Mysteries of TGF-beta paradox in benign and malignant cells

TGF-beta regulates a wide range of biological functions including embryonic development, wound healing, organogenesis, immune modulation, and cancer progression. Interestingly, TGF-beta is known to inhibit cell growth in benign cells but promote progression in cancer cells; this phenomenon is known as TGF-beta paradox. To date, the mechanism of this paradox still remains a scientific mystery. In this review, we present our experience, along with the literature, in an attempt to answer this mystery. First, we observed that, on TGF-beta engagement, there is a differential activation of Erk between benign and cancer cells. Since activated Erk is a major mediator in tumor progression and metastasis, a differentially activated Erk represents the answer to this mystery. Second, we identified a key player, PP2A-B56 alpha, which is differentially recruited by the activated type I TGF-beta receptor (TB RI) in benign and tumor cells, resulting in differential Erk activation. Finally, TGF-beta stimulation leads to suppressed TBRs in tumor cells but not in benign cells. This differentially suppressed TBRs triggers differential recruitment of PP2A-B56a and, thus, differential activation of Erk. The above three events explain the mysteries of TGF-beta paradox. Understanding the mechanism of TGF-beta paradox will help us to predict indolent from aggressive cancers and develop novel anti-cancer strategies.