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

Abstract

SummaryMany 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-β 1 , type I and type II receptor mRNA and immunohistochemical staining of TGF-β 1 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 1 mRNA and the protein were detected in all colorectal cancers. TGF-β receptor mRNAs and TGF-β 1 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.Keywords: TGF-β; TGF-β receptor; Smad, colorectal cancer; colorectal adenoma 194British Journal of Cancer (1999) 80(1/2), 194-205 © 1999 Cancer Research Campaign Article no. bjoc.1998 Received 30 receptors, and alterations in post-receptor pathways. Several reports indicate that elevated levels of TGF-β mRNA and protein in colorectal cancer are associated with cancer progression (Tsushima et al, 1996). If TGF-β is indeed an inhibitor for epithelial cells, how then do colorectal cancer cells manage to proliferate despite elevated TGF-β production by tumour cells? Concerning the mechanisms of resistance to the anti-proliferative effects of TGF-β in colorectal cancer, Markowitz et al (1995) identified a specific TGF-β RII mutation that is associated with defective DNA mismatch repair in colon cancer cells. However, numerous reports also indicate that transcriptional regulation makes an important contribution to determination of the expression level of TGF-β receptors (Birchenall-Roberts et al, 1995;Kim et al, 1997). Accordingly, to clarify the mechanisms of resistance to the antiproliferative effects of TGF-β in vivo, we estimated the transcriptional level of TGF-β receptors in colorectal cancer using in situ hybridization and Northern blot hybridization as the standard for those in normal colorectal epithelial cells.In addition, no studies of human colorectal tumour to date have compared in situ levels of TGF-β 1 with those of its receptors as a presumptive target gene, and with the presence of ligand protein.To ascertain if TGF-β from colorectal cancer act...

Prognostic Significance of Transforming Growth Factor β Receptor II in Estrogen Receptor-Negative Breast Cancer Patients

“…In colon and prostate cancer loss of T␤RI expression was associated with increased malignant potential (25,32,33). No comparable studies exist for breast cancer.…”

Overexpression of FOXG1 contributes to TGF-β resistance through inhibition of p21WAF1/CIP1 expression in ovarian cancer

“…Apart from genetic and/or epigenetic lesions in TGF-b receptors or TGF-b/Smad transducers that can contribute to TGF-b resistance in human cancers (Arai et al, 1998;Ko et al, 1998;Matsushita et al, 1999;Venkatasubbarao et al, 2000;Maurice et al, 2001;Fukushima et al, 2003;Sakaguchi et al, 2005;Zhong et al, 2006), emerging data have also suggested that the expressions of viral proto-oncogenes and oncogenes are capable of inducing TGF-b resistance through blocking the functions of Smads (Datta and Bagchi, 1994;Hahm et al, 1999;Mori et al, 2001;Lee et al, 2002;Dowdy et al, 2003;He et al, 2003;Wang et al, 2008). In this study, we found that FOXG1 was overexpressed in ovarian cancer cell lines and tissue samples.…”

“…For examples, decreased expressions or mutations in TGF-b R1, TGF-b RII and Smad4 have been frequently detected in a number of human cancers. (Eisma et al, 1996;Kim et al, 1996;Ko et al, 1998;Korchynskyi et al, 1999;Matsushita et al, 1999;Venkatasubbarao et al, 2000;Maurice et al, 2001;Paik et al, 2003;Sakaguchi et al, 2005;Perttu et al, 2006;Zhong et al, 2006).…”

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