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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 Research4.48
· DOI :10.1158/1541-7786.MCR-16-0103
Thomas M. Clausen9
Estimated H-index: 9
,
Marina Ayres Pereira5
Estimated H-index: 5
(UCPH: University of Copenhagen)
+ 14 AuthorsAli Salanti35
Estimated H-index: 35
(UCPH: 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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  • References (58)
  • Citations (13)
References58
Newest
#1Ali Salanti (UCPH: University of Copenhagen)H-Index: 35
#2Thomas M. ClausenH-Index: 9
Last.Bradley John Hedberg (Centre for Drug Research and Development)H-Index: 3
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#1Salomé S. PinhoH-Index: 15
#2Celso A. Reis (Institute of Molecular Pathology and Immunology of the University of Porto)H-Index: 44
#1Angeliki Korpetinou (University of Patras)H-Index: 6
#2Spyros S. Skandalis (University of Patras)H-Index: 20
Last.Anna M. Blom (Lund University)H-Index: 53
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#1Zeyana Rivera (UH: University of Hawaii)H-Index: 7
#2Soldano FerroneH-Index: 89
Last.Michele Carbone (U.H.: University of Hawaii at Manoa)H-Index: 45
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#1Nikos Afratis (University of Patras)H-Index: 6
#2Chrisostomi Gialeli (University of Patras)H-Index: 11
Last.Nikos K. Karamanos (University of Patras)H-Index: 40
view all 9 authors...
#1Elena Garusi (University of Parma)H-Index: 1
#2Silvia Rossi (University of Parma)H-Index: 3
Last.Roberto Perris (University of Parma)H-Index: 31
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#1Matthew Price (UMN: University of Minnesota)H-Index: 41
#2Leah E. Colvin Wanshura (UMN: University of Minnesota)H-Index: 2
Last.James B. McCarthy (UMN: University of Minnesota)H-Index: 62
view all 10 authors...
Cited By13
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#1Adam Pudełko (Medical University of Silesia)H-Index: 4
#2Grzegorz Wisowski (Medical University of Silesia)H-Index: 7
Last.Ewa M. Koźma (Medical University of Silesia)H-Index: 4
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#1Mette Ø. Agerbæk (Copenhagen University Hospital)H-Index: 7
#2Sara R. Bang-Christensen (Copenhagen University Hospital)H-Index: 2
Last.Ali Salanti (Copenhagen University Hospital)H-Index: 35
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#1Mette Ø. Agerbæk (Vancouver Prostate Centre)H-Index: 7
#2Sara R. Bang-Christensen (Copenhagen University Hospital)H-Index: 2
Last.Tobias Gustavsson (Copenhagen University Hospital)H-Index: 8
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#1Htoo Zarni Oo (Vancouver Prostate Centre)H-Index: 13
#2Roland Seiler (University of Bern)H-Index: 18
Last.Mads Daugaard (Vancouver Prostate Centre)H-Index: 15
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