Perspective - Journal of Cancer Clinical Research (2025) Volume 8, Issue 1

Transforming Growth Factor-�² (TGF-�²) as a Central Regulator in Physiological and Pathological Processes

Article type: Perspective

Home Page URL:  https://www.alliedacademies.org/journal-cancer-clinical-research/

Journal short name: J Can Clinical Res

Volume: 8

Issue: 1

PDF No: 179

Citation: Narula J. Transforming Growth Factor-β (TGF-β) as a Central Regulator in Physiological and Pathological Processes. J Can Clinical Res. 2025; 8(1):179

^*Correspondence to: Jagat Narula, Professor of Cardiology, University of California, Irvine, USA. Email: jnarula@hs.uci.edu       

Received: 27-May-2025, Manuscript No. AACCR-25-169791; Editor assigned: 01-Jun-2025, PreQC No. AACCR-25-169791 (PQ); Reviewed: 15- Jun-2025, QC No. AACCR-25-169791; Revised: 22- Jun-2025, Manuscript No. AACCR-25-169791 (R); Published: 29- Jun-2025, DOI:10.35841/AATCC-8.1.179

Transforming Growth Factor-β (TGF-β) as a Central Regulator in Physiological and Pathological Processes

Jagat Narul*

Professor of Cardiology, University of California, Irvine, USA

Introduction

Transforming Growth Factor-β (TGF-β) is a pleiotropic cytokine that plays a central role in various cellular processes, including proliferation, differentiation, apoptosis, immune regulation, and extracellular matrix production. It exists in three isoforms in mammals—TGF-β1, TGF-β2, and TGF-β3—each with distinct but overlapping biological functions. TGF-β is secreted by many cell types and exerts its effects through a well-conserved signaling pathway involving the activation of serine/threonine kinase receptors, Smad-dependent transcriptional regulators, and a variety of non-Smad pathways. Its involvement in multiple physiological and pathological conditions has rendered it one of the most extensively studied cytokines in modern biomedical science.The TGF-β signaling pathway begins with the binding of the ligand to the TGF-β type II receptor (TβRII), which then recruits and phosphorylates the type I receptor (TβRI). Activated TβRI subsequently phosphorylates receptor-regulated Smads (R-Smads), primarily Smad2 and Smad3. These R-Smads form a complex with Smad4, translocate into the nucleus, and regulate the transcription of target genes. In addition to the canonical Smad pathway, TGF-β also activates several non-canonical signaling cascades such as MAPK, PI3K/AKT, and Rho-like GTPase pathways, broadening its impact on cellular behavior.

In the immune system, TGF-β plays a dual role. It maintains immune homeostasis by suppressing the activation and proliferation of lymphocytes, macrophages, and dendritic cells. It also promotes the differentiation of regulatory T cells (Tregs), which are essential for peripheral tolerance. On the other hand, in the presence of pro-inflammatory cytokines like IL-6, TGF-β can drive the differentiation of pro-inflammatory Th17 cells, contributing to autoimmunity. This context-dependent behavior underscores the complex immunomodulatory functions of TGF-β.In the context of cancer, TGF-β functions as a double-edged sword. In the early stages of tumorigenesis, it acts as a tumor suppressor by inhibiting cell proliferation and inducing apoptosis. However, in advanced cancers, tumor cells often develop resistance to its growth-inhibitory effects and instead exploit TGF-β signaling to promote invasion, metastasis, and immune evasion. TGF-β induces epithelial-mesenchymal transition (EMT), a critical process in which epithelial cells lose their polarity and adhesion properties, acquiring a mesenchymal phenotype conducive to migration and metastasis. Moreover, TGF-β contributes to the formation of an immunosuppressive tumor microenvironment by recruiting Tregs and myeloid-derived suppressor cells (MDSCs) and inhibiting the function of cytotoxic T lymphocytes and natural killer cells.

In fibrotic diseases, TGF-β is recognized as a master regulator. It promotes the activation of fibroblasts and their differentiation into myofibroblasts, which secrete excessive amounts of extracellular matrix components, leading to tissue scarring and organ dysfunction. Elevated levels of TGF-β have been implicated in the pathogenesis of pulmonary fibrosis, liver cirrhosis, kidney fibrosis, and systemic sclerosis. The fibrotic actions of TGF-β are primarily mediated through Smad3, which directly stimulates the transcription of collagen and fibronectin genes. Moreover, TGF-β can suppress the expression of matrix-degrading enzymes while enhancing the production of tissue inhibitors of metalloproteinases (TIMPs), further favoring matrix accumulation.

TGF-β also plays a crucial role in cardiovascular biology. It regulates the development and maintenance of the vasculature, modulates endothelial function, and contributes to vascular remodeling. Dysregulated TGF-β signaling has been associated with various cardiovascular disorders, including atherosclerosis, hypertension, and cardiac fibrosis. In atherosclerosis, TGF-β exerts both protective and pathogenic roles. While it can suppress inflammation and stabilize plaques by promoting the deposition of a fibrous cap, excessive TGF-β activity can lead to pathological fibrosis and vascular stiffening. In the heart, TGF-β is a key driver of fibrotic remodeling post-myocardial infarction, leading to impaired cardiac function and heart failure.In the field of regenerative medicine, TGF-β has shown both potential and limitations. It is involved in wound healing by modulating inflammation, promoting re-epithelialization, and stimulating the production of extracellular matrix. However, prolonged or excessive TGF-β signaling can result in hypertrophic scars or keloids. In stem cell biology, TGF-β influences the maintenance and differentiation of various stem cell populations. For instance, it maintains the pluripotency of embryonic stem cells under certain conditions and guides lineage specification during development.

TGF-β’s role in the nervous system is also gaining increasing attention. It contributes to neurodevelopment, neuroprotection, and repair mechanisms. In the central nervous system (CNS), TGF-β is secreted by astrocytes and microglia and modulates neuroinflammation. While low levels of TGF-β are neuroprotective, high levels can be detrimental, contributing to neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis. Its involvement in the blood-brain barrier (BBB) integrity, synaptic plasticity, and response to injury further highlights its importance in brain physiology and pathology.Given its diverse functions, TGF-β has emerged as a promising therapeutic target in multiple diseases. Several strategies have been developed to modulate TGF-β signaling, including neutralizing antibodies, ligand traps, receptor kinase inhibitors, and antisense oligonucleotides. In oncology, inhibitors of TGF-β signaling are being tested to enhance the efficacy of immune checkpoint inhibitors and prevent metastasis. In fibrotic diseases, antifibrotic agents targeting TGF-β aim to halt or reverse tissue scarring. However, due to its broad and context-specific actions, systemic inhibition of TGF-β carries significant risks, including impaired wound healing, autoimmunity, and tissue degeneration. Thus, a precise understanding of disease context and careful patient selection are crucial for the success of TGF-β-targeted therapies.

Conclusion

Transforming Growth Factor-β (TGF-β) is a central regulator of diverse physiological and pathological processes, ranging from immune regulation and tissue repair to cancer progression and organ fibrosis. Its context-dependent actions make it both a protector and a perpetrator, necessitating a nuanced approach to therapeutic targeting. As our understanding of TGF-β signaling deepens through cutting-edge technologies and interdisciplinary research, new opportunities will emerge to harness its power for clinical benefit. The challenge lies not only in deciphering the complexity of its actions but also in translating this knowledge into safe and effective therapies that can transform the treatment landscape for some of the most challenging diseases of our time

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