Transforming growth factor-β (TGF-β) is a multifunctional cytokine that plays pivotal roles in cellular processes such as proliferation, differentiation, and apoptosis. However, in cancer, TGF-β exhibits a dual nature: it can act as a tumor suppressor in normal cells and early-stage tumors but promotes tumor progression and metastasis in advanced cancers. This complexity makes TGF-β a challenging yet promising target for cancer therapy. This article explores the mechanisms by which dysregulated TGF-β signaling contributes to various cancers and discusses potential therapeutic strategies.
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Fig. 1 Transforming growth factor beta in cancer (Boye A. 2021).
Structure of TGF-β
The TGF-β family in mammals includes 33 genes, each encoding a polypeptide with three key regions: a secretion signal peptide, a pro-domain of approximately 250 residues, and a growth factor (GF) domain of about 110 residues. In humans, TGF-β is a 25 kD disulfide-linked dimeric protein, existing in three isoforms: TGF-β1, TGF-β2, and TGF-β3. These proteins are initially synthesized as inactive Pro-TGF-β molecules. Activation involves cleavage by furin, a subtilisin-like pro-protein convertase, separating the N-terminal latency-associated peptide (LAP) from the C-terminal mature peptide, leading to dimerization and functional TGF-β formation.
The cleaved complex is then transported to the extracellular matrix (ECM), where it binds to the latent TGF-β binding protein (LTBP), forming large latent complexes. These complexes interact with specific proteases in the ECM, which trigger the activation of TGF-β, allowing it to engage in cell signaling processes. TGF-β1 is the most prevalent isoform, promoting the growth and differentiation of bones, cartilage, skin, and endochondral tissues.
Distinctive functions and distributions of the TGF-β family are influenced not only by Type I and Type II receptors, which show a degree of promiscuity towards various growth factors but also by other factors such as binding proteins and enzymes. These elements diversify signaling activities, incorporating Type III co-receptors and repulsive guidance molecule (RGM) co-receptors, along with various binding proteins like noggin, follistatin, chordin, and Dan proteins. Enzymes, including pro-protein convertases (PCs) and matrix metalloproteinases, further modulate the signaling by cleaving pro-domains from GF domains intracellularly during biosynthesis or extracellularly.
Biological Function of TGF-β
TGF-β1, the most common isoform, plays a crucial role in promoting the growth and differentiation of bones, cartilage, skin, and endochondral tissues. It is vital during embryogenesis and in maintaining tissue homeostasis in multicellular organisms. For instance, Bone morphogenetic protein 4 (BMP4), a TGF-β superfamily member, is involved in early cell proliferation and development of neural, pituitary, bone, and dermal cells. TGF-β superfamily members regulate embryonic stem cells and tumor suppression by inhibiting multi-potent hematopoietic progenitors, suppressing epithelial tumors, and promoting lineage commitment of neural precursors.
TGF-β exerts growth restraints on neoplastic cells, inhibiting cell proliferation while promoting differentiation in normal cells. It suppresses cell proliferation in epithelial, neuronal, and hematopoietic cells through a coordinated cytostatic response, interfering with tumorigenesis by targeting critical cell cycle stages, promoting apoptosis, and suppressing other growth factors involved in cell cycle regulation. In neoplastic cells, TGF-β induces cell cycle arrest at the G1 phase by upregulating cyclin-dependent kinase (CDK) inhibitors and inhibiting c-Myc. Additionally, it inhibits cyclin protein complex formation, stimulates the expression of p15ink4b or p21, and induces pro-apoptotic proteins, mediating dephosphorylation of p70S6K by PP2A, resulting in cell cycle arrest. TGF-β also activates caspase 3 in early tumorigenesis by modulating the balance between Bax and Bcl-2.
Smad Proteins as Key Downstream Mediators of TGF-β Signaling
The discovery of Smad proteins originated from genetic studies on Caenorhabditis elegans and Drosophila melanogaster. These proteins are central to TGF-β signaling, functioning as substrate transcription factors that mediate intracellular responses. Smads are modular proteins with conserved Mad-homology (MH), MH1, intermediate linker, and MH2 domains. There are three types of Smad proteins:
Receptor-activated Smads (R-Smads): These include Smad1, Smad2, Smad3, Smad5, and Smad8, which interact with and are phosphorylated by active TβRI following TGF-β activation of TβRII.
Co-Smad (Smad4): Acts as a common mediator for R-Smads, facilitating their translocation into the nucleus.
Inhibitory Smads (Smad6 and Smad7): These prevent TGF-β receptor binding, phosphorylation, and the translocation of Smad2/3/4 complexes into the nucleus by recruiting ubiquitin ligases that induce proteasomal degradation.
Canonical TGF-β/Smad Signaling
TGF-β binding to its serine/threonine membrane receptors (TβRI and TβRII) induces phosphorylation of R-Smads. These phosphorylated Smads oligomerize with Smad4, forming a complex that translocates to the nucleus to regulate gene transcription. The Smad2/3/4 complex shuttles between the cytoplasm and the nucleus, undergoing cycles of phosphorylation and dephosphorylation. Smad7 recruits the PP1/GADD34 complex to activated TGF-β receptors, preventing further phosphorylation and thus inhibiting the signaling pathway. TGF-β has a dual role, acting as a tumor suppressor in early tumorigenesis but promoting tumor growth in later stages due to mutations in Smads and other signaling mediators.
Non-Smad TGF-β Signaling
TGF-β signaling involves both canonical Smad-dependent and non-canonical Smad-independent pathways. Cross-signaling with other pathways, such as MAPK, modulates downstream responses. For example, TGF-β activation of JNK or ERK1/2 leads to cell-type-specific outcomes, including transcription of oncogenes that promote proliferation and survival in cancer cells. The involvement of MAPKs in cancer and inflammatory diseases has led to the development of small molecule inhibitors targeting TGF-β/MAPK signaling, showing promise in treating certain cancers.
TGF-β and Cancer Initiation and Progression
In breast cancer, TGF-β induces epithelial-mesenchymal transition (EMT) via the PI3K/Akt/GSK-3β/β-catenin pathway, enhancing tumor invasiveness and migration. It also promotes cancer cell dissemination through the lymphatic system mediated by CCR7/CCL21 chemotaxis. TGF-β enhances vascularization by increasing pericyte-endothelium interactions and supports fibroblast-mediated tumor growth through MMP-9. Moreover, HER2/EGFR signaling switches TGF-β's role from tumor suppression to the promotion of invasiveness by regulating the nuclear localization of Smad3 via AKT.
TGF-β signaling in prostate cancer induces EMT and increases invasive potential, especially in PTEN/TP53-null models. Androgen receptor (AR) and miR-21 downregulate TGF-β receptor II (TβRII), suggesting that targeting AR and miR-21 could be therapeutic. AR also suppresses Smad3 function, thus inhibiting TGF-β's tumor-suppressive effects.
TGF-β promotes EMT and invasion in melanomas through pathways involving PDGF and PI3K. It also stimulates VEGF secretion via TβRII/Smad3 signaling, enhancing tumor vascularization. Inhibitors of TGF-β signaling, such as Smad7 and TβR1 inhibitors, have shown promise in reducing tumor growth and metastasis.
In colorectal cancer, TGF-β/Smad signaling enhances metastasis by increasing vimentin and reducing E-cadherin expression. miR-4775 also promotes EMT and invasion via Smad2-mediated pathways. Inhibitors like LY2152299 have demonstrated efficacy in suppressing tumorigenesis by targeting TGF-β signaling.
TGF-β promotes EMT and metastasis in lung cancer through pathways involving SOX9, PI3K/MEK1, and IL-6/JAK/STAT3 signaling. Elevated TGF-β1 expression correlates with poor prognosis. Targeting TGF-β signaling, including cross-talk with PI3/Akt and MAPK pathways, could inhibit lung cancer progression.
In pancreatic cancer, resistance to TGF-β and mutations in Smad4 contribute to tumor progression. TGF-β stimulates a pro-inflammatory environment through exosome-mediated activation of Kupffer cells. Targeting Smad4 and TGF-β signaling pathways offers therapeutic potential.
TGF-β enhances ovarian cancer metastasis through Smad3-dependent mechanisms and upregulation of MMPs. It also triggers nc886 expression, which suppresses microRNAs and promotes cell adhesion, migration, and drug resistance. Inhibitors like TβR1 inhibitors show promise in reducing cancer cell proliferation and invasion.
Loss of TGF-β signaling components and cross-talk with Wnt/β-catenin pathways promote cervical cancer progression. Overexpression of let-7a reduces TGF-β1/Smad4 levels, suggesting a diagnostic potential. Inhibitors targeting these pathways could be effective therapeutic strategies.
TGF-β signaling in liver cancer promotes EMT and metastasis through pathways involving MEF2, Egr1, and integrin subunits. HBV and HCV infections exacerbate TGF-β signaling, enhancing tumor progression. Targeting integrin subunits and signaling intermediates like SULF1 and CXCR4 could inhibit tumor growth.
In gliomas, TGF-β induces cell migration and proliferation via integrins and PDGF signaling. Inhibition of TGF-β signaling reduces tumor invasion and improves survival in experimental models. Small molecule inhibitors and siRNA targeting TGF-β pathways show therapeutic potential.
Therapeutic Implications and Future Directions
The complex roles of TGF-β in cancer underscore the need for targeted therapies that minimize systemic side effects. Monoclonal antibodies and specific inhibitors targeting upstream or downstream components of TGF-β signaling offer promising avenues. The extracellular matrix (ECM), a critical regulator of TGF-β activity, also presents therapeutic opportunities. Modulating ECM components and their interactions could effectively disrupt TGF-β-driven tumorigenesis.
Conclusion
Dysregulated TGF-β signaling is a hallmark of various cancers, driving processes such as EMT, invasion, and metastasis. Understanding the molecular mechanisms underlying TGF-β's dual roles in cancer progression provides valuable insights for developing targeted therapies. Future research should focus on refining these therapeutic strategies to achieve specificity and minimize adverse effects, ultimately improving patient outcomes in TGF-β-related cancers.
References
- Boye A. A cytokine in turmoil: transforming growth factor beta in cancer. Biomedicine & Pharmacotherapy. 2021, 139: 111657.
- Bierie B., Moses H.L. Transforming growth factor beta (TGF-β) and inflammation in cancer. Cytokine & Growth Factor Reviews. 2010, 21 (1): 49-59.
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