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

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 (K(d;) 0.14 +/- 0.02 nmol/L, n = 18). However, specific (125)IGF-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 alpha-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.

• Authors: Matthias M Weber, Christian Fottner, Sun Bin Liu, M Christina Jung, Dieter Engelhardt, Gustavo B Baretton
• Journal: Cancer (Cancer) Vol. 95 Issue 10 Pg. 2086-95 (Nov 15 2002) ISSN: 0008-543X [Print] United States
• PMID: 12412161 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2002 American Cancer Society.

Chemical References

• RNA, Messenger
• Receptor, IGF Type 1

Topics

• Adenocarcinoma (metabolism)
• Colorectal Neoplasms (metabolism)
• Female
• Gene Expression
• Gene Expression Regulation, Neoplastic
• Humans
• Immunohistochemistry
• Male
• Middle Aged
• RNA, Messenger (analysis, metabolism)
• Receptor, IGF Type 1 (genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction