Transforming growth factor‐β enhances invasion and metastasis in Ras‐transfected human malignant epidermal keratinocytes

Summary Transforming growth factor‐β (TGF‐β) is known to act as a tumour suppressor early in carcinogenesis, but then switches to a pro‐metastatic factor in some late stage cancers. However, the actions of TGF‐β are context dependent, and it is currently unclear how TGF‐β influences the progression of human squamous cell carcinoma (SCC). This study examined the effect of overexpression of TGF‐β1 or TGF‐β2 in Ras‐transfected human malignant epidermal keratinocytes that represent the early stages of human SCC. In vitro , the proliferation of cells overexpressing TGF‐β1 or TGF‐β2 was inhibited by exogenous TGF‐β1; cells overexpressing TGF‐β1 also grew more slowly than controls, but the growth rate of TGF‐β2 overexpressing cells was unaltered. However, cells that overexpressed either TGF‐β1 or TGF‐β2 were markedly more invasive than controls in an organotypic model of SCC. The proliferation of the invading TGF‐β1 overexpressing cells in the organotypic assays was higher than controls. Similarly, tumours formed by the TGF‐β1 overexpressing cells following transplantation to athymic mice were larger than tumours formed by control cells and proliferated at a higher rate. Our results demonstrate that elevated expression of either TGF‐β1 or TGF‐β2 in cells that represent the early stages in the development of human SCC results in a more aggressive phenotype.