title: 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-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.
  
  
  
  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.
authors.affiliation: Centre for Medical Parasitology at Department of International Health, Immunology and Microbiology, University of Copenhagen, Denmark. tmc@sund.ku.dk mads.daugaard@ubc.ca salanti@sund.ku.dk.|Vancouver Prostate Centre, Vancouver, British Columbia, Canada.|Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.|Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada.
authors.forename: Thomas Mandel
authors.initials: TM
authors.lastname: Clausen
authors.affiliation: Centre for Medical Parasitology at Department of International Health, Immunology and Microbiology, University of Copenhagen, Denmark.
authors.forename: Marina Ayres
authors.initials: MA
authors.lastname: Pereira
authors.affiliation: Vancouver Prostate Centre, Vancouver, British Columbia, Canada.|Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Nader
authors.initials: N
authors.lastname: Al Nakouzi
authors.affiliation: Vancouver Prostate Centre, Vancouver, British Columbia, Canada.|Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.|Molecular Pathology and Cell Imaging Laboratory, Vancouver Prostate Centre, Vancouver, British Columbia, Canada.
authors.forename: Htoo Zarni
authors.initials: HZ
authors.lastname: Oo
authors.affiliation: Centre for Medical Parasitology at Department of International Health, Immunology and Microbiology, University of Copenhagen, Denmark.|Vancouver Prostate Centre, Vancouver, British Columbia, Canada.|Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Mette Ø
authors.initials: MØ
authors.lastname: Agerbæk
authors.affiliation: Vancouver Prostate Centre, Vancouver, British Columbia, Canada.
authors.forename: Sherry
authors.initials: S
authors.lastname: Lee
authors.affiliation: Centre for Medical Parasitology at Department of International Health, Immunology and Microbiology, University of Copenhagen, Denmark.|Vancouver Prostate Centre, Vancouver, British Columbia, Canada.
authors.forename: Maj Sofie
authors.initials: MS
authors.lastname: Ørum-Madsen
authors.affiliation: Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada.
authors.forename: Anders Riis
authors.initials: AR
authors.lastname: Kristensen
authors.affiliation: Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada.
authors.forename: Amal
authors.initials: A
authors.lastname: El-Naggar
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Grandgenett
authors.affiliation: Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Jean L
authors.initials: JL
authors.lastname: Grem
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Hollingsworth
authors.affiliation: Centre for Medical Parasitology at Department of International Health, Immunology and Microbiology, University of Copenhagen, Denmark.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Holst
authors.affiliation: Centre for Medical Parasitology at Department of International Health, Immunology and Microbiology, University of Copenhagen, Denmark.
authors.forename: Thor
authors.initials: T
authors.lastname: Theander
authors.affiliation: Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada.
authors.forename: Poul H
authors.initials: PH
authors.lastname: Sorensen
authors.affiliation: Vancouver Prostate Centre, Vancouver, British Columbia, Canada. tmc@sund.ku.dk mads.daugaard@ubc.ca salanti@sund.ku.dk.|Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.|Molecular Pathology and Cell Imaging Laboratory, Vancouver Prostate Centre, Vancouver, British Columbia, Canada.
authors.forename: Mads
authors.initials: M
authors.lastname: Daugaard
authors.affiliation: Centre for Medical Parasitology at Department of International Health, Immunology and Microbiology, University of Copenhagen, Denmark.
authors.forename: Ali
authors.initials: A
authors.lastname: Salanti
mesh_terms: D000818:Animals; D000953:Antigens, Protozoan / Q000235:genetics* / Q000378:metabolism; D018827:Carcinoma, Lewis Lung / Q000378:metabolism; D045744:Cell Line, Tumor; D002809:Chondroitin Sulfates / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D008546:Melanoma, Experimental / Q000378:metabolism; D051379:Mice; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction
chemical_list: D000953:Antigens, Protozoan; D016023:Integrins; C512601:VAR2CSA protein, Plasmodium falciparum; C038142:chondroitin sulfate glycosaminoglycan; D002809:Chondroitin Sulfates