Down-regulation of TGF-β receptors in human colorectal cancer: Implications for cancer development

Abstract

Many colorectal cancer cells are resistant to the anti-proliferative effects of transforming growth factor-β (TGF-β). TGF-β also acts as paracrine factor from cancer cells on their mesenchymal cells. The aim of this study was to examine the expression of TGF-β and its receptors in human colorectal cancer tissue and determine any relationship with cancer growth. In situ hybridization and Northern blot hybridization detection of TGF-β1, type I and type II receptor mRNA and immunohistochemical staining of TGF-β1 were performed using 11 human colorectal adenomas, 22 colorectal cancers and ten normal colorectal mucosas as control. TGF-β receptor mRNAs were expressed mainly by normal colorectal epithelial cells and adenoma. However, mRNAs for TGF-β receptors were only faintly if at all, expressed in eight of 22 human colorectal cancers. In addition, intense signals of TGF-β, mRNA and the protein were detected in all colorectal cancers. TGF-β receptor mRNAs and TGF-β1 protein were also distributed in fibroblasts and endothelial cells in the interstitium. Moreover, Smad 4 protein was translocated to nucleus in primarily cultured adenoma cells, but not in cancer cells after TGF-β stimulation. The escape of human colon cancer from TGF-β-mediated growth inhibition by down-regulation of TGF-β receptors as well as the effects of TGF-β on stroma formation and angiogenesis indicate a possible role for TGF-β in the progression of colon cancer in an intact host.