Gastric Adenocarcinomas Express the Glycosphingolipid Gb3/CD77: Targeting of Gastric Cancer Cells with Shiga Toxin B-Subunit
Gastric Adenocarcinomas Express the Glycosphingolipid Gb3/CD77: Targeting of Gastric Cancer Cells with Shiga Toxin B-Subunit
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DOI：
10.1158/1535-7163.mct-15-0633
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发表时间：
2016-05-01
影响因子：
5.7
通讯作者：
Janssen, Klaus-Peter
中科院分区：
文献类型：
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作者：
Geyer, Philipp Emanuel;Maak, Matthias;Janssen, Klaus-Peter
细菌性志贺毒素（STxB）的b亚基是无毒的，免疫原性低，可用于乳腺癌、结肠癌和胰腺癌的肿瘤靶向治疗。在这里，我们测试了人类胃癌（最具侵袭性的肿瘤实体之一）是否表达志贺毒素的细胞受体，糖鞘脂球三烷基神经酰胺（Gb(3)/CD77）。大多数病例显示广泛的Gb(3)染色（36/50例，72%），手术切除标本的组织切片证明了这一点。Gb(3)的表达与类型（弥漫性/肠型）无关，与肿瘤-淋巴结-转移分期的增加呈负相关（P = 0.0385），并与衰老标志物呈负相关。Gb(3)在未患病胃黏膜中的表达仅限于胃腺底部的主细胞和壁细胞，在胃炎的内镜标本中不升高（n = 10）。Gb(3)在已建立的胃癌细胞系中的表达具有异质性，流式细胞术证实，10株细胞系中有6株表达阳性。STxB被活的Gb(3)阳性胃癌细胞迅速吸收，遵循细胞内逆行运输途径，避开溶酶体，迅速到达高尔基体和内质网。用STxB偶联拓扑异构酶I型抑制剂伊立替康的活性代谢物SN38处理表达Gb(3)的胃癌细胞株St3051，与单独使用伊立替康相比，其细胞毒性增加了100倍。对缺乏Gb(3)表达的胃癌细胞系未观察到细胞毒性，表明STxB-SN38化合物具有受体特异性。因此，STxB是胃癌细胞毒性药物的高度特异性转运载体。(c) 2016年aacr。
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.