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

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 A majority of primary colon carc