin-1alpha promotes extracellular shedding of syndecan-2 via induction of matrix metalloproteinase-7 expression. Biochem Biophys Res Commun 446:487–492

    Article  CAS  PubMed  Google Scholar 

  • Lambert KE, Huang H, Mythreye K, Blobe GC (2011) The type III transforming growth factor-beta receptor inhibits proliferation, migration, and adhesion in human myeloma cells. Mol Biol Cell 22:1463–1472

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lange K, Kammerer M, Hegi ME, Grotegut S, Dittmann A, Huang W, Fluri E, Yip GW, Gotte M, Ruiz C, Orend G (2007) Endothelin receptor type B counteracts tenascin-C-induced endothelin receptor type A-dependent focal adhesion and actin stress fiber disorganization. Cancer Res 67:6163–6173

    Article  CAS  PubMed  Google Scholar 

  • Lazard D, Sastre X, Frid MG, Glukhova MA, Thiery JP, Koteliansky VE (1993) Expression of smooth muscle-specific proteins in myoepithelium and stromal myofibroblasts of normal and malignant human breast tissue. Proc Natl Acad Sci U S A 90:999–1003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li Q, Park PW, Wilson CL, Parks WC (2002) Matrilysin shedding of syndecan-1 regulates chemokine mobilization and transepithelial efflux of neutrophils in acute lung injury. Cell 111:635–646

    Article  CAS  PubMed  Google Scholar 

  • Li R, Zhang L, Jia L, Duan Y, Li Y, Wang J, Bao L, Sha N (2014) MicroRNA-143 targets Syndecan-1 to repress cell growth in melanoma. PLoS One 9:e94855

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Li X, Truty MA, Kang Y, Chopin-Laly X, Zhang R, Roife D, Chatterjee D, Lin E, Thomas RM, Wang H, Katz MH, Fleming JB (2014) Extracellular lumican inhibits pancreatic cancer cell growth and is associated with prolonged survival after surgery. Clin Cancer Res 20:6529–6540

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lim HC, Multhaupt HA, Couchman JR (2015) Cell surface heparan sulfate proteoglycans control adhesion and invasion of breast carcinoma cells. Mol Cancer 14:15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lofgren L, Sahlin L, Jiang S, Von Schoultz B, Fernstad R, Skoog L, Von Schoultz E (2007) Expression of syndecan-1 in paired samples of normal and malignant breast tissue from postmenopausal women. Anticancer Res 27:3045–3050

    CAS  PubMed  Google Scholar 

  • Lovell R, Dunn JA, Begum G, Barth NJ, Plant T, Moss PA, Drayson MT, Pratt G, Working Party on Leukaemia in Adults of the National Cancer Research Institute Haematological Oncology Clinical Studies G (2005) Soluble syndecan-1 level at diagnosis is an independent prognostic factor in multiple myeloma and the extent of fall from diagnosis to plateau predicts for overall survival. Br J Haematol 130:542–548

    Article  CAS  PubMed  Google Scholar 

  • Lu P, Takai K, Weaver VM, Werb Z (2011) Extracellular matrix degradation and remodeling in development and disease. Cold Spring Harb Perspect Biol 3:a005058

    Article  PubMed  PubMed Central  Google Scholar 

  • Lu LL, Sun J, Lai JJ, Jiang Y, Bai LH, Zhang LD (2015) Neuron-glial antigen 2 overexpression in hepatocellular carcinoma predicts poor prognosis. World J Gastroenterol 21:6649–6659

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Manon-Jensen T, Itoh Y, Couchman JR (2010) Proteoglycans in health and disease: the multiple roles of syndecan shedding. FEBS J 277:3876–3889

    Article  CAS  PubMed  Google Scholar 

  • Meng W, Xia Q, Wu L, Chen S, He X, Zhang L, Gao Q, Zhou H (2011) Downregulation of TGF-beta receptor types II and III in oral squamous cell carcinoma and oral carcinoma-associated fibroblasts. BMC Cancer 11:88

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Miles FL, Sikes RA (2014) Insidious changes in stromal matrix fuel cancer progression. Mol Cancer Res 12:297–312

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mueller MM, Fusenig NE (2004) Friends or foes—bipolar effects of the tumour stroma in cancer. Nat Rev Cancer 4:839–849

    Article  CAS  PubMed  Google Scholar 

  • Mukunyadzi P, Liu K, Hanna EY, Suen JY, Fan CY (2003) Induced expression of syndecan-1 in the stroma of head and neck squamous cell carcinoma. Mod Pathol 16:796–801

    Article  PubMed  Google Scholar 

  • Nakatsura T, Kageshita T, Ito S, Wakamatsu K, Monji M, Ikuta Y, Senju S, Ono T, Nishimura Y (2004) Identification of glypican-3 as a novel tumor marker for melanoma. Clin Cancer Res 10:6612–6621

    Article  CAS  PubMed  Google Scholar 

  • Nam EJ, Park PW (2012) Shedding of cell membrane-bound proteoglycans. Methods Mol Biol 836:291–305

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Neill T, Schaefer L, Iozzo RV (2012) Decorin: a guardian from the matrix. Am J Pathol 181:380–387

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Neill T, Schaefer L, Iozzo RV (2016) Decorin as a multivalent therapeutic agent against cancer. Adv Drug Deliv Rev 97:174–185

    Article  CAS  PubMed  Google Scholar 

  • Nikolova V, Koo CY, Ibrahim SA, Wang Z, Spillmann D, Dreier R, Kelsch R, Fischgrabe J, Smollich M, Rossi LH, Sibrowski W, Wulfing P, Kiesel L, Yip GW, Gotte M (2009) Differential roles for membrane-bound and soluble syndecan-1 (CD138) in breast cancer progression. Carcinogenesis 30:397–407

    Article  CAS  PubMed  Google Scholar 

  • Nishihara T, Remacle AG, Angert M, Shubayev I, Shiryaev SA, Liu H, Dolkas J, Chernov AV, Strongin AY, Shubayev VI (2015) Matrix metalloproteinase-14 both sheds cell surface neuronal glial antigen 2 (NG2) proteoglycan on macrophages and governs the response to peripheral nerve injury. J Biol Chem 290:3693–3707

    Article  CAS  PubMed  Google Scholar 

  • Oh SY, Knelson EH, Blobe GC, Mythreye K (2013) The type III TGFbeta receptor regulates filopodia formation via a Cdc42-mediated IRSp53-N-WASP interaction in epithelial cells. Biochem J 454:79–89

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Olumi AF, Grossfeld GD, Hayward SW, Carroll PR, Tlsty TD, Cunha GR (1999) Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res 59:5002–5011

    CAS  PubMed  Google Scholar 

  • Paget S (1889) The distribution of secondary growths in cancer of the breast. Lancet 1:571–573

    Article  Google Scholar 

  • Park SY, Kim HM, Koo JS (2015) Differential expression of cancer-associated fibroblast-related proteins according to molecular subtype and stromal histology in breast cancer. Breast Cancer Res Treat 149:727–741

    Article  CAS  PubMed  Google Scholar 

  • Pasqualon T, Pruessmeyer J, Jankowski V, Babendreyer A, Groth E, Schumacher J, Koenen A, Weidenfeld S, Schwarz N, Denecke B, Jahr H, Dreymueller D, Jankowski J, Ludwig A (2015) A cytoplasmic C-terminal fragment of Syndecan-1 is generated by sequential proteolysis and antagonizes Syndecan-1 dependent lung tumor cell migration. Oncotarget 6:31295–31312

    PubMed  PubMed Central  Google Scholar 

  • Piperigkou Z, Karamanou K, Afratis NA, Bouris P, Gialeli C, Belmiro CL, Pavao MS, Vynios DH, Tsatsakis AM (2016) Biochemical and toxicological evaluation of nano-heparins in cell functional properties, proteasome activation and expression of key matrix molecules. Toxicol Lett 240:32–42

    Article  CAS  PubMed  Google Scholar 

  • Price MA, Colvin Wanshura LE, Yang J, Carlson J, Xiang B, Li G, Ferrone S, Dudek AZ, Turley EA, McCarthy JB (2011) CSPG4, a potential therapeutic target, facilitates malignant progression of melanoma. Pigment Cell Melanoma Res 24:1148–1157

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Pruessmeyer J, Martin C, Hess FM, Schwarz N, Schmidt S, Kogel T, Hoettecke N, Schmidt B, Sechi A, Uhlig S, Ludwig A (2010) A disintegrin and metalloproteinase 17 (ADAM17) mediates inflammation-induced shedding of syndecan-1 and -4 by lung epithelial cells. J Biol Chem 285:555–564

    Article  CAS  PubMed  Google Scholar 

  • Purushothaman A, Uyama T, Kobayashi F, Yamada S, Sugahara K, Rapraeger AC, Sanderson RD (2010) Heparanase-enhanced shedding of syndecan-1 by myeloma cells promotes endothelial invasion and angiogenesis. Blood 115:2449–2457

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rapraeger AC (2013) Synstatin: a selective inhibitor of the syndecan-1-coupled IGF1R-alphavbeta3 integrin complex in tumorigenesis and angiogenesis. FEBS J 280:2207–2215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rehm M, Bruegger D, Christ F, Conzen P, Thiel M, Jacob M, Chappell D, Stoeckelhuber M, Welsch U, Reichart B, Peter K, Becker BF (2007) Shedding of the endothelial glycocalyx in patients undergoing major vascular surgery with global and regional ischemia. Circulation 116:1896–1906

    Article  CAS  PubMed  Google Scholar 

  • Reizes O, Benoit SC, Strader AD, Clegg DJ, Akunuru S, Seeley RJ (2003) Syndecan-3 modulates food intake by interacting with the melanocortin/AgRP pathway. Ann N Y Acad Sci 994:66–73

    Article  CAS  PubMed  Google Scholar 

  • Rodriguez-Manzaneque JC, Carpizo D, Plaza-Calonge Mdel C, Torres-Collado AX, Thai SN, Simons M, Horowitz A, Iruela-Arispe ML (2009) Cleavage of syndecan-4 by ADAMTS1 provokes defects in adhesion. Int J Biochem Cell Biol 41:800–810

    Article  CAS  PubMed  Google Scholar 

  • Sakry D, Neitz A, Singh J, Frischknecht R, Marongiu D, Biname F, Perera SS, Endres K, Lutz B, Radyushkin K, Trotter J, Mittmann T (2014) Oligodendrocyte precursor cells modulate the neuronal network by activity-dependent ectodomain cleavage of glial NG2. PLoS Biol 12:e1001993

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Schaefer L, Schaefer RM (2010) Proteoglycans: from structural compounds to signaling molecules. Cell Tissue Res 339:237–246

    Article  CAS  PubMed  Google Scholar 

  • Schmidt A, Echtermeyer F, Alozie A, Brands K, Buddecke E (2005) Plasmin- and thrombin-accelerated shedding of syndecan-4 ectodomain generates cleavage sites at Lys(114)-Arg(115) and Lys(129)-Val(130) bonds. J Biol Chem 280:34441–34446

    Article  CAS  PubMed  Google Scholar 

  • Schultz N, Nielsen HM, Minthon L, Wennstrom M (2014) Involvement of matrix metalloproteinase-9 in amyloid-beta 1-42-induced shedding of the pericyte proteoglycan NG2. J Neuropathol Exp Neurol 73:684–692

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Seidel C, Ringden O, Remberger M (2003) Increased levels of syndecan-1 in serum during acute graft-versus-host disease. Transplantation 76:423–426

    Article  PubMed  Google Scholar 

  • Sieuwerts AM, Klijn JG, Henzen-Logmand SC, Bouwman I, Van Roozendaal KE, Peters HA, Setyono-Han B, Foekens JA (1998) Urokinase-type-plasminogen-activator (uPA) production by human breast (myo) fibroblasts in vitro: influence of transforming growth factor-beta(1) [TGF beta(1)] compared with factor(s) released by human epithelial-carcinoma cells. Int J Cancer 76:829–835

  • Skandalis SS, Labropoulou VT, Ravazoula P, Likaki-Karatza E, Dobra K, Kalofonos HP, Karamanos NK, Theocharis AD (2011) Versican but not decorin accumulation is related to malignancy in mammographically detected high density and malignant-appearing microcalcifications in non-palpable breast carcinomas. BMC Cancer 11:314

    Article  PubMed  PubMed Central  Google Scholar 

  • Sofeu Feugaing DD, Gotte M, Viola M (2013) More than matrix: the multifaceted role of decorin in cancer. Eur J Cell Biol 92:1–11

    Article  CAS  PubMed  Google Scholar 

  • Steppan J, Hofer S, Funke B, Brenner T, Henrich M, Martin E, Weitz J, Hofmann U, Weigand MA (2011) Sepsis and major abdominal surgery lead to flaking of the endothelial glycocalix. J Surg Res 165:136–141

    Article  PubMed  Google Scholar 

  • Stewart MD, Ramani VC, Sanderson RD (2015) Shed syndecan-1 translocates to the nucleus of cells delivering growth factors and inhibiting histone acetylation: a novel mechanism of tumor-host cross-talk. J Biol Chem 290:941–949

    Article  CAS  PubMed  Google Scholar 

  • Su G, Blaine SA, Qiao D, Friedl A (2008) Membrane type 1 matrix metalloproteinase-mediated stromal syndecan-1 shedding stimulates breast carcinoma cell proliferation. Cancer Res 68:9558–9565

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Subramanian SV, Fitzgerald ML, Bernfield M (1997) Regulated shedding of syndecan-1 and -4 ectodomains by thrombin and growth factor receptor activation. J Biol Chem 272:14713–14720

    Article  CAS  PubMed  Google Scholar 

  • Suhovskih AV, Mostovich LA, Kunin IS, Boboev MM, Nepomnyashchikh GI, Aidagulova SV, Grigorieva EV (2013) Proteoglycan expression in normal human prostate tissue and prostate cancer. ISRN Oncol 2013:680136

    PubMed  PubMed Central  Google Scholar 

  • Sun L, Chen C (1997) Expression of transforming growth factor beta type III receptor suppresses tumorigenicity of human breast cancer MDA-MB-231 cells. J Biol Chem 272:25367–25372

    Article  CAS  PubMed  Google Scholar 

  • Szarvas T, Reis H, Kramer G, Shariat SF, Vom Dorp F, Tschirdewahn S, Schmid KW, Kovalszky I, Rubben H (2014) Enhanced stromal syndecan-1 expression is an independent risk factor for poor survival in bladder cancer. Hum Pathol 45:674–682

    Article  CAS  PubMed  Google Scholar 

  • Takahashi Y, Kuwabara H, Yoneda M, Isogai Z, Tanigawa N, Shibayama Y (2012) Versican G1 and G3 domains are upregulated and latent transforming growth factor-beta binding protein-4 is downregulated in breast cancer stroma. Breast Cancer 19:46–53

    Article  PubMed  Google Scholar 

  • Theocharis AD, Skandalis SS, Tzanakakis GN, Karamanos NK (2010) Proteoglycans in health and disease: novel roles for proteoglycans in malignancy and their pharmacological targeting. FEBS J 277:3904–3923

    Article  CAS  PubMed  Google Scholar 

  • Theocharis AD, Gialeli C, Bouris P, Giannopoulou E, Skandalis SS, Aletras AJ, Iozzo RV, Karamanos NK (2014) Cell-matrix interactions: focus on proteoglycan-proteinase interplay and pharmacological targeting in cancer. FEBS J 281:5023–5042

    Article  CAS  PubMed  Google Scholar 

  • Theocharis AD, Skandalis SS, Gialeli C, Karamanos NK (2015a) Extracellular matrix structure. Adv Drug Deliv Rev 97:4-27

    Article  PubMed  CAS  Google Scholar 

  • Theocharis AD, Skandalis SS, Neill T, Multhaupt HA, Hubo M, Frey H, Gopal S, Gomes A, Afratis N, Lim HC, Couchman JR, Filmus J, Sanderson RD, Schaefer L, Iozzo RV, Karamanos NK (2015b) Insights into the key roles of proteoglycans in breast cancer biology and translational medicine. Biochim Biophys Acta 1855:276–300

    CAS  PubMed  PubMed Central  Google Scholar 

  • Traister A, Shi W, Filmus J (2008) Mammalian Notum induces the release of glypicans and other GPI-anchored proteins from the cell surface. Biochem J 410:503–511

    Article  CAS  PubMed  Google Scholar 

  • Tsonis AI, Afratis N, Gialeli C, Ellina MI, Piperigkou Z, Skandalis SS, Theocharis AD, Tzanakakis GN, Karamanos NK (2013) Evaluation of the coordinated actions of estrogen receptors with epidermal growth factor receptor and insulin-like growth factor receptor in the expression of cell surface heparan sulfate proteoglycans and cell motility in breast cancer cells. FEBS J 280:2248–2259

    Article  CAS  PubMed  Google Scholar 

  • Vassilakopoulos TP, Kyrtsonis MC, Papadogiannis A, Nadali G, Angelopoulou MK, Tzenou T, Dimopoulou MN, Siakantaris MP, Kontopidou FN, Kalpadakis C, Kokoris SI, Dimitriadou EM, Tsaftaridis P, Pizzolo G, Pangalis GA (2005) Serum levels of soluble syndecan-1 in Hodgkin’s lymphoma. Anticancer Res 25:4743–4746

    CAS  PubMed  Google Scholar 

  • Velasco-Loyden G, Arribas J, Lopez-Casillas F (2004) The shedding of betaglycan is regulated by pervanadate and mediated by membrane type matrix metalloprotease-1. J Biol Chem 279:7721–7733

    Article  CAS  PubMed  Google Scholar 

  • Vijaya Kumar A, Salem Gassar E, Spillmann D, Stock C, Sen YP, Zhang T, Van Kuppevelt TH, Hulsewig C, Koszlowski EO, Pavao MS, Ibrahim SA, Poeter M, Rescher U, Kiesel L, Koduru S, Yip GW, Gotte M (2014) HS3ST2 modulates breast cancer cell invasiveness via MAP kinase- and Tcf4 (Tcf7l2)-dependent regulation of protease and cadherin expression. Int J Cancer 135:2579–2592

    Article  CAS  PubMed  Google Scholar 

  • Vogelstein B, Kinzler KW (1993) The multistep nature of cancer. Trends Genet 9:138–141

    Article  CAS  PubMed  Google Scholar 

  • Wang Z, Gotte M, Bernfield M, Reizes O (2005) Constitutive and accelerated shedding of murine syndecan-1 is mediated by cleavage of its core protein at a specific juxtamembrane site. Biochemistry 44:12355–12361

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Webber J, Steadman R, Mason MD, Tabi Z, Clayton A (2010) Cancer exosomes trigger fibroblast to myofibroblast differentiation. Cancer Res 70:9621–9630

    Article  CAS  PubMed  Google Scholar 

  • Wight TN, Kang I, Merrilees MJ (2014) Versican and the control of inflammation. Matrix Biol 35:152–161

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang Y, Yaccoby S, Liu W, Langford JK, Pumphrey CY, Theus A, Epstein J, Sanderson RD (2002) Soluble syndecan-1 promotes growth of myeloma tumors in vivo. Blood 100:610–617

    Article  CAS  PubMed  Google Scholar 

  • Yip GW, Smollich M, Gotte M (2006) Therapeutic value of glycosaminoglycans in cancer. Mol Cancer Ther 5:2139–2148

    Article  CAS  PubMed  Google Scholar 

  • You HJ, How T, Blobe GC (2009) The type III transforming growth factor-beta receptor negatively regulates nuclear factor kappa B signaling through its interaction with beta-arrestin2. Carcinogenesis 30:1281–1287

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • You WK, Yotsumoto F, Sakimura K, Adams RH, Stallcup WB (2014) NG2 proteoglycan promotes tumor vascularization via integrin-dependent effects on pericyte function. Angiogenesis 17:61–76

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Gynecology and Obstetrics, Münster University Hospital, Münster, Germany

    Zoi Piperigkou, Benedikt Mohr & Martin Götte

  2. Biochemistry, Biochemical Analysis & Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, 26500, Patras, Greece

    Zoi Piperigkou & Nikos Karamanos

Authors
  1. Zoi Piperigkou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Benedikt Mohr
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nikos Karamanos
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Martin Götte
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Martin Götte.

Ethics declarations

Conflict of interest

The authors declare that no conflicts of interest exist.

Additional information

Original research on the topic of this review was funded by the program Research Grants - Short-Term Grants, 2016 of the German Academic Exchange Service DAAD, grant no. 57214227 to Z.P. and by EU H2020 RISE-MSCA Project grant number 645756 (GLYCANC) to M.G. and N.K.K.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Piperigkou, Z., Mohr, B., Karamanos, N. et al. Shed proteoglycans in tumor stroma. Cell Tissue Res 365, 643–655 (2016). https://doi.org/10.1007/s00441-016-2452-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00441-016-2452-4

Keywords

Search

Navigation