Blockade of the insulin‐like growth‐factor‐I receptor inhibits growth of human colorectal cancer cells: Evidence of a functional IGF‐II‐mediated autocrine loop

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Abstract
Insulin‐like growth factors (IGFs) are potent proliferation stimulators for numerous tumor cells and often function as autocrine growth factors. We have previously shown that exogenous IGF‐I and IGF‐II enhance proliferation of colorectal carcinoma cells. The biological signal of both factors is transmitted through the IGF‐I receptor (IGF‐I‐R). This receptor was expressed in 12/12 colorectal carcinoma cell lines tested. αIR3, a neutralizing monoclonal antibody (MAb) directed against the human IGF‐I‐R, inhibited proliferation in 7/12 lines (Caco‐2, HT‐29, LS411N, LSS13, LS1034, WiDr and SW620), as reflected by a reduction of MTT conversion (19 to 42%), a decrease in cell number (39 to 72%) and an increase in doubling time (up to 2‐fold). In addition, in 4 cell lines (Caco‐2. LSS13, LS1034, WiDr) αIR3 suppressed colony formation in methylcellulose (40 to 84%). Excess of exogenous IGF completely neutralized αIR3‐mediated inhibitory effects. Northern blot analysis revealed abundant expression of 2 IGF‐II transcripts of 5.0 and 4.3 kb in LS1034 cells. In addition, we observed that growth inhibition by αIR3 was correlated with a more differentiated phenotype. Our results suggest that growth of many colorectal carcinoma cell lines is regulated by autocrine IGF‐II‐mediated stimulation of the IGF‐I‐R.