Abstract
Pancreatic carcinoma is one of the most aggressive tumor entities, and standard chemotherapy provides only modest benefit. Therefore, specific targeting of pancreatic cancer for early diagnosis and therapeutic intervention is of great interest. We have previously shown that the cellular receptor for Shiga toxin B (STxB), the glycosphingolipid globotriaosylceramide (Gb(3) or CD77) is strongly increased in colorectal adenocarcinoma and their metastases. Here, we report an upregulation of Gb(3) in pancreatic adenocarcinoma (21 of 27 cases) as compared with matched normal tissue (n = 27). The mean expression was highly significantly increased from 30 ± 16 ng Gb(3)/mg tissue in normal pancreas to 61 ± 41 ng Gb(3)/mg tissue (mean ± SD, P = 0.0006), as evidenced by thin layer chromatography. Upregulation of Gb(3) levels did not depend on tumor stage or grading and showed no correlation with clinical outcome. Tumor cells and endothelial cells were identified as the source of increased Gb(3) expression by immunocytochemistry. Pancreatic cancer cell lines showed rapid intracellular uptake of STxB to the Golgi apparatus, following the retrograde pathway. The therapeutic application of STxB was tested by specific delivery of covalently coupled SN38, an active metabolite of the topoisomerase I inhibitor irinotecan. The cytotoxic effect of the STxB-SN38 compound in pancreatic cancer cell lines was increased more than 100-fold compared with irinotecan. Moreover, this effect was effectively blocked by competing incubation with nonlabeled STxB, showing the specificity of the targeting. Thus, STxB constitutes a promising new tool for specific targeting of pancreatic cancer.
Highlights
Pancreatic carcinoma is one of the most aggressive tumor entities with a median survival of 6 months and a 5-year survival rate of less than 5% [1]
Gb3 was clearly upregulated in pancreatic adenocarcinoma, in good accordance with recent observations [14]
Gb3 was detectable by lipid extraction and by Shiga toxin B (STxB) overlay on cryosections, albeit at lower levels than in carcinoma samples
Summary
Pancreatic carcinoma is one of the most aggressive tumor entities with a median survival of 6 months and a 5-year survival rate of less than 5% [1]. The targeting of pancreatic cancer for early diagnosis (e.g., by imaging methods) and for therapeutic purposes (e.g., by specific delivery of cytotoxic compounds to pancreatic tumor cells) is of great clinical interest. The nontoxic B-subunit of the bacterial Shiga toxin (STxB) is a promising new option for diag-. We and others showed previously that the expression of the cellular receptor of Shiga toxin, the glycosphingolipid Gb3 (CD77), is significantly increased in colorectal carcinoma and their metastases [4, 5]. Studies on genetic mouse models for human digestive cancer showed that STxB is suitable for noninvasive tumor imaging [6]. STxB is taken up rapidly by tumor cells that express the receptor Gb3 on their surface membrane, and STxB follows the so-called retrograde route [7]. STxB is transported from the endosome to the transGolgi network and to the Golgi apparatus and is transported from there to the endoplasmic reticulum [8,9,10]
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