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Oncofetal Chondroitin Sulfate Glycosaminoglycans Are Key Players in Integrin Signaling and Tumor Cell Motility
Abstract
Many tumors express proteoglycans modified with oncofetal chondroitin sulfate glycosaminoglycan chains (ofCS), which are normally restricted to the placenta. However, the role of ofCS in cancer is largely unknown. The function of ofCS in cancer was analyzed using the recombinant ofCS-binding VAR2CSA protein (rVAR2) derived from the malaria parasite, Plasmodium falciparum. We demonstrate that ofCS plays a key role in tumor cell motility by affecting canonical integrin signaling pathways. Binding of rVAR2 to tumor cells inhibited the interaction of cells with extracellular matrix (ECM) components, which correlated with decreased phosphorylation of Src kinase. Moreover, rVAR2 binding decreased migration, invasion and anchorage-independent growth of tumor cells in vitro. Mass spectrometry of ofCS-modified proteoglycan complexes affinity purified from tumor cell lines on rVAR2 columns, revealed an overrepresentation of proteins involved in cell motility and integrin signaling, such as integrin beta1 (ITGB1) and integrin alpha4 (ITGA4). Saturating concentrations of rVAR2 inhibited downstream integrin signaling, which was mimicked by knockdown of the core CS synthesis enzymes Beta-1,3-Glucuronyltransferase 1 (B3GAT1) and Chondroitin Sulfate N-Acetylgalactosaminyltransferase 1 (CSGALNACT1). The ofCS modification was highly expressed in both human and murine metastatic lesions in situ and pre-incubation or early intravenous treatment of tumor cells with rVAR2 inhibited seeding and spreading of tumor cells in mice. This was associated with a significant increase in survival of the animals. These data functionally link ofCS modifications with cancer cell motility and further highlights ofCS as a novel therapeutic cancer target. Implications: The cancer specific expression of oncofetal chondroitin sulfate aids in metastatic phenotypes and is a candidate target for therapy.
  • References (57)
  • Cited By (9)
Célia Regina C. Franco11
Estimated H-index: 11
,
Edvaldo S. Trindade12
Estimated H-index: 12
,
Hugo Alexandre Oliveira Rocha24
Estimated H-index: 24
... more
L'integrine α 5 β 1 des cellules CHO sauvages (CHO-K1) et deficientes en biosynthese de proteoglycanes (CHO-745) est modifiee au niveau post-traductionnel par des chaines de glycosaminoglycanes. Nous l'avons demontre a l'aide d'un marquage metabolique des cellules au [ 35 S]sulfate, par degradation enzymatique, par immunoprecipitation a l'aide d'un anticorps monoclonal, par microscopie en fluorescence et par cytometrie de flux. L'heterodimere α 5 β 1 est un proteroglycane hybride contenant des c...
Cited 11
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2015 in Nature Reviews Cancer [IF: 37.15]
Salomé S. Pinho15
Estimated H-index: 15
(Institute of Molecular Pathology and Immunology of the University of Porto),
Celso A. Reis42
Estimated H-index: 42
This Review discusses the importance of glycobiology in cancer research, given its role in cancer development and progression, and provides an overview of possible targets for diagnostic application and therapeutic strategies.
Ref 219Cited 429
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1975 in Cancer Research [IF: 9.12]
P Janik1
Estimated H-index: 1
,
P Briand1
Estimated H-index: 1
,
N R Hartmann1
Estimated H-index: 1
Summary Hormone-dependent mammary tumors were induced in virgin GR mice by treatment with estrone and progesterone. Discontinuation of hormonal treatment was followed by regression of the tumor. This response to hormone treatment was also observed in the first transplant generation in inbred syngeneic hosts, but after several transplantations the tumor growth became hormone independent. The hormone dependence of the primary tumors and tumors after a single transplantation was demonstrated by gro...
Cited 182
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Achilleas D. Theocharis30
Estimated H-index: 30
(University of Crete),
Ioannis A. Tsolakis9
Estimated H-index: 9
(University of Crete),
G.N. Tzanakakis1
Estimated H-index: 1
(University of Crete)
... more
Publisher Summary This chapter discusses the molecular involvement of CS in the progression of two main human diseases: cancer and atherosclerosis. Chondroitin sulfate (CS) is a glycosaminoglycan (GAG) composed of repeating disaccharides of glucuronic acid and N ‐acetyl‐galactosamine, which are variously substituted by sulfate groups. It is covalently attached on several core proteins creating a variety of proteoglycans (PGs) found in the extracellular matrix (ECM) and cell membrane, but also in...
Ref 45Cited 40
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1979 in Cancer Research [IF: 9.12]
E. V. Chandrasekaran1
Estimated H-index: 1
,
Eugene A. Davidson32
Estimated H-index: 32
Abstract Glycosaminoglycans have been characterized from a normal human breast cell line (HBL-100) and two different cell lines from human breast carcinoma (MDA-MB-231 and MCF-7). The glycosaminoglycans were labeled by exposure of cell cultures to [ 3 H]glucosamine and [ 35 S]sulfate and then isolated from both spent media and cells by pronase digestion and cetylpyridinium chloride fractionation. They were further characterized by ( a ) hexosamine composition, ( b ) controlled-pore glass exclusi...
Ref 22Cited 50
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Silvio S. Veiga13
Estimated H-index: 13
(Federal University of Paraná),
M. C.Q.B. Elias3
Estimated H-index: 3
(Ludwig Institute for Cancer Research),
Waldemiro Gremski3
Estimated H-index: 3
(Federal University of Paraná)
... more
Abstract Cell-fibronectin interactions, mediated through several different receptors, have been implicated in a wide variety of cellular properties. Among the cell surface receptors for fibronectin, integrins are the best characterized, particularly the prototype α5β1 integrin. Using [125I]iodine cell surface labeling or metabolic radiolabeling with sodium [35S]sulfate, we identified α5β1 integrin as the only sulfated integrin among β1 integrin heterodimers expressed by the human melanoma cell l...
Ref 48Cited 30
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1995 in Cancer Research [IF: 9.12]
Joji Iida18
Estimated H-index: 18
(University of Minnesota),
Alexandra M. L. Meijne5
Estimated H-index: 5
(University of Minnesota),
Robert Christopher Spiro10
Estimated H-index: 10
... more
Abstract In this study, we evaluated the potential role for a specific melanoma-associated chondroitin sulfate proteoglycan core protein, termed NG2, to collaborate with α4β1 integrin in focal contact formation in human melanoma cells. Although melanoma cells adhered to substrata coated with either the α4β1 integrin binding fibronectin synthetic peptide CS1-OVA or anti-NG2 mAbs, no spreading or focal contact formation was observed on either substratum. However, melanoma cells spread and formed f...
Ref 38Cited 98
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Yanusz Wegrowski15
Estimated H-index: 15
(Centre national de la recherche scientifique),
François-Xavier Maquart21
Estimated H-index: 21
(Centre national de la recherche scientifique)
Publisher Summary This chapter discusses the implication of stromal and cell surface chondroitin sulfate proteoglycans (CSPGs) to the different aspects of tumor growth and metastasis. In a developing tumor, several CSPGs are overexpressed and deposited into extracellular matrix (ECM) during the stromal reaction. The accumulated PGs participate in the organization of ECM and modulate tumor cell behavior. Whereas large CSPGs of the hyalectan (lectican) family, like versican or nervous tissue BEHAB...
Ref 197Cited 30
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2012 in FEBS Journal [IF: 3.90]
Nikos Afratis6
Estimated H-index: 6
(University of Patras),
Chrisostomi Gialeli10
Estimated H-index: 10
(University of Patras),
Dragana Nikitovic24
Estimated H-index: 24
(University of Crete)
... more
Glycosaminoglycans are natural heteropolysaccharides that are present in every mammalian tissue. They are composed of repeating disaccharide units that consist of either sulfated or non-sulfated monosaccharides. Their molecular size and the sulfation type vary depending on the tissue, and their state either as part of proteoglycan or as free chains. In this regard, glycosami-noglycans play important roles in physiological and pathological conditions. During recent years, cell biology studies hav...
Ref 178Cited 216
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2009 in in Vivo
Eleni Fthenou16
Estimated H-index: 16
,
Fang Zong6
Estimated H-index: 6
,
Alexandros Zafiropoulos14
Estimated H-index: 14
... more
Fibrosarcoma is an uncommon soft tissue tumor with a complex cell microenvironment, particularly rich in glycosaminoglycans/proteoglycans (GAGs/PGs). Chondroitin sulfate proteoglycans (CSPGs) participate in the modulation of various cellular functions, including adhesion and migration. The role of chondroitin sulfate (CS) chains on adhesion, chemotaxis and migration of poorly differentiated fibrosarcoma B6FS cell was studied, utilizing exogenous CS treatment and chondroitinase digestions as well...
Ref 44Cited 15 Source
  • References (57)
  • Cited By (9)
Mette Ø. Agerbæk6
Estimated H-index: 6
(Copenhagen University Hospital),
Marina Ayres Pereira4
Estimated H-index: 4
(Copenhagen University Hospital),
Thomas M. Clausen7
Estimated H-index: 7
(Vancouver Prostate Centre)
... more
Burkitt lymphoma (BL) is a malignant disease, which is frequently found in areas with holoendemic Plasmodium falciparum malaria. We have previously found that the VAR2CSA protein is present on malaria-infected erythrocytes and facilitates a highly specific binding to the placenta. ofCS is absent in other non-malignant tissues and thus VAR2CSA generally facilitates parasite sequestration and accumulation in pregnant women. In this study, we show that the specific receptor for VAR2CSA, the oncofet...
Ref 52Cited 2
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Leticia Oliveira-Ferrer12
Estimated H-index: 12
(University of Hamburg),
Karen Legler2
Estimated H-index: 2
(University of Hamburg),
Karin Milde-Langosch36
Estimated H-index: 36
(University of Hamburg)
Abstract Although altered glycosylation has been detected in human cancer cells decades ago, only investigations in the last years have enormously increased our knowledge about the details of protein glycosylation and its role in tumour progression. Many proteins, which are heavily glycosylated, i.e. adhesion proteins or proteases, play an important role in cancer metastasis that represents the crucial and frequently life-threatening step in progression of most tumour types. Compared to normal t...
Ref 136Cited 16
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2017 in Cancers
William B. Stallcup46
Estimated H-index: 46
By physically interacting with beta-1 integrins, the NG2 proteoglycan enhances activation of the integrin heterodimers. In glioma cells, co-localization of NG2 and 31 integrin in individual cells (cis interaction) can be demonstrated by immunolabeling, and the NG2-integrin interaction can be confirmed by co-immunoprecipitation. NG2-dependent integrin activation is detected via use of conformationally sensitive monoclonal antibodies that reveal the activated state of the beta-1 subunit in NG2-p...
Ref 76Cited 7
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Roland Seiler16
Estimated H-index: 16
(University of Bern),
Htoo Zarni Oo11
Estimated H-index: 11
(Vancouver Prostate Centre),
Davide Tortora2
Estimated H-index: 2
(Vancouver Prostate Centre)
... more
Abstract Background Although cisplatin-based neoadjuvant chemotherapy (NAC) improves survival of unselected patients with muscle-invasive bladder cancer (MIBC), only a minority responds to therapy and chemoresistance remains a major challenge in this disease setting. Objective To investigate the clinical significance of oncofetal chondroitin sulfate (ofCS) glycosaminoglycan chains in cisplatin-resistant MIBC and to evaluate these as targets for second-line therapy. Design, setting, and participa...
Ref 30Cited 3
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Christentze Schmiegelow12
Estimated H-index: 12
(University of Copenhagen),
Sungwa Matondo3
Estimated H-index: 3
(Kilimanjaro Christian Medical College),
Daniel T. R. Minja14
Estimated H-index: 14
(National Institute for Medical Research)
... more
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2017 in Matrix Biology [IF: 7.40]
Achilleas D. Theocharis30
Estimated H-index: 30
(University of Patras),
Nikos K. Karamanos39
Estimated H-index: 39
(University of Patras)
• Matrix remodeling in tumor stroma is regulatory for cancer cell phenotype and aggressiveness.
Ref 504Cited 15
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Mette Ø. Agerbæk6
Estimated H-index: 6
(Vancouver Prostate Centre),
Sara R. Bang-Christensen1
Estimated H-index: 1
(Copenhagen University Hospital),
Ming-Hsin Yang2
Estimated H-index: 2
(National Defense Medical Center)
... more
Isolation of metastatic circulating tumor cells (CTCs) from cancer patients is of high value for disease monitoring and molecular characterization. Despite the development of many new CTC isolation platforms in the last decade, their isolation and detection has remained a challenge due to the lack of specific and sensitive markers. In this feasibility study, we present a method for CTC isolation based on the specific binding of the malaria rVAR2 protein to oncofetal chondroitin sulfate (ofCS). W...
Ref 62Cited 4 Download PDF Cite this paper
Htoo Zarni Oo11
Estimated H-index: 11
(Vancouver Prostate Centre),
Roland Seiler16
Estimated H-index: 16
(University of Bern),
Peter C. Black30
Estimated H-index: 30
(Vancouver Prostate Centre)
... more
Over the past decade, genomic and transcriptomic analyses have uncovered promising tumor antigens including immunotherapeutic targets in bladder cancer (BCa). Conventional tumor antigens are proteins expressed on the plasma membrane of tumor cells such as EGFR, FGFR3, and ERBB2 in BCa, which can be targeted by antibodies or similar epitope-specific binding reagents. The cellular proteome consists of ∼100,000 proteins but the expression of these proteins is rarely unique to tumor cells. Many tumo...
Ref 107
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Claudia Rossig20
Estimated H-index: 20
,
Sareetha Kailayangiri4
Estimated H-index: 4
,
Silke Jamitzky2
Estimated H-index: 2
... more
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