Human colorectal tumors and metastases express Gb3 and can be targeted by an intestinal pathogen-based delivery tool.
The targeting of solid tumors requires delivery tools that resist intracellular and extracellular inactivation, and that are taken up specifically by tumor cells. We have shown previously that the recombinant nontoxic B-subunit of Shiga toxin (STxB) can serve as a delivery tool to target digestive tumors in animal models. The aim of this study was to expand these experiments to human colorectal cancer. Tissue samples of normal colon, benign adenomas, colorectal carcinomas, and liver metastases from 111 patients were obtained for the quantification of the expression of the cellular STxB receptor, the glycosphingolipid globotriaosyl ceramide (Gb(3) or CD77). We found that compared with normal tissue, the expression of Gb(3) was strongly increased in colorectal adenocarcinomas and their metastases, but not in benign adenomas. Short-term primary cultures were prepared from samples of 43 patients, and STxB uptake was studied by immunofluorescence microscopy. Of a given tumor sample, on average, 80% of the cells could visibly bind STxB, and upon incubation at 37 degrees C, STxB was transported to the Golgi apparatus, following the retrograde route. This STxB-specific intracellular targeting allows the molecule to avoid recycling and degradation, and STxB could consequently be detected on tumor cells even 5 days after initial uptake. In conclusion, the targeting properties of STxB could be diverted for the delivery of contrast agents to human colorectal tumors and their metastases, whose early detection and specific targeting remains one of the principal challenges in oncology.
Falguières
Thomas
T
Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Ismaninger Strasse 22, Munich, Germany.
Maak
Matthias
M
von Weyhern
Claus
C
Sarr
Marianne
M
Sastre
Xavier
X
Poupon
Marie-France
MF
Robine
Sylvie
S
Johannes
Ludger
L
Janssen
Klaus-Peter
KP
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015295:Antigens, Tumor-Associated, Carbohydrate / Q000096:biosynthesis*; D002855:Chromatography, Thin Layer; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D005260:Female; D006801:Humans; D007422:Intestines / Q000382:microbiology*; D008113:Liver Neoplasms / Q000378:metabolism / Q000556:secondary; D008297:Male; D008875:Middle Aged; D022603:Shiga Toxins / Q000378:metabolism*; D014281:Trihexosylceramides / Q000096:biosynthesis
D015295:Antigens, Tumor-Associated, Carbohydrate; C472766:Gb3 antigen; D022603:Shiga Toxins; D014281:Trihexosylceramides; C077239:stxB toxin; C018549:globotriaosylceramide