Over‐expression of TGF‐β1 in Smad4‐deficient human oral carcinoma cells causes tumour regression in vivo by mechanisms that sensitize cells to apoptosis

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Abstract
We have shown previously that transforming growth factor‐β (TGF‐β) is a potent tumour suppressor in Smad4‐deficient human malignant oral keratinocytes but the mechanism by which this occurs is unknown. In the present study, we show that over‐expression of TGF‐β1 causes regression of tumours derived from Smad4‐deficient oral keratinocytes transplanted orthotopically to athymic mice. Further, tumour regression is associated with the induction of apoptosis without changes in cell proliferation. In vitro, TGF‐β1 did not induce apoptosis directly in these cells but sensitized cells to cisplatin, but not Fas, ‐induced cell death. The data suggest that TGF‐β1 induces tumour regression in vivo by Smad4‐independent pathways that sensitize keratinocytes to mitochondrial‐mediated apoptosis. Copyright © 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.