Editors' ChoiceCancer

Finding the good in malaria

Sci. Signal.  20 Oct 2015:
Vol. 8, Issue 399, pp. ec297
DOI: 10.1126/scisignal.aad6490

Malaria is a mosquito-borne infectious disease that can be fatal, particularly to fetuses and newborn babies. The protein VAR2CSA anchors malaria-infected erythrocytes to chondroitin sulfate A (CSA) that is exclusively present on placental cells, thereby promoting their infection. However, Salanti et al. found a way to use this mechanism to kill tumor cells. Cancer cells often reexpress genes that are normally restricted to development. Immunohistochemical staining revealed that placenta-specific CSA was present on the plasma membrane or in the surrounding stroma of various tumor tissues. In melanoma, the abundance of CSA increased with the advanced stage of the tumor. High expression of the gene encoding an enzyme that promotes the maturation of CSA (CHST11) correlated with poor survival in lung cancer patients. In culture, recombinant V5-tagged VAR2CSA (rVAR2) and erythrocytes infected with Plasmodium falciparum expressing VAR2CSA bound to various patient-derived cancer cells but not to normal cells, and this interaction was decreased by the addition of soluble CSA to the medium. Various cancer cells internalized fluorescent-conjugated constructs of rVAR2, and intravenously injected fluorescent-tagged rVARs accumulated in prostate or melanoma tumor xenografts. The use of drugs and natural toxins in cancer therapy is often clinically limited by toxicity. However, administration of drug conjugates in which rVAR2 was fused to either diphtheria toxin or an analog (KT886) of the antimitotic peptide hemiasterlin, a marine sponge extract, was markedly more potent than diphtheria toxin or KT886 alone and selectively killed various tumor cells but not normal cells in culture and killed various tumor xenografts in mice without inducing detectable toxicity in normal tissues. The findings indicate that fusing cytotoxic drugs to VAR2CSA may enable more targeted drug delivery to tumors.

A. Salanti, T. M. Clausen, M. Ø. Agerbæk, N. Al Nakouzi, M. Dahlbäck, H. Z. Oo, S. Lee, T. Gustavsson, J. R. Rich, B. J. Hedberg, Y. Mao, L. Barington, M. A. Pereira, J. LoBello, M. Endo, L. Fazli, J. Soden, C. K. Wang, A. F. Sander, R. Dagil, S. Thrane, P. J. Holst, L. Meng, F. Favero, G. J. Weiss, M. A. Nielsen, J. Freeth, T. O. Nielsen, J. Zaia, N. L. Tran, J. Trent, J. S. Babcook, T. G. Theander, P. H. Sorensen, M. Daugaard, Targeting human cancer by a glycosaminoglycan binding malaria protein. Cancer Cell 28, 500–514 (2015). [PubMed]