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PMID: 19714252 Published · epublish English Journal Article Research Support, Non-U.S. Gov't

Shiga toxin receptor Gb3Cer/CD77: tumor-association and promising therapeutic target in pancreas and colon cancer.

PloS one ·Vol. 4 ·No. 8 ·2009-08-28 ·Pages e6813

Distler U, Souady J, Hülsewig M, Drmić-Hofman I, Haier J, Friedrich AW, Karch H, Senninger N, Dreisewerd K, Berkenkamp S, Schmidt MA, Peter-Katalinić J, Müthing J

Abstract

Despite 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. Tissue 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. Enhanced 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.

MeSH Terms
Adenocarcinoma/drug therapy,metabolism Carbohydrate Sequence Chromatography, Thin Layer Colonic Neoplasms/drug therapy,metabolism Humans Immunohistochemistry Molecular Sequence Data Pancreatic Neoplasms/drug therapy,metabolism Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Trihexosylceramides/chemistry,metabolism,therapeutic use
Chemicals
Trihexosylceramides globotriaosylceramide
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Distler Ute
Institute of Hygiene, University of Münster, Münster, Germany.
Souady Jamal
Hülsewig Marcel
Drmić-Hofman Irena
Haier Jörg
Friedrich Alexander W
Karch Helge
Senninger Norbert
Dreisewerd Klaus
Berkenkamp Stefan
Schmidt M Alexander
Peter-Katalinić Jasna
Müthing Johannes
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Article Info
Journal
PloS one
Abbr.
PLoS One
ISSN
1932-6203
DOI
10.1371/journal.pone.0006813
Published
2009-08-28
Epub
2009-00-28
Pages
e6813
Language
English
Region
United States
NLM ID
101285081
PMCID
PMC2730034
Subset
IM
External Links
PubMed source DOI: 10.1371/journal.pone.0006813 PMC Full Text View journal details
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