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

It is now generally accepted that TGF-beta acts as a pro-metastatic factor in advanced human breast cancer. However, it is well documented, that TGF-beta is context dependent, and whether the TGF-beta pathway switches to promote metastasis during the progression of squamous cell carcinoma (SCC) is unknown. This study examined the role of TGF-beta signalling in SCC using a series of genetically related keratinocyte cell lines representing later stages of the disease, stably transduced with a dominant negative T beta RII cDNA (dnT beta RII). We demonstrated that clones expressing T beta RII lost their growth inhibitory response to TGF-beta in vitro, while ligand expression remained unchanged. Following transplantation of transduced cells to athymic mice in vivo, we showed that attenuation of the TGF-beta signal resulted in a loss of differentiation and increased metastasis. In human tissue samples loss of TGF-beta signal transduction as measured by pSmad2 activity also correlated with a loss of differentiation. Id1, previously shown to be down regulated by TGF-beta, 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-beta does not switch to promote metastasis in late stage human SCC of the skin and that inhibition of TGF-beta signalling results in a loss of differentiation and increased metastasis in the later stages of this disease. (C) 2010 Elsevier Ireland Ltd. All rights reserved.