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Journal Article

Gastric Adenocarcinomas Express the Glycosphingolipid Gb(3)/CD77: Targeting of Gastric Cancer Cells with Shiga Toxin B-Subunit


Geyer,  Philipp Emanuel
Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society;

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Geyer, P. E., Maak, M., Nitsche, U., Perl, M., Novotny, A., Slotta-Huspenina, J., et al. (2016). Gastric Adenocarcinomas Express the Glycosphingolipid Gb(3)/CD77: Targeting of Gastric Cancer Cells with Shiga Toxin B-Subunit. Molecular Cancer Therapeutics, 15(5), 1008-1017. doi:10.1158/1535-7163.MCT-15-0633.

Cite as: https://hdl.handle.net/11858/00-001M-0000-002A-E481-8
The B-subunit of the bacterial Shiga toxin (STxB), which is nontoxic and has low immunogenicity, can be used for tumor targeting of breast, colon, and pancreatic cancer. Here, we tested whether human gastric cancers, which are among the most aggressive tumor entities, express the cellular receptor of Shiga toxin, the glycosphingolipid globotriaosylceramide (Gb(3)/CD77). The majority of cases showed an extensive staining for Gb(3) (36/50 cases, 72%), as evidenced on tissue sections of surgically resected specimen. Gb(3) expression was detected independent of type (diffuse/intestinal), and was negatively correlated to increasing tumor-node-metastasis stages (P = 0.0385), as well as with markers for senescence. Gb(3) expression in nondiseased gastric mucosa was restricted to chief and parietal cells at the bottom of the gastric glands, and was not elevated in endoscopic samples of gastritis (n = 10). Gb(3) expression in established cell lines of gastric carcinoma was heterogeneous, with 6 of 10 lines being positive, evidenced by flow cytometry. STxB was taken up rapidly by live Gb(3)-positive gastric cancer cells, following the intracellular retrograde transport route, avoiding lysosomes and rapidly reaching the Golgi apparatus and the endoplasmic reticulum. Treatment of the Gb(3)-expressing gastric carcinoma cell line St3051 with STxB coupled to SN38, the active metabolite of the topoisomerase type I inhibitor irinotecan, resulted in >100-fold increased cytotoxicity, as compared with irinotecan alone. No cytotoxicity was observed on gastric cancer cell lines lacking Gb(3) expression, demonstrating receptor specificity of the STxB-SN38 compound. Thus, STxB is a highly specific transport vehicle for cytotoxic agents in gastric carcinoma. (C) 2016 AACR.