IGFBP-3 mediates TGF beta 1 proliferative response in colon cancer cells

Many human tumor cells are resistant to growth inhibition by TGF beta 1. Re sistance may be caused by mutations in TGF beta receptors or in other compo nents of the TGF beta signal transduction systems, or by knockout of the re tinoblastoma (Rb) gene, which in fibroblasts converts cellular response to TGF beta 1 from growth inhibition to growth stimulation. Our earlier studie s showed such a switch in response to TGF beta 1 occurred in 45% of colon c ancers but without deletion of Rb. We now show that insulin-like growth fac tor binding protein 3 (IGFBP-3) mediates the TGF beta 1-induced proliferati on of 3 metastatic or highly aggressive colon carcinoma cell lines. TGF bet a 1 increases IGFBP-3 abundance while phosphorothiolated antisense oligonuc leotides 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 advan tage 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 no rmal tissue. Int. J. Cancer 87:373-378, 2000. (C) 2000 Wiley-Liss, Inc.