Mysteries of TGF-β Paradox in Benign and Malignant Cells.

Qiang Zhang,Chung Lee,Nengwang Yu

doi:10.3389/fonc.2014.00094

Abstract

TGF-β regulates a wide range of biological functions including embryonic development, wound healing, organogenesis, immune modulation, and cancer progression. Interestingly, TGF-β is known to inhibit cell growth in benign cells but promote progression in cancer cells; this phenomenon is known as TGF-β 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-β 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-B56α, which is differentially recruited by the activated type I TGF-β receptor (TBRI) in benign and tumor cells, resulting in differential Erk activation. Finally, TGF-β stimulation leads to suppressed TBRs in tumor cells but not in benign cells. This differentially suppressed TBRs triggers differential recruitment of PP2A-B56α and, thus, differential activation of Erk. The above three events explain the mysteries of TGF-β paradox. Understanding the mechanism of TGF-β paradox will help us to predict indolent from aggressive cancers and develop novel anti-cancer strategies.

Highlights

TGF-β was initially described in 1982 [1]
Erk is constantly in an activated state [17, 20] and Smad activation is suppressed, regardless of the level of TGF-β employed. This finding has an important implication in TGF-β paradox, that is, in benign cells or early stage cancer cells, TGF-β offers a mechanism for homeostasis; whereas in advanced cancer cells, it promotes tumor progression (Figure 1)
POSITIVE FEEDBACK OF TGF-β SIGNALING IN TUMOR PROGRESSION In summary, this review indicates that a differential Erk activation plays a central role in deciding whether the target cell will undergo growth arrest or proliferation in response to TGF-β

Summary

Introduction

TGF-β was initially described in 1982 [1]. It was already known to have bi-functional effects, as it can stimulate or inhibit growth of the same cell, depending on conditions [2]. In advanced cancer cells, treatment with TGF-β would result in Erk activation and cell proliferation [16, 17, 21, 24]. This phenomenon is applied only to benign cells or early-stage cancer cells, as in advanced cancer cells, there will be no such linear relationship in Smad activation and Erk inactivation upon TGF-β stimulation.

Results

Conclusion