Role of insulin-like growth factor-I (IGF-I) receptor, IGF-I, and IGF binding protein-2 in human colorectal cancers

The identification of novel autocrine/paracrine signaling pathways and poss ible markers represents an important component in the understanding of tumo r growth control. In this study, we assessed the potential role of insulin- like growth factor-I (IGF-I), the IGF-I receptor (IGF-IR) and IGF binding p rotein-2 (IGFBP-2) in human colorectal cancer. Initial studies demonstratin g increased IGF-I binding and IGF-IR density in human colon cancer tissue r evealed that a component of iodinated (3-[(125)-I]iodotyrosyl) IGF-I (I-125 -IGF-I) binding was not attributable to IGF-IR. Binding studies and Western blot analysis suggested that this second component of (125I)-IGF-I binding could be due to IGFBP-2. Further analysis by a specific solution hybridiza tion/RNase protection assay for IGF-IR mRNA levels, IGFBP-2 mRNA levels and in situ hybridization for IGFBP-2 localization, was carried out in nine pa tients with colon cancer. IGF-IR mRNA levels by RNAse protection assays wer e unchanged, whereas IGFBP-2 mRNA levels were increased 4-8-fold in patient s with colon cancer compared to controls. Three patients with Dukes stage C disease had the highest levels of IGFBP-2 mRNA. In situ hybridization stud ies localized IGFBP-2 mRNA to malignant cells and not to the surrounding st romal cells, suggesting an autocrine role for IGFBP-2. The discrepancy betw een increased IGF-I binding, IGF-IR density, IGFBP-2 mRNA and the minimal m odulation of the IGF-IR mRNA implies post-transcriptional regulation of IGF -IRs. Our results suggest that IGFBP-2 may be implicated in colon cancer me tastases and prognosis. Its usefulness as a potential tumor marker should b e further investigated.