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The insulin-like growth factor II (IGF-II) is a small protein implicated in fetal growth and development. It may play a role in the neoplastic process. The IGF-II gene is located on the short arm of chromosome II near insulin and c-Ha-ras I genes. Three distinct promoters control the transcription of this gene, leading to different IGF-II mRNA species. We have analyzed 21 human colorectal tumors and found overexpression of IGF-II in 6 of them (30%). When compared with expression in normal adjacent tissues, IGF-II mRNA increase in these tumors was either moderate (2- to 15-fold) or very marked (200- to 800-fold). In situ hybridization experiments confirmed that high IGF-II mRNA amounts were localized in cancer cells of the tumors overexpressing the IGF-II gene. In addition, DNA analysis revealed a structural modification of one IGF-II locus in one tumor characterized by very high IGF-II mRNA.

Abnormal expression and structural modification of the IGF-II gene in correlation with high IGF-II production have recently been described in human colorectal tumors in comparison with normal adjacent tissues. Here, we have studied IGF-II in 2 human colon-carcinoma cell lines, HT29 and COLO 320DM. RFLP analyses revealed no apparent alteration at the IGF-II locus in these 2 cell lines. HT29 cells weakly expressed IGF-II mRNA in comparison with the high over-expression previously observed in some colorectal tumors, and only the 4.8-kb mRNA species was present. In addition, the serum-free medium conditioned by HT29 cells contained high IGF-II levels (approx. 900 ng/10(8) cells), as measured in a specific IGF-II radioimmunoassay (RIA). After chromatography on Bio-Gel P-60, we observed that 64% of the total IGF-II secreted by HT29 cells were present as a high-molecular-weight form of about 17 kDa. In contrast, no detectable expression of the IGF-II gene was observed in COLO 320DM cells, and low IGF-II levels were secreted by these cells in the serum-free medium, with only 9% total IGF-II represented by the large species.

We have recently reported abnormal insulin-like growth factor-II (IGF-II) mRNA levels in a number of human colorectal adenocarcinomas. Using an IGF-II radioimmunoassay, we have now detected high levels of both 10-kDa and 7.5-kDa IGF-II species (2,370 ng/g) in a right colon tumor showing a 800-fold IGF-II gene over-expression in comparison to the normal adjacent tissue. The higher-molecular-mass form represents 74% of the total immunoreactive IGF-II detected in the tumor. This form appears to be less reactive in the radioreceptor assay than in the radioimmunoassay. The insulin-like growth factor-I (IGF-I) concentration in the tumor is low. The patient's pre-operative serum IGF-II level is not increased and the proportion of the 10-kDa species is normal. In addition, the IGF-II/IGF-I ratio is 3 in the serum and 308 in the tumor. Our results show that the very high IGF-II level produced by the tumor does not influence the seric concentration of the growth factor.

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