Recent advances in TGFβ‐regulated transcription during carcinogenesis

Abstract

The multifunctional activities of transforming growth factor-beta (TGFβ) endow it with both tumor suppressor and tumor promoting activities, depending on the stage of carcinogenesis and the cellular activation state. In early tumor stages, TGFβ inhibits epithelial cell growth through induction of apoptosis and transcriptional regulation of cell cycle controlling genes. During tumor progression, however, many cancer cells escape from TGFβ-induced growth inhibition and, instead, respond to TGFβ with increased malignancy. TGFβ stimulates tumor promotion particularly in those tumor cells in which Smad-signaling remains functional and through transcriptional regulation of gene expression. Thus, loss of sensitivity to growth inhibition by TGFβ is not synonymous with complete loss of TGFβ signaling. Rather, it suggests that tumor cells gain advantage by selective inactivation of TGFβ tumor suppressor activities while retaining its tumor promoting functions. In this review we focus on novel aspects in TGFβ signaling and transcription and in particular on the role of Smad-interacting transcription factors. We also summarize recent advances in both cytoplasmic and nuclear crosstalk mechanisms between Smad and non-Smad signaling pathways and how this interaction results in the fine-tuning of Smad-mediated transcription during cancer progression. This knowledge will help to better understand the molecular mechanisms responsible for the switch of TGFβ from a tumor suppressor to a tumor promotor.