The TGF-β Paradox in Human Cancer: An Update

Abstract

Summary Transforming growth factor-β (TGF-β) plays an essential role in maintaining tissue homeostasis through its ability to induce cell cycle arrest, differentiation, apoptosis, and to preserve genomic stability. Thus, TGF-β is a potent anticancer agent that prohibits the uncontrolled proliferation of epithelial, endothelial, and hematopoietic cells. Interestingly, tumorigenesis typically elicits aberrations in the TGF-β signaling pathway that engenders resistance to the cytostatic activities of TGF-β, thereby enhancing the development and progression of human malignances. Moreover, these genetic and epigenetic events conspire to convert TGF-β from a suppressor of tumor formation to a promoter of their growth, invasion, and metastasis. The dichotomous nature of TGF-β during tumorigenesis is known as the “TGF-β Paradox,” which remains the most critical and mysterious question concerning the physiopathological role of this multifunctional cytokine. Here we review recent findings that directly impact our understanding of the “TGF-β Paradox” and discuss their importance to targeting the oncogenic activities of TGF-β in developing and progressing neoplasms.

Deletion of periostin reduces muscular dystrophy and fibrosis in mice by modulating the transforming growth factor-β pathway

“…The use of the TGF-β-blocking antibody worsened MD and resulted in greater functional decline in double-null mice. These findings support a complex interaction between periostin and TGF-β that may be related to the TGF-β paradox, where it can be both beneficial and deleterious depending on dosage and costimulatory factors (17). Periostin expression in epithelial cells has been shown to stimulate TGF-β signaling and lead to enhanced collagen production and expression of matrix metalloproteinase 2 and MMP9 for further matrix remodeling (31).…”

“…Although inhibition of TGF-β is typically protective in MD, the protection that we observed in dystrophic mice lacking Postn was reversed by administration of a TGF-β-blocking antibody, suggesting another example of the so-called "TGF-β paradox" (17). Thus, therapeutic manipulation of periostin may offer another means of altering MD disease progression when TGF-β responsiveness is targeted.…”

“…6B). The deleterious effects of TGF-β blockade in the Sgcd −/− Postn −/− mice may be related to the TGF-β paradox described in the oncology literature (17), which in skeletal muscle may reflect an interplay between myofiber regeneration versus ongoing fibrosis and ECM remodeling. Indeed, assessment of regeneration by reexpression of MyoD, myogenin, and Pax7 in the different groups of mice suggested that TGF-β-neutralizing antibody enhanced regeneration in single-null Sgcd mice, but inhibited regeneration in Sgcd −/− Postn −/− mice (Fig.…”

Construction of eukaryotic expression vector pTAR-GET- DNT?R? and its expression in breast cancer COS-7 cells

“…In our study, we synthesize the gene of human dominant-negative transforming growth factor beta receptor (DNTβR Ⅱ ) by PCR amplification, and construction of pTAR-GET-DNTβR Ⅱ eukaryotic expression vector. DNTβR Ⅱ does not contain Ser/Thr kinase domain in it, so it also can combine with TβRII, but it can't start the downstream signaling pathways (Tian and Schiemann, 2009;Massague and Gomis, 2006). In addition, peptide chain which express a large number of DNTβRⅡ transfer to the cell membrane, competitive inhibition of normal TβRII, blocking of TGF-β signaling pathways in In our study, we synthesize the gene of human dominant-negative transforming growth factor beta receptor (DNTβR Ⅱ ) by means of oligo chemic synthesis and PCR amplification, and successfully construction of eukaryotic expression vector pTAR-GET-DNTβR Ⅱ .…”

“…Based on various prospective and retrospective studies, blocking of TGF-β signaling pathway can obviously enhance the antitumor effect of adoptive T-cells (Wrzesinski et al, 2007;Joshi and Cao, 2010). TGF-β starts the downstream signaling pathways should first combined with TβRⅡ in cell membrane, the transfection of DNTβR Ⅱ can competitive inhibition of normal TβRII , blocking of TGF-β signaling pathways, as a result, the construction of eukaryotic expression vector is a basis for further study (Tian and Schiemann, 2009). In our study, we construct eukaryotic expression vector pTAR-GET-DNTβRⅡ and express it successfully in breast cancer COS-7 cells, and may provide basis for further study of breast cancer anti-tumor immunotherapy by adoptive immune cell therapy.…”