Transforming Growth Factor (TGF) is a class of biologically active peptides that regulate cell growth, differentiation, and function. TGF, including TGF-α and TGF-β, have important physiological regulatory effects on cell development, growth, proliferation, differentiation, and apoptosis.

TGF-α is a mitogenic polypeptide that belongs to the epidermal growth factor superfamily of cytokines. TGF-α consists of 50 amino acids and shares 35-40% homology with EGF, the prototypic member of the EGF superfamily. Like EGF, TGF-α is a ligand for the epidermal growth factor receptor (EGFR). TGF-α binds to EGFR and stimulates the intact RAS/RAF/MAPK pathway, leading to the transcription of genes associated with cell proliferation, invasion, and metastasis.

TGF-β is a multifunctional cytokine synthesized by a variety of tissue cells. It regulates cell growth and differentiation in an autocrine or paracrine manner and is widely involved in various pathophysiological processes in mammals, playing an important role in embryonic development, trauma healing, bone remodeling, immune regulation, neurological development, and tumor prevention and treatment.

Currently, TGF-β-targeting agents have become a new hot research direction. Understanding the mechanism of TGF-β signaling and the current status of the application of TGF-β inhibitors is crucial for the efficacy of tumor therapy and the reduction of side effects.

 

Since the discovery of TGF-β1, more than 30 members of the TGF-β superfamily have been identified and characterized, sharing commonalities in their synthesis, signaling mechanisms, and functions. Based on their structural and functional similarities, the TGF-β superfamily is divided into the TGF-β and bone morphogenetic protein (BMP) subfamilies.
 
Typically, the TGF-β subfamily includes TGF-βs, activins, Nodal, while the BMP subfamily contains BMP, growth and differentiation factors (GDF), and anti-Mullerian hormone (AMH).
 
Three highly homologous TGF-β isoforms exist in mammals, TGF-β1, TGF-β2, and TGF-β3. Among the TGF-β superfamily, the TGF-β subtype has been studied most extensively. According to The Cancer Genome Atlas (TCGA), TGF-β1 is the most commonly expressed subtype in most human cancers. In addition, TGF-β1 expression is most closely associated with TGF-β signaling activation compared to TGF-β2 and TGF-β3.

 

TGF-β superfamily members

03 "Double-sided" Targets TGF-β

The TGF-β signaling pathway contains a variety of functional cytokines, and there are three subtypes of TGF-β1, TGF-β2, and TGF-β3. TGF-β plays an important role in cell proliferation, differentiation, migration, apoptosis, epithelial-mesenchymal transition (EMT), extracellular matrix deposition, and regulation of inflammation through the TGF-β/SMAD signaling pathway, and is involved in mediating biological processes such as normal growth and development of tissues and organs, and immune responses.
 

 
TGF-β cell signaling pathway

In the early stage of tumor formation, TGF-β inhibits tumor growth mainly by triggering the cell arrest and apoptosis programs of cancer cells. During tumor development, the inhibitory effect of TGF-β on the proliferation of tumor cells will be reduced or even disappear and a large amount of TGF-β will be secreted, which can then become a promoter of tumor cell growth.

TGF-β achieves its tumor-promoting effects through a variety of mechanisms. For example, TGF-β can achieve immunosuppression by inhibiting the proliferation and function of some immune cells, such as T cells; TGF-β induces the secretion of connective tissue growth factor (CTGF), endothelin-1, and vascular endothelial growth factor (VEGF), and promotes the formation of blood vessels and tumor fibrous mesenchyme.

Importantly, TGF-β signaling in tumor epithelial cells also induces the formation of a microenvironment (TME) conducive to tumor metastasis, which promotes epithelial-mesenchymal transition (EMT) of tumors by inducing the expression of transcription factors such as Snail1/2, ZEB1/2, and HMGA2, which in turn represses the expression of epithelial cell adhesion proteins, and induces the expression of mesenchymal proteins. EMT transformation is associated with tumor metastasis and chemotherapy resistance.
 

 
TGF-β signaling for cancer inhibition and promotion

04 TGF Function

Promotes cell growth: activate intracellular signaling pathways by binding to serine/threonine kinase receptors on the cell surface, thereby promoting cell growth and proliferation.

Promote cell differentiation: induce stem cells to differentiate into specific types of cells, such as cardiomyocytes, osteocytes, etc.

Promote cell migration: induce cells to move from one place to another and participate in the process of tissue repair and regeneration.

Inhibit apoptosis: prolong cell life and maintains tissue homeostasis by inhibiting the expression of apoptosis-related proteins.

Regulation of immune response: affect the growth, differentiation and function of immune cells, involved in immune response and inflammatory response.

05 TGF Application

Due to the important role of transforming growth factors in organisms, they have a wide range of applications in medical and biological research. Such as:

Tumor research: certain transforming growth factors can promote the growth and invasion of tumor cells, and thus can be used as targets for tumor therapy.

Tissue engineering: the use of transforming growth factors to induce the differentiation of stem cells into specific types of cells can enable cell replacement therapy in tissue engineering.

TGF is a class of cytokines with important roles in both the maintenance of normal physiological functions of the body and the development of diseases. Its in-depth study can help provide new targets and strategies for the diagnosis and treatment of related diseases.