Targeting Human Cancer by a Glycosaminoglycan Binding Malaria Protein.

Abstract

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.

• Authors: Ali Salanti, Thomas M Clausen, Mette Ø Agerbæk, Nader Al Nakouzi, Madeleine Dahlbäck, Htoo Zarni Oo, Sherry Lee, Tobias Gustavsson, Jamie R Rich, Bradley J Hedberg, Yang Mao, Line Barington, Marina A Pereira, Janine LoBello, Makoto Endo, Ladan Fazli, Jo Soden, Chris K Wang, Adam F Sander, Robert Dagil, Susan Thrane, Peter J Holst, Le Meng, Francesco Favero, Glen J Weiss, Morten A Nielsen, Jim Freeth, Torsten O Nielsen, Joseph Zaia, Nhan L Tran, Jeff Trent, John S Babcook, Thor G Theander, Poul H Sorensen, Mads Daugaard
• Journal: Cancer cell (Cancer Cell) Vol. 28 Issue 4 Pg. 500-514 (10 12 2015) ISSN: 1878-3686 [Electronic] United States
• PMID: 26461094 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Antigens, Protozoan
• CD44 protein, human
• CSPG4 protein, human
• Chondroitin Sulfate Proteoglycans
• Hyaluronan Receptors
• Membrane Proteins
• Oligopeptides
• Recombinant Proteins
• VAR2CSA protein, Plasmodium falciparum
• hemiasterlin
• Chondroitin Sulfates

Topics

• Animals
• Antigens, Protozoan (genetics, metabolism)
• Cell Line, Tumor
• Chondroitin Sulfate Proteoglycans (metabolism)
• Chondroitin Sulfates (metabolism)
• Female
• HEK293 Cells
• Human Umbilical Vein Endothelial Cells
• Humans
• Hyaluronan Receptors (metabolism)
• Melanoma, Experimental (metabolism, therapy)
• Membrane Proteins (metabolism)
• Mice
• Molecular Targeted Therapy
• Oligopeptides (genetics, metabolism)
• Organ Specificity
• Placenta (metabolism)
• Pregnancy
• Recombinant Proteins (administration & dosage, pharmacology)
• Skin Neoplasms (metabolism, therapy)