BLOCKADE OF THE INSULIN-LIKE GROWTH-FACTOR-I RECEPTOR INHIBITS GROWTHOF HUMAN COLORECTAL-CANCER CELLS - EVIDENCE OF A FUNCTIONAL IGF-II-MEDIATED AUTOCRINE LOOP

Insulin like growth factors (IGFs) are potent proliferation stimulator s for numerous tumor cells and often function as autocrine growth fact ors. We have previously shown that exogenous IGF-I and IGF-II enhance proliferation of colorectal carcinoma cells. The biological signal of bath factors is transmitted through the IGF-I receptor (IGF-I-R). This receptor was expressed in 12/12 colorectal carcinoma cell lines teste d. alpha IR3, a neutralizing monoclonal antibody (MAb) directed agains t the human IGF-I-R, inhibited proliferation in 7/12 lines (Caco-2, HT -29, LS411N, LS513, LS1034, WiDr and SW620), as reflected by a reducti on of MTT conversion (19 to 42%), a decrease in cell number (39 to 72% ) and an increase in doubting time (up to 2-fold). In addition, in 4 c ell lines (Caco-2, LS513, LS1034, WiDr) alpha IR3 suppressed colony fo rmation in methylcellulose (40 to 84%). Excess of exogenous IGF comple tely neutralized alpha IR3-mediated inhibitory effects. Northern blot analysis revealed abundant expression of 2 IGF-II transcripts of 5.0 a nd 4.3 kb in LS1034 cells. In addition, we observed that growth inhibi tion by alpha IR3 was correlated with a more differentiated phenotype. Our results suggest that growth of many colorectal carcinoma cell lin es is regulated by autocrine IGF-II-mediated stimulation of the IGF-I- R. (C) 1994 Wiley-Liss, Inc.