TGF-β inhibits metastasis in late stage human squamous cell carcinoma of the skin by a mechanism that does not involve Id1

• Published in: Cancer letters Vol. 298; no. 1; pp. 107 - 118
• Main Authors: Ganapathy, Anu, Paterson, Ian C, Prime, Stephen S, Eveson, John W, Pring, Miranda, Price, Nicky, Threadgold, Suzy P, Davies, Maria
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 01.12.2010
• Subjects: Animals; Carcinogenesis; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - pathology; Carcinoma, Squamous Cell - therapy; Cell Differentiation - physiology; Hematology, Oncology and Palliative Medicine; Humans; Id1; Immunohistochemistry; Inhibitor of Differentiation Protein 1 - genetics; Inhibitor of Differentiation Protein 1 - metabolism; Keratinocyte; Mice; Mice, Nude; Neoplasm Metastasis; Signal Transduction; Skin Neoplasms - genetics; Skin Neoplasms - metabolism; Skin Neoplasms - pathology; Skin Neoplasms - therapy; Squamous cell carcinoma; TGF-β; Transfection; Transforming Growth Factor beta - antagonists & inhibitors; Transforming Growth Factor beta - genetics; Transforming Growth Factor beta - metabolism; Up-Regulation; TGF-β; Keratinocyte; Squamous cell carcinoma; Carcinogenesis; Id1
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2010.06.008

Abstract It is now generally accepted that TGF-β acts as a pro-metastatic factor in advanced human breast cancer. However, it is well documented, that TGF-β is context dependent, and whether the TGF-β pathway switches to promote metastasis during the progression of squamous cell carcinoma (SCC) is unknown. This study examined the role of TGF-β signalling in SCC using a series of genetically related keratinocyte cell lines representing later stages of the disease, stably transduced with a dominant negative TβRII cDNA (dnTβRII). We demonstrated that clones expressing dnTβRII lost their growth inhibitory response to TGF-β in vitro, while ligand expression remained unchanged. Following transplantation of transduced cells to athymic mice in vivo, we showed that attenuation of the TGF-β signal resulted in a loss of differentiation and increased metastasis. In human tissue samples loss of TGF-β signal transduction as measured by pSmad2 activity also correlated with a loss of differentiation. Id1, previously shown to be down regulated by TGF-β, an inhibitor of differentiation and associated with metastasis, was weakly expressed in focal areas of a small number of human tumours but expression did not correlate with low levels of pSmad2. Our data demonstrate that TGF-β does not switch to promote metastasis in late stage human SCC of the skin and that inhibition of TGF-β signalling results in a loss of differentiation and increased metastasis in the later stages of this disease.