Targeting Human Cancer by a Glycosaminoglycan Binding Malaria Protein

Ali Salanti, Thomas M Clausen, Mette Ø Agerbæk, Nader Al Nakouzi, Madeleine Dahlbäck, Htoo Z Oo, Sherry Lee, Tobias Gustavsson, Jamie R Rich, Bradley J Hedberg, Yang Mao, Line Alsøe Barington, Marina A Pereira, Janine LoBello, Makoto Endo, Ladan Fazli, Jo Soden, Chris K Wang, Adam F Sander, Robert DagilSusan Thrane, Peter J Holst, Le Meng, Francesco Favero, Glen J Weiss, Morten A Nielsen, Jim Freeth, Torsten Nielsen, Joseph Zaia, Nhan L Tran, Jeff Trent, John S Babcook, Thor G Theander, Poul H Sorensen, Mads Daugaard

    126 Citationer (Scopus)

    Abstrakt

    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 protein localizes to tumors in vivo and rVAR2 fused to diphtheria toxin or conjugated to hemiasterlin compounds strongly inhibits in vivo tumor cell growth and metastasis. Our data demonstrate how an evolutionarily refined parasite-derived protein can be exploited to target a common, but complex, malignancy-associated glycosaminoglycan modification.

    OriginalsprogEngelsk
    TidsskriftCancer Cell
    Vol/bind28
    Udgave nummer4
    Sider (fra-til)500-14
    Antal sider15
    ISSN1535-6108
    DOI
    StatusUdgivet - 12 okt. 2015

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