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Targeting CD24 for Treatment of Colorectal and Pancreatic Cancer by Monoclonal Antibodies or Small Interfering RNA

¹ The Integrated Cancer Prevention Center and ² Lung and Allergy Institute, Tel Aviv Medical Center; ³ The David and Inez Myers Laboratory for Genetic Research; ⁴ Department of Molecular Genetics and Biochemistry, Tel Aviv University, Tel Aviv, Israel; ⁵ Tumor Immunology Programme, D010, German Cancer Research Center, Heidelberg, Germany; and ⁶ Columbia University, New York, New York

Requests for reprints: Nadir Arber, Integrated Cancer Prevention Center, Tel Aviv Medical Center, 6 Weizmann Street, Tel Aviv 64239, Israel. Phone: 972-3-697-4968; Fax: 972-3-695-0339; E-mail: narber{at}post.tau.ac.il.

Key Words: CD24 • monoclonal antibodies • siRNA • microarray • chemotherapy

CD24 is a potential oncogene reported to be overexpressed in a large variety of human malignancies. We have shown that CD24 is overexpressed in 90% of colorectal tumors at a fairly early stage in the multistep process of carcinogenesis. Anti-CD24 monoclonal antibodies (mAb) induce a significant growth inhibition in colorectal and pancreatic cancer cell lines that express the protein. This study is designed to investigate further the effects of CD24 down-regulation using mAb or small interfering RNA in vitro and in vivo. Western blot analysis showed that anti-CD24 mAb induced CD24 protein down-regulation through lysosomal degradation. mAb augmented growth inhibition in combination with five classic chemotherapies. Xenograft models in vivo showed that tumor growth was significantly reduced in mAb-treated mice. Similarly, stable growth inhibition of cancer cell lines was achieved by down-regulation of CD24 expression using short hairpin RNA (shRNA). The produced clones proliferated more slowly, reached lower saturation densities, and showed impaired motility. Most importantly, down-regulation of CD24 retarded tumorigenicity of human cancer cell lines in nude mice. Microarray analysis revealed a similar pattern of gene expression alterations when cells were subjected to anti-CD24 mAb or shRNA. Genes in the Ras pathway, mitogen-activated protein kinase, or BCL-2 family and others of oncogenic association were frequently down-regulated. As a putative new oncogene that is overexpressed in gastrointestinal malignancies early in the carcinogenesis process, CD24 is a potential target for early intervention in the prevention and treatment of cancer. [Cancer Res 2008;68(8):2803–12]

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