Targeting CD24 for treatment of colorectal and pancreatic cancer by monoclonal antibodies or small interfering RNA

被引:134
作者
Sagiv, Eyal [1 ,4 ]
Starr, Alex [2 ,4 ]
Rozovski, Uri [1 ,4 ]
Khosravi, Rami [3 ]
Altevogt, Peter [5 ]
Wang, Timothy [6 ]
Arber, Nadir [1 ,4 ]
机构
[1] Tel Aviv Med Ctr & Sch Med, Integrated Canc Prevent Ctr, IL-64239 Tel Aviv, Israel
[2] Tel Aviv Med Ctr & Sch Med, Lung & Allergy Inst, Tel Aviv, Israel
[3] David Inez Myers Lab Genet Res, Tel Aviv, Israel
[4] Tel Aviv Univ, Dept Mol Genet & Biochem, IL-69978 Tel Aviv, Israel
[5] Tumor Immunol Programme, Heidelberg, Germany
[6] Columbia Univ, New York, NY USA
关键词
D O I
10.1158/0008-5472.CAN-07-6463
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
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页码:2803 / 2812
页数:10
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