Many human tumor cells are resistant to growth inhibition by TGF beta 1. Resistance may be caused by mutations in TGFbeta receptors or in other components of the TGF beta signal transduction systems, or by knockout of the retinoblastoma (Rb) gene, which in fibroblasts converts cellular response to TGF beta 1 from growth inhibition to growth stimulation. Our earlier studies showed such a switch in response to TGF beta 1 occurred in 45% of colon cancers but without deletion of Rb. We now show that insulin-like growth factor binding protein 3 (IGFBP-3) mediates the TGF beta 1-induced proliferation of 3 metastatic or highly aggressive colon carcinoma cell lines. TGF beta 1 increases IGFBP-3 abundance while phosphorothiolated antisense oligonucleotides to IGFBP-3 block the growth-promoting effect of TGF beta 1 in each of 3 lines.IGFBP-3 induces carcinoma cell growth in a dose-dependent and time-dependent manner in vitro. IGFBP-3 may confer a selective growth advantage on tumor cells in vivo because levels of mature IGFBP-3 were elevated at least 2-fold in 7 of 10 resected colon cancers compared with adjacent normal tissue.
Copyright 2000 Wiley-Liss, Inc.