Editorial: TGF-β in Human Disease: Friend or Foe?
Guoping Zheng1,2*† 
David C. H. Harris1,2,3†- 1Westmead Institute for Medical Research, Sydney, NSW, Australia
- 2Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
- 3Westmead Hospital, Westmead, NSW, Australia
Editorial on the Research Topic
TGF-β in Human Disease: Friend or Foe?
TGF-β is a family of essential multifunctional cytokines regulating (1) cell growth & development at both embryonic and adult stages; (2) inflammation and maintenance of host resistance mechanisms; and (3) remodeling and repair processes including angiogenesis and regeneration. However, conflicting roles of TGF-β in human diseases create a major challenge to the therapeutic targeting of this multifunctional cytokine.
In this issue, the protean roles of TGF-β in humans are discussed in chronic inflammatory diseases characterized with inflammation and fibrosis, in cerebrovascular disease and in cancer. The chronic inflammatory diseases included are chronic kidney disease, diabetic kidney disease, cardiac fibrosis, pulmonary arterial hypertension, atherosclerosis, and fibrosis of other organs. TGF-β-induced fibrosis of the diseased organs is one of the most prominent features of these diseases. TGF-β contributes to organ fibrosis by induction of mesenchymal transition, namely epithelial-mesenchymal transition (EMT) and endothelial-mesenchymal transition (EndoMT), although their direct contribution to the origin of myofibroblasts in organ fibrosis has been debated (Ma et al.). The potential of TGF-β-induced EndoMT in tissue engineering is reviewed. In addition, TGF-β's induction of mesenchymal transition is discussed with regard to its contribution to development of cerebrovascular diseases such as cerebral cavernous malformation due to maladaptive dysfunction of TGF-β (Zhang and Yang). Post-translational modification of SMAD ubiquitin regulatory factor 2 (Smurf2) is reviewed for its role in regulating TGF-β signaling and its potential for targeting TGF-β signaling in human fibrotic diseases and cancer (Bai and Ying). p53, a tumor suppressor, was found to complex with SMADs to transcriptionally regulate genomic TGF-β1 fibrotic-response gene profiles. SMADs/p53 targeted genes and cross-talking pathways are discussed as targets for treating kidney fibrosis (Higgins et al.). The protective anti-inflammatory roles of TGF-β via differential functions of the SMAD family members are reviewed in kidney disease (Gu et al.). New candidate targets for treatment of kidney fibrosis, receptor interacting protein kinase 3 (RIPK3) (Shi et al.) and calcium-activated potassium channel KCa3.1 (Huang et al.) are discussed. An important review article discusses in depth the lack of success of on-target anti-TGF-β therapies in clinical cancer treatment as well as remaining challenges (Teixeira et al.).
The conflicting roles of TGF-β, which may slow or accelerate progression of various human diseases, render it unsuitable as a therapeutic target. Indeed, anti-TGF-β therapies have proven unsuccessful in clinical trials for fibro-inflammatory kidney disease (Vincenti et al., 2017), and in cancer clinical trials (Ahmadi et al., 2019).
To resolve the conflicting anti-inflammatory and profibrotic roles of TGF-β in inflammatory diseases, rebalancing of Smad3/Smad7 signaling or specifically targeting Smad3-dependent non-coding RNAs that regulate kidney fibrosis or inflammation suggested as better therapeutic approaches for kidney fibrosis (Gu et al.).
Similarly in cancer, TGF-β inhibits proliferation and induces apoptosis of cancer cells, but it also promotes metastasis by inducing the invasive phenotype of tumor cells through induction of epithelial-mesenchymal transition (EMT). Furthermore, it causes immuno-suppression, including the induction of immunosuppressive checkpoint molecule PD-1, which inactivates the anti-tumor function of immune cells. Combination of anti-TGF-β therapies with immune checkpoint inhibitors, or more spatio-temporal controlled interventions, are suggested by Teixeira et al for improved treatment of cancer (Teixeira et al.).
Previously, a mechanism to explain the multiple functions of TGF-β had been proposed by Massagué. He suggested that the net outcome of TGF-β signals is determined by a cell specific complex network of cross-talking signals. The combined DNA-binding specificity of a SMAD-cofactor complex dictates the choice of target gene, whereas SMAD affinity for DNA is too low to do that alone (Massague, 2000). β-catenin binding to SMAD as a cofactor enables a cell specific cross-talk between TGF-β and Wnt pathways. Foxo has been identified as another co-factor of β-catenin competing with TCF.
β-catenin binds to either TCF or Foxo to produce opposite signaling outcomes: proliferation (β-catenin/TCF) or cell cycle arrest for survival under oxidative stress (β-catenin/Foxo). TGF-β mediates pro-fibrotic signaling via cross-talk with multiple pathways including Wnt/β-catenin, integrin/integrin linked kinase (ILK), the renin angiotensin system (RAS), Notch/NICD and mROR, all converging at activation of β-catenin/TCF (Figure 1). In this context, Qiao and colleagues revealed in murine models of kidney fibrosis that the inhibition of β-catenin/TCF prevented the profibrotic effects of TGF-β while promoting its anti-inflammatory function via concomitant β-catenin/Foxo1-induction of regulatory T cells (Tregs) (Qiao et al., 2018, Rao et al., 2019, Rao et al., 2021; Figure 1). This has been confirmed by other labs; the β-catenin/Foxo complex induces Tregs (Sumida et al., 2018) and protects against kidney fibrosis (Nlandu-Khodo et al., 2020).
Figure 1. Cell specific cross-talking pathways in fibro-inflammatory disease and cancer.
In summary, the papers in this issue illustrate how the various paradoxical functions of TGF-β signaling may be targeted to design and optimize therapeutic approaches for patients suffering from diseases associated with TGF-β. More importantly, dissection of the unique and often conflicting roles of transcription cofactor complexes holds great promise for targeting TGF-β pathways in human disease (Emami et al., 2004).
Author Contributions
GZ contributed to conception and drafting and final approval of the manuscript. DH contributed to conception and final approval of the manuscript. All authors contributed equally to the article and approved the submitted version.
Funding
GZ and DH are supported by NHMRC project grant 1141235 and investigator grant 1195473.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher's Note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
Ahmadi, A., Najafi, M., Farhood, B., and Mortezaee, K. (2019). Transforming growth factor-beta signaling: tumorigenesis and targeting for cancer therapy. J. Cell. Physiol. 234, 12173–12187. doi: 10.1002/jcp.27955
Emami, K.H., Nguyen, C., Ma, H., Kim, D.H., Jeong, K.W., Eguchi, M., et al. (2004). A small molecule inhibitor of beta-catenin/CREB-binding protein transcription [corrected]. Proc. Natl. Acad. Sci. U.S.A. 101, 12682–12687. doi: 10.1073/pnas.0404875101
Massague, J. (2000). How cells read TGF-beta signals. Nat. Rev. Mol. Cell Biol. 1, 169–178. doi: 10.1038/35043051
Nlandu-Khodo, S., Osaki, Y., Scarfe, L., Yang, H., Phillips-Mignemi, M., Tonello, J., et al. (2020). Tubular β-catenin and FoxO3 interactions protect in chronic kidney disease. JCI Insight. 5:e135454. doi: 10.1172/jci.insight.135454
Qiao, X., Rao, P., Zhang, Y., Liu, L., Pang, M., Wang, H., et al. (2018). Redirecting TGF-beta signaling through the beta-catenin/foxo complex prevents kidney fibrosis. J. Am. Soc. Nephrol. 29, 557–570. doi: 10.1681/ASN.2016121362
Rao, P., Pang, M., Qiao, X., Yu, H., Wang, H., Yang, Y., et al. (2019). Promotion of beta-catenin/Foxo1 signaling ameliorates renal interstitial fibrosis. Lab. Invest. 99, 1689–1701. doi: 10.1038/s41374-019-0276-z
Rao, P., Qiao, X., Hua, W., Hu, M., Tahan, M., Chen, T., et al. (2021). Promotion of β-catenin/Foxo signaling mediates epithelial repair in kidney injury. Am. J. Pathol. 191:993–1009. doi: 10.1016/j.ajpath.2021.03.005
Sumida, T., Lincoln, M. R., Ukeje, C. M., Rodriguez, D. M., Akazawa, H., Noda, T., et al. (2018). Activated beta-catenin in Foxp3(+) regulatory T cells links inflammatory environments to autoimmunity. Nat. Immunol. 19, 1391–1402. doi: 10.1038/s41590-018-0236-6
Vincenti, F., Fervenza, F. C., Campbell, K. N., Diaz, M., Gesualdo, L., Nelson, P., et al. (2017). A Phase 2, Double-blind, placebo-controlled, randomized study of fresolimumab in patients with steroid-resistant primary focal segmental glomerulosclerosis. Kidney Int. Rep. 2, 800–810. doi: 10.1016/j.ekir.2017.03.011
Keywords: TGF-β, inflammation, fibrosis, cancer, TCF, Foxo (forkhead box protein O), p53, SMAD
Citation: Zheng G and Harris DCH (2021) Editorial: TGF-β in Human Disease: Friend or Foe? Front. Cell Dev. Biol. 9:739172. doi: 10.3389/fcell.2021.739172
Received: 10 July 2021; Accepted: 08 September 2021;
Published: 29 September 2021.
Edited and reviewed by: Ramani Ramchandran, Medical College of Wisconsin, United States
Copyright © 2021 Zheng and Harris. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Guoping Zheng, guoping.zheng@sydney.edu.au
†These authors share senior authorship