Abstract
BackgroundDespite progress in adjuvant chemotherapy in the recent decades, pancreatic and colon cancers remain common causes of death worldwide. Bacterial toxins, which specifically bind to cell surface-exposed glycosphingolipids, are a potential novel therapy. We determined the expression of globotriaosylceramide (Gb3Cer/CD77), the Shiga toxin receptor, in human pancreatic and colon adenocarcinomas.Methodology/Principal FindingsTissue lipid extracts of matched pairs of cancerous and adjacent normal tissue from 21 pancreatic and 16 colon cancer patients were investigated with thin-layer chromatography overlay assay combined with a novel mass spectrometry approach. Gb3Cer/CD77 was localized by immunofluorescence microscopy of cryosections from malignant and corresponding healthy tissue samples. 62% of pancreatic and 81% of colon adenocarcinomas showed increased Gb3Cer/CD77 expression, whereas 38% and 19% of malignant pancreas and colon tissue, respectively, did not, indicating an association of this marker with neoplastic transformation. Also, Gb3Cer/CD77 was associated with poor differentiation (G>2) in pancreatic cancer (P = 0.039). Mass spectrometric analysis evidenced enhanced expression of Gb3Cer/CD77 with long (C24) and short chain fatty acids (C16) in malignant tissues and pointed to the presence of hydroxylated fatty acid lipoforms, which are proposed to be important for receptor targeting. They could be detected in 86% of pancreatic and about 19% of colon adenocarcinomas. Immunohistology of tissue cryosections indicated tumor-association of these receptors.Conclusions/SignificanceEnhanced expression of Gb3Cer/CD77 in most pancreatic and colon adenocarcinomas prompts consideration of Shiga toxin, its B-subunit or B-subunit-derivatives as novel therapeutic strategies for the treatment of these challenging malignancies.
Highlights
Pancreatic and colon cancers are the fourth and second most frequent causes of cancer mortality in the Western world, respectively, accounting for estimated 84,250 deaths in 2008 in the U
Crude lipid extracts and cryosections from postoperative matched pairs of malignant versus adjacent unaffected tissues from the same patients were analyzed by means of thin-layer chromatography (TLC) overlay technique and immunofluorescence microscopy
In addition to monoclonal antibodies, plant and bacterial toxins that bind to GSLs are currently under investigation for clinical purposes
Summary
Pancreatic and colon cancers are the fourth and second most frequent causes of cancer mortality in the Western world, respectively, accounting for estimated 84,250 deaths in 2008 in the U. About 10–15% of the pancreatic cancer patients are candidates for potentially curative surgery [3,4], underlining the urgent need to develop novel strategies to treat patients with these unresectable tumors. For example, based on bacterial and plant toxins or monoclonal antibodies, which recognize cell surface glycosphingolipids (GSLs), that are overexpressed in pancreas and/or colon cancer, might prove to be promising approaches for adjunct therapy after surgery [5,6,7,8,9]. Despite progress in adjuvant chemotherapy in the recent decades, pancreatic and colon cancers remain common causes of death worldwide. Bacterial toxins, which bind to cell surface-exposed glycosphingolipids, are a potential novel therapy. We determined the expression of globotriaosylceramide (Gb3Cer/CD77), the Shiga toxin receptor, in human pancreatic and colon adenocarcinomas
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