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


RESULTS
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.


CONCLUSIONS
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.
Distler
Ute
U
Institute of Hygiene, University of Münster, Münster, Germany.
Souady
Jamal
J
Hülsewig
Marcel
M
Drmić-Hofman
Irena
I
Haier
Jörg
J
Friedrich
Alexander W
AW
Karch
Helge
H
Senninger
Norbert
N
Dreisewerd
Klaus
K
Berkenkamp
Stefan
S
Schmidt
M Alexander
MA
Peter-Katalinić
Jasna
J
Müthing
Johannes
J
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism; D002240:Carbohydrate Sequence; D002855:Chromatography, Thin Layer; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008969:Molecular Sequence Data; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014281:Trihexosylceramides / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use
D014281:Trihexosylceramides; C018549:globotriaosylceramide