Review Article
Koichi Matsuzaki *
Abstract
Initial experiments leading to discovery of TGF-β and its designation as a "transforming" growth factor involved its ability to induce malignant behavior in mesenchymal cells such as fibroblasts. TGF-β, together with growth factors signaling via the receptor tyrosine kinase/Ras pathway, allowed proliferation of fibroblasts under anchorage-deficient conditions, a hallmark of cellular transformation. Several years later, TGF-β proved to have profound growthsuppressive effects in normal epithelial cells after transient Ras activation. As human benign tumors progress to carcinoma in situ, tumors with Ras-activating mutations tend to lose susceptibility to growth arrest by TGF-β. At invasive fronts of human advanced cancers, however, Ras and TGF-β pathways synergistically enable cancer cells to undergo epithelial-to-mesenchymal transition, thereby acquiring invasive and metastatic potential. Insights into the stepwise human carcinogenesis have emerged from recent detailed analyses of cell type-specific and contextdependent TGF-β signaling processes directed by multiple phosphorylated forms (phospho-isoforms) of Smad mediators.This review links advances in basic science with real-world clinical problems concerning Smadphosphoisoform signaling.