TGF‐β Signaling in Cancer

Abstract

The transforming growth factor-β (TGF-β) is a family of structurally related proteins that comprises of TGF-β, activins/inhibins, and bone morphogenic proteins (BMPs). Members of the TGF-β family control numerous cellular functions including proliferation, apoptosis, differentiation, epithelial-mesenchymal transition (EMT), and migration. The first identified member, TGF-β is implicated in several human diseases, such as vascular diseases, autoimmune disorders, and carcinogenesis. Activation of the TGF-β receptor by its ligands induces the phosphorylation of serine/threonine residues and triggers phosphorylation of the intracellular effectors, SMADs. Upon activation, SMAD proteins translocate to the nucleus and induce transcription of their target genes, regulating several cellular functions. TGF-β dysregulation has been implicated in carcinogenesis. In early stages of cancer, TGF-β exhibits tumor suppressive effects by inhibiting cell cycle progression and promoting apoptosis. However, in late stages TGF-β exerts tumor promoting effects, increasing tumor invasiveness, and metastasis. Furthermore, the TGF-β signaling pathway communicates with other signaling pathways in a synergistic or antagonistic manner and regulates cellular functions. Elevated TGF-β activity has been associated with poor clinical outcome. Given the pivotal role of TGF-β in tumor progression, this pathway is an attractive target for cancer therapy. Several therapeutic tools such as TGF-β antibodies, antisense oligonucleotides, and small molecules inhibitors of TGF-β receptor-1 (TGF-βR1) have shown immense potential to inhibit TGF-β signaling. Finally, in the interest of developing future therapies, further studies are warranted to identify novel points of convergence of TGF-β with other signaling pathways and oncogenic factors in the tumor microenvironment.

Transforming growth factor-beta1 suppresses hepatocellular carcinoma proliferation via activation of Hippo signaling

“…TGF-β1 has multiple functions in tumors [19–22]. On the one hand, it induces EMT in tumor cells, while on the other hand, it can suppress the invasion and metastasis of cancer cells.…”

The concomitant apoptosis and EMT underlie the fundamental functions of TGF-β

“…The later identification of EMT-induction and other effects of TGF-β strengthened this notion of the dual effects of TGF-β on tumor development and progression, and also prompted the emerge of a modified notion of the dual effects of TGF-β, which emphasized the tumor suppressing effect at early stage and the promoting effect at late stage of tumorigenesis. According to this understanding, TGF-β was considered to be a tumor suppressor at early stage of tumorigenesis due to its growth arrest and/or pro-apoptotic effect on cells, and a tumor promoter at late stage of tumorigenesis because of its other effects including the induction of EMT [26][27][28][29][30]. However, several basic aspects of this proposed notion need to be clarified.…”

TRPP2 Enhances Metastasis by Regulating Epithelial-Mesenchymal Transition in Laryngeal Squamous Cell Carcinoma

“…Unequivocally, transforming growth factor-β (TGF-β) is a major inducer of different subtypes of EMT, including development, fibrosis, and carcinogenesis, in various cells [28]. In particular, TGF-β plays a major role in carcinoma progression into a motile, invasive state in which cells migrate and form a metastasis during tumour development, whereas in the early stages of tumour growth, TGF-β may have a tumour suppressive effect by inducing growth arrest and apoptosis [18,28,29]. Hence, as natural intracellular receptors of TGF-β, many Smad proteins, such as Smad2, Smad3 and Smad4, are phosphorylated after TGF-β binding to regulate the transcription of related genes and may participate in EMT as well [28,29].…”

“…In particular, TGF-β plays a major role in carcinoma progression into a motile, invasive state in which cells migrate and form a metastasis during tumour development, whereas in the early stages of tumour growth, TGF-β may have a tumour suppressive effect by inducing growth arrest and apoptosis [18,28,29]. Hence, as natural intracellular receptors of TGF-β, many Smad proteins, such as Smad2, Smad3 and Smad4, are phosphorylated after TGF-β binding to regulate the transcription of related genes and may participate in EMT as well [28,29]. In addition, previous reports have indicated that the transcription factor signal transducer and activator of transcription 3 (STAT3) can induce EMT in cancer cells through activation of TWIST gene expression by cooperating with the EGFR [30].…”