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Research Articles: Therapeutics, Targets, and Development

Human colorectal tumors and metastases express Gb₃ and can be targeted by an intestinal pathogen-based delivery tool

¹ Centre de Recherche, Institut Curie, CNRS UMR144, Paris, France; ² Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Germany; ³ Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Germany; ⁴ Service d'Anatomo-pathologie, Institut Curie, Paris, France; and ⁵ Unité 612 INSERM/Institut Curie, Paris, France

Requests for reprints: Klaus-Peter Janssen, Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675 Munich, Germany. Phone: 49-89-4140-2066; Fax: 49-89-4140-6031. E-mail: klaus-peter.janssen{at}lrz.tum.de

Abstract

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 (Gb₃ or CD77). We found that compared with normal tissue, the expression of Gb₃ 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°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. [Mol Cancer Ther 2008;7(8):2498–508]

Grant support: The French Ministry of Research (ACI Biologie du Développement et Physiologie Intégrative), Fondation de France, Association pour la Recherche sur le Cancer (nos. 3105, 4803, and 5177), Cancéropôle Ile-de-France, and Institut Curie (PIC Vectorisation; L. Johannes); a fellowship from Ligue Nationale contre le Cancer (T. Falguières); and the Deutsche Forschungsgemeinschaft and Kommission fuer Klinische Forschung (K.P. Janssen).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: T. Falguières and M. Maak contributed equally to this work.

Current address for T. Falguières: Department of Biochemistry, University of Geneva-Sciences II, Geneva, Switzerland.

Principal investigators: L. Johannes and K.P. Janssen.

⁶ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

⁷ Unpublished observations.

Received 8/29/07; revised 5/ 2/08; accepted 5/22/08.