IGFBP-3 mediates TGFβ1 proliferative response in colon cancer cells

Abstract

Many human tumor cells are resistant to growth inhibition by TGFβ1. Resistance may be caused by mutations in TGFβ receptors or in other components of the TGFβ signal transduction systems, or by knockout of the retinoblastoma (Rb) gene, which in fibroblasts converts cellular response to TGFβ1 from growth inhibition to growth stimulation. Our earlier studies showed such a switch in response to TGFβ1 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 TGFβ1-induced proliferation of 3 metastatic or highly aggressive colon carcinoma cell lines. TGFβ1 increases IGFBP-3 abundance while phosphorothiolated antisense oligonucleotides to IGFBP-3 block the growth-promoting effect of TGFβ1 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. (C) 2000 Wiley-Liss, Inc.