Overexpression of the insulin-like growth factor I receptor in human colon carcinomas

Authors

  • Matthias M. Weber M.D., Ph.D.,

    Corresponding author
    1. Klinik II und Poliklinik für Innere Medizin der Universität zu Köln und Lehrstuhl II für Innere Medizin, Köln, Germany
    • Lehrstuhl II für Innere Medizin der Universität zu Köln, Medizinische Universitätsklinik Köln-Merheim, Ostmerheimerstraße 200, 51109 Köln, Germany
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  • Christian Fottner M.D.,

    1. Klinik II und Poliklinik für Innere Medizin der Universität zu Köln und Lehrstuhl II für Innere Medizin, Köln, Germany
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  • Sun Bin Liu,

    1. Medizinische Klinik II, Klinikum Grosshadern, Ludwig-Maximilians-Universität, München, Germany
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  • M. Christina Jung M.D., Ph.D.,

    1. Medizinische Klinik II, Klinikum Grosshadern, Ludwig-Maximilians-Universität, München, Germany
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  • Dieter Engelhardt M.D., Ph.D.,

    1. Medizinische Klinik II, Klinikum Grosshadern, Ludwig-Maximilians-Universität, München, Germany
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  • Gustavo B. Baretton M.D., Ph.D.

    1. Institut für Pathologie, Universitätsklinikum Carl Gustav Carus, Dresden, Germany
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Abstract

BACKGROUND

High concentrations of insulin-like growth factor (IGF)-I and IGF-II have been demonstrated in human colonic adenocarcinomas and exert mitogenic effects through paracrine/autocrine interactions with the IGF-I receptor (IGF-IR). However, definitive studies of IGF-IR expression in these tissues have not been performed.

METHODS

To study changes in the levels of the IGF-IR in colorectal carcinoma, we analyzed the expression of IGF-IR in 40 paired samples of normal and carcinomatous colonic tissue by quantitative reverse-transcription–polymerase chain reaction (RT-PCR), immunohistochemistry, and ligand binding.

RESULTS

As measured by RT-PCR, the IGF-IR mRNA ratio in paired tumor and adjacent normal mucosa was higher than 2.0 in 32 of 40 (80%) samples. The overall mean IGF-IR mRNA level was five-fold higher in tumor versus adjacent normal mucosa (P < 0.0001). Overexpression of IGF-IR in colon carcinomas was confirmed at the protein level by immunohistochemistry and receptor-binding studies. Colon carcinoma cells exhibited a positive staining for IGF-IR in 91% of all tumors (30 of 33) whereas the adjacent normal colonic epithelial cells showed only a very faint or no significant IGF-IR immunoreactivity. Radioligand assays and Scatchard analysis in both tissue types revealed a single class of high-affinity IGF-IR–binding sites with a similar dissociation constant (Kd; 0.14 ± 0.02 nmol/L, n = 18). However, specific 125IGF-I–binding and receptor concentrations were elevated in tumor membranes compared with normal mucosa (33.6 ± 5.6 vs. 22.7 ± 3.4 fmol/mg protein, P < 0.05). IGF-I affinity crosslinking and sodium dodecyl sulfate–polyacrylamide gel electrophoresis displayed specific bands corresponding to the size of the normal α-subunit of the IGF-IR that were more intense in carcinomatous samples. IGF-II mRNA levels were significantly elevated in colorectal carcinomas (P < 0.0001). The IGF-II mRNA ratio in tumor versus normal tissue was elevated more than twofold in 28 of 40 paired samples and a positive correlation was observed between the overexpression of IGF-II and IGF-IR in the tumors.

CONCLUSIONS

Our results demonstrate that, in addition to IGF-II, a strong overexpression of IGF-IR is found in the majority of colorectal carcinomas, supporting the hypothesis of an important role of the IGF system in the pathogenesis of colorectal carcinoma. Cancer 2002;95:2086–95. © 2002 American Cancer Society.

DOI 10.1002/cncr.10945

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