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Oncofetal Chondroitin Sulfate Glycosaminoglycans Are Key Players in Integrin Signaling and Tumor Cell Motility

Published on Dec 1, 2016in Molecular Cancer Research 4.60
· DOI :10.1158/1541-7786.MCR-16-0103
Thomas M. Clausen9
Estimated H-index: 9
,
Marina Ayres Pereira5
Estimated H-index: 5
(University of Copenhagen)
+ 14 AuthorsAli Salanti35
Estimated H-index: 35
(University of Copenhagen)
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-β1 (ITGB1) and integrin-α4 (ITGA4). Saturating concentrations of rVAR2 inhibited downstream integrin signaling, which was mimicked by knockdown of the core chondroitin sulfate synthesis enzymes β-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 preincubation 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 ofCS aids in metastatic phenotypes and is a candidate target for therapy. Mol Cancer Res; 14(12); 1288–99. ©2016 AACR .
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  • Citations (13)
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References58
Newest
Published on Oct 1, 2015in Cancer Cell 22.84
Ali Salanti35
Estimated H-index: 35
(University of Copenhagen),
Thomas M. Clausen9
Estimated H-index: 9
+ 32 AuthorsBradley John Hedberg3
Estimated H-index: 3
(Centre for Drug Research and Development)
Plasmodium falciparum engineer infected erythrocytes to present the malarial protein, VAR2CSA, which binds a distinct type chondroitin sulfate (CS) exclusively expressed in the placenta. Here, we show that the same CS modification is present on a high proportion of malignant cells and that it can be specifically targeted by recombinant VAR2CSA (rVAR2). In tumors, placental-like CS chains are linked to a limited repertoire of cancer-associated proteoglycans including CD44 and CSPG4. The rVAR2 pro...
48 Citations Source Cite
Published on Sep 1, 2015in Nature Reviews Cancer 42.78
Salomé S. Pinho15
Estimated H-index: 15
,
Celso A. Reis44
Estimated H-index: 44
(Institute of Molecular Pathology and Immunology of the University of Porto)
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.
505 Citations Source Cite
Published on Jul 1, 2014in Nature 41.58
Matthew J. Paszek9
Estimated H-index: 9
,
Christopher C. DuFort7
Estimated H-index: 7
+ 17 AuthorsLuke Cassereau7
Estimated H-index: 7
Metastatic cancer cells are shown to have a tendency towards forming a bulky glycocalyx owing to the production of large glycoproteins, and this cancer-associated glycocalyx has a mechanical effect on the spatial organization of integrins — by funnelling integrins into adhesions, integrin clustering and signalling is promoted, which leads to enhanced cell survival and proliferation.
231 Citations Source Cite
Published on Oct 31, 2013in PLOS ONE 2.77
Angeliki Korpetinou6
Estimated H-index: 6
(University of Patras),
Spyros S. Skandalis20
Estimated H-index: 20
(University of Patras)
+ 9 AuthorsAnna M. Blom53
Estimated H-index: 53
(Lund University)
Serglycin is a proteoglycan expressed by some malignant cells. It promotes metastasis and protects some tumor cells from complement system attack. In the present study, we show for the first time the in situ expression of serglycin by breast cancer cells by immunohistochemistry in patients' material. Moreover, we demonstrate high expression and constitutive secretion of serglycin in the aggressive MDA-MB-231 breast cancer cell line. Serglycin exhibited a strong cytoplasmic staining in these cell...
30 Citations Source Cite
Published on Dec 21, 2012in Journal of Biological Chemistry 4.01
Nobuo Sugiura15
Estimated H-index: 15
,
Tatsumasa Shioiri3
Estimated H-index: 3
+ 4 AuthorsHideto Watanabe25
Estimated H-index: 25
Abstract Chondroitin sulfate (CS) is a linear acidic polysaccharide, composed of repeating disaccharide units of glucuronic acid and N-acetyl-d-galactosamine and modified with sulfate residues at different positions, which plays various roles in development and disease. Here, we chemo-enzymatically synthesized various CS species with defined lengths and defined sulfate compositions, from chondroitin hexasaccharide conjugated with hexamethylenediamine at the reducing ends, using bacterial chondro...
30 Citations Source Cite
Published on Oct 1, 2012in Clinical Cancer Research 10.20
Zeyana Rivera7
Estimated H-index: 7
(University of Hawaii),
Soldano Ferrone89
Estimated H-index: 89
+ 6 AuthorsMichele Carbone45
Estimated H-index: 45
(University of Hawaii at Manoa)
Purpose: Malignant mesothelioma (MM) is an aggressive cancer, resistant to current therapies. Membrane chondroitin sulphate proteoglycan 4 (CSPG4), which has been successfully targeted in melanoma and breast cancer, was found highly expressed in MM, but not in normal mesothelium. Therefore, we explored CSPG4 as a suitable target for monoclonal antibody (mAb)–based immunotherapy for MM. Experimental design: We assayed adhesion, motility, invasiveness, wound-healing, apoptosis, and anchorage-indep...
36 Citations Source Cite
Published on Jul 6, 2012in Journal of Biological Chemistry 4.01
Thomas M. Clausen9
Estimated H-index: 9
,
Stig Christoffersen4
Estimated H-index: 4
+ 12 AuthorsSisse B. Ditlev14
Estimated H-index: 14
Malaria is a major global health problem. Pregnant women are susceptible to infection regardless of previously acquired immunity. Placental malaria is caused by parasites capable of sequestering in the placenta. This is mediated by VAR2CSA, a parasite antigen that interacts with chondroitin sulfate A (CSA). One vaccine strategy is to block this interaction with VAR2CSA-specific antibodies. It is a priority to define a small VAR2CSA fragment that can be used in an adhesion blocking vaccine. In th...
88 Citations Source Cite
Published on Apr 1, 2012in FEBS Journal 4.53
Nikos Afratis6
Estimated H-index: 6
(University of Patras),
Chrisostomi Gialeli11
Estimated H-index: 11
(University of Patras)
+ 6 AuthorsNikos K. Karamanos40
Estimated H-index: 40
(University of Patras)
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...
234 Citations Source Cite
Published on Feb 1, 2012in Cellular and Molecular Life Sciences 6.72
Elena Garusi1
Estimated H-index: 1
(University of Parma),
Silvia Rossi3
Estimated H-index: 3
(University of Parma),
Roberto Perris31
Estimated H-index: 31
(University of Parma)
Proteoglycans (PGs), a family of complex post-translationally sculptured macromolecules, are fundamental regulators of most normal and aberrant cellular functions. The unparalleled structural–functional diversity of PGs endows them with the ability to serve as critical mediators of the tumor cells’ interaction with the host microenvironment, while directly contributing to the organization and dynamic remodeling of this milieu. Despite their indisputable importance during embryonic development an...
20 Citations Source Cite
Published on Dec 1, 2011in Pigment Cell & Melanoma Research 6.12
Matthew Price41
Estimated H-index: 41
(University of Minnesota),
Leah E. Colvin Wanshura2
Estimated H-index: 2
(University of Minnesota)
+ 7 AuthorsJames B. McCarthy62
Estimated H-index: 62
(University of Minnesota)
Chondroitin sulfate proteoglycan 4 (CSPG4), a transmembrane proteoglycan originally identified as a highly immunogenic tumor antigen on the surface of melanoma cells, is associated with melanoma tumor formation and poor prognosis in certain melanomas and several other tumor types. The complex mechanisms by which CSPG4 affects melanoma progression have started to be defined, in particular the association with other cell surface proteins and receptor tyrosine kinases (RTKs) and its central role in...
71 Citations Source Cite
Cited By13
Newest
Published on May 1, 2019in FEBS Journal 4.53
Adam Pudełko4
Estimated H-index: 4
(Medical University of Silesia),
Grzegorz Wisowski7
Estimated H-index: 7
(Medical University of Silesia)
+ 1 AuthorsEwa M. Koźma4
Estimated H-index: 4
(Medical University of Silesia)
4 Citations Source Cite
Published on Mar 1, 2019in Trends in Parasitology 7.93
Mette Ø. Agerbæk7
Estimated H-index: 7
(Copenhagen University Hospital),
Sara R. Bang-Christensen1
Estimated H-index: 1
(Copenhagen University Hospital),
Ali Salanti35
Estimated H-index: 35
(Copenhagen University Hospital)
Malaria research has led to the discovery of oncofetal chondroitin sulfate, which appears to be shared between placental trophoblasts and cancer cells and can be detected by the evolutionary refined malaria protein VAR2CSA. Interestingly, using recombinant VAR2CSA to target oncofetal chondroitin sulfate shows promise for novel cancer diagnostics and therapeutics.
1 Citations Source Cite
Published on Dec 27, 2018in The Journal of Infectious Diseases 5.19
Sofie L. Moeller1
Estimated H-index: 1
,
Jens R. Nyengaard52
Estimated H-index: 52
(Aarhus University)
+ 7 AuthorsChristentze Schmiegelow12
Estimated H-index: 12
(University of Copenhagen)
1 Citations Source Cite
Published on Dec 1, 2018in Nature Communications 12.35
Mette Ø. Agerbæk7
Estimated H-index: 7
(Vancouver Prostate Centre),
Sara R. Bang-Christensen1
Estimated H-index: 1
(Copenhagen University Hospital)
+ 16 AuthorsTobias Gustavsson8
Estimated H-index: 8
(Copenhagen University Hospital)
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...
13 Citations Source Cite
Published on Nov 12, 2018in Frontiers in Oncology
Claudia Rossig24
Estimated H-index: 24
,
Sareetha Kailayangiri8
Estimated H-index: 8
+ 1 AuthorsBianca Altvater15
Estimated H-index: 15
2 Citations Source Cite
Htoo Zarni Oo13
Estimated H-index: 13
(Vancouver Prostate Centre),
Roland Seiler18
Estimated H-index: 18
(University of Bern)
+ 1 AuthorsMads Daugaard15
Estimated H-index: 15
(Vancouver Prostate Centre)
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...
1 Citations Source Cite
Published on Dec 19, 2017in The Journal of Infectious Diseases 5.19
Christentze Schmiegelow12
Estimated H-index: 12
(University of Copenhagen),
Sungwa Matondo4
Estimated H-index: 4
(Kilimanjaro Christian Medical College)
+ 9 AuthorsAli Salanti35
Estimated H-index: 35
(University of Copenhagen)
7 Citations Source Cite
Published on Nov 1, 2017in Matrix Biology 8.14
Achilleas D. Theocharis33
Estimated H-index: 33
(University of Patras),
Nikos K. Karamanos40
Estimated H-index: 40
(University of Patras)
Abstract Extracellular matrix is a highly dynamic macromolecular network. Proteoglycans are major components of extracellular matrix playing key roles in its structural organization and cell signaling contributing to the control of numerous normal and pathological processes. As multifunctional molecules, proteoglycans participate in various cell functions during morphogenesis, wound healing, inflammation and tumorigenesis. Their interactions with matrix effectors, cell surface receptors and enzy...
23 Citations Source Cite
Published on Jul 1, 2017in European Urology 17.58
Roland Seiler18
Estimated H-index: 18
(University of Bern),
Htoo Zarni Oo13
Estimated H-index: 13
(Vancouver Prostate Centre)
+ 27 AuthorsTobias Gustavsson8
Estimated H-index: 8
(University of Copenhagen)
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...
7 Citations Source Cite