Des‐(1–3)‐IGF‐I, an insulin‐like growth factor analog used to mimic a potential IGF‐II autocrine loop, promotes the differentiation of human colon‐carcinoma cells

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Abstract
HT29-D4 human colon-carcinoma cells have been shown to secrete insulin-like growth factor (IGF)-II and to simultaneously express type-I IGF receptors. However, the sequestration of IGF-II by several molecular forms of IGF-binding proteins (IGFBP) in the culture medium prevents the establishment of an operative IGF-II autocrine loop. IGFBPs secreted by HT29-D4 cells (HT29-D4 IGFBP) comprise isoforms of IGFBP-4 (25, 27 and 30 kDa) and 2 unidentified forms (34.5 and 32-34 kDa). This latter does not bind 125I-IGF-I. The net affinity of HT29-D4 IGFBP is about 12 times stronger for IGF-II (KD approx. 10−10 M) than for IGF-I. All the HT29-D4 IGFBP molecular forms are unable to bind the N-terminally truncated IGF-I analog, des-(1–3)-IGF-1. In contrast, HT29-D4 cell-surface type-l IGF receptors bind IGF-I and des-(1–3)-IGF-l identically (KD approx. 5 × 10−10M). We have taken advantage of these particular binding properties to use des-(1–3)-IGF-1 to mimic a potential IGF autocrine loop and to observe its biological consequences. Nanomolar concentrations of des-(1–3)-IGF-1 induce HT29-D4 cells to develop into a differentiated phenotype, as judged by a substantial carcinoembryonic antigen release and the induction of numerous intercellular cysts with well-organized microvilli. In the same way, des-(1–3)-IGF-1 early induces a slight inhibition of HT29-D4 cell proliferation. Based on these findings, we conclude that the type-l IGF receptor primarily controls the differentiation of these colonic cells, and that HT29-D4 cancer cells remain in an undifferentiated state because of their inability to use endogenous IGF-II as an autocrine regulatory factor.

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