IGFBP-2 overexpression reduces the appearance of dysplastic aberrant crypt foci and inhibits growth of adenomas in chemically induced colorectal carcinogenesis

Authors

  • Daniela Diehl,

    1. Institute of Molecular Animal Breeding and Biotechnology, Gene Center, LMU Munich, Munich, Germany
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    • The first two authors contributed equally to this work.

  • Esther Hessel,

    1. Institute of Molecular Animal Breeding and Biotechnology, Gene Center, LMU Munich, Munich, Germany
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    • The first two authors contributed equally to this work.

  • Doris Oesterle,

    1. Institute of Toxicology, Helmholtz Center for Environment and Health, Neuherberg, Germany
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  • Ingrid Renner-Müller,

    1. Institute of Molecular Animal Breeding and Biotechnology, Gene Center, LMU Munich, Munich, Germany
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  • Martin Elmlinger,

    1. Pediatric Endocrinology, Children's Hospital, University of Tübingen, Tübingen, Germany
    2. Altana Pharma AG, Konstanz, Germany
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  • Martina Langhammer,

    1. Laboratory of Mouse Genetics, Research Unit Genetics and Biometry, Research Institute for the Biology of Farm Animals (FBN), Dummerstorf, Germany
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  • Martin Göttlicher,

    1. Institute of Toxicology, Helmholtz Center for Environment and Health, Neuherberg, Germany
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  • Eckhard Wolf,

    1. Institute of Molecular Animal Breeding and Biotechnology, Gene Center, LMU Munich, Munich, Germany
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  • Harald Lahm,

    1. Institute of Molecular Animal Breeding and Biotechnology, Gene Center, LMU Munich, Munich, Germany
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  • Andreas Hoeflich

    Corresponding author
    1. Institute of Molecular Animal Breeding and Biotechnology, Gene Center, LMU Munich, Munich, Germany
    2. Laboratory of Mouse Genetics, Research Unit Genetics and Biometry, Research Institute for the Biology of Farm Animals (FBN), Dummerstorf, Germany
    • Laboratory of Mouse Genetics, Research Unit Genetics and Biometry, FBN Dummerstorf, Wilhelm-Stahl-Allee 2, D-18196 Dummerstorf, Germany
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    • Fax: +49-38-208 68 902.


Abstract

Colon cancer patients frequently show increased levels of serum insulin-like growth factor-binding protein-2 (IGFBP-2), however, the pathogenetic relevance of this phenomenon for colorectal cancer is unclear. Therefore, we have used IGFBP-2 transgenic animals which overexpress IGFBP-2 systemically and locally in the intestine to study its role in chemically induced colorectal carcinogenesis. Mice received intraperitoneal injections of 1,2-dimethylhydrazine (DMH) (40 mg/kg body weight) once a week for 6 weeks to selectively induce aberrant crypt foci (ACF) and tumors in the colon. While tumor incidence was comparable in transgenic and control mice, the volume of adenomas in IGFBP-2 transgenic mice was reduced more than 2-fold. Furthermore, serum IGFBP-2 levels negatively correlated with tumor volume in the IGFBP-2 transgenic group. Histological examination showed that IGFBP-2 transgenic mice developed significantly less dysplastic ACF with a high potential to progress to advanced stages. The reduced tumor volume in IGFBP-2 transgenic animals was due to significantly reduced proliferative capacity, evidenced by a lower proportion of cells positive for Ki67. Our results demonstrate for the first time in an experimental model that IGFBP-2 overabundance prior to the onset and during colorectal carcinogenesis reduces tumor growth by inhibition of cell proliferation. © 2008 Wiley-Liss, Inc.

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