Introduction

Oral cancer is a significant global health concern, with over 300,000 new diagnoses and approximately 145,000 deaths each year, ranking it as the sixth most common cancer worldwide. Affecting primarily individuals aged 45 to 64, this major subtype of head and neck cancer continues to present challenges in treatment, particularly in advanced stages where the five-year survival rates have only improved marginally. The standard therapeutic approaches-surgery, radiation, and chemotherapy-remain essential, yet the high rates of recurrence and metastasis necessitate innovative strategies to enhance patient outcomes. Among the many molecular players involved in tumorigenesis, transforming growth factor β (TGF-β) has emerged as a crucial factor in the progression of oral cancers. TGF-β exhibits complex dual functionalities, acting both as a tumor suppressor and promoter depending on the context and stage of the disease.

TGF-β Signaling Pathways

The TGF-β superfamily, comprising over 30 cytokines including TGF-β1, -2, and -3, plays a fundamental role in regulating various cellular processes such as growth, differentiation, and migration. In its inactive form, TGF-β is released as homodimeric polypeptides, forming a latent complex with latency-associated peptide (LAP) and latent TGF-β-binding proteins. Activation of TGF-β involves proteolytic cleavage by matrix metalloproteinases (MMPs) and requires certain physiological conditions to release active TGF-β for receptor binding.

Fig. 1 Overview of TGF-β signaling pathway (Guo Y., et al. 2023).

TGF-β signals through specific receptor complexes that include type I (TβRI) and type II (TβRII) receptors with serine/threonine kinase activities. Upon ligand binding, TβRII recruits and phosphorylates TβRI, which initiates downstream signaling through both SMAD-dependent and noncanonical pathways. The SMADs, including R-SMADs (SMAD2, SMAD3) and the common mediator SMAD4, transduce extracellular signals to the nucleus, thereby regulating gene expression related to cellular processes like growth arrest and apoptosis.

TGF-β in Oral Squamous Cell Carcinomas

Oral squamous cell carcinomas (OSCCs), which arise from the mucosal epithelium of the oral cavity, account for more than 90% of all oral cancers. The role of TGF-β signaling in OSCC is paradoxical; it exhibits both tumor-suppressive and tumor-promoting activities based on the phase of cancer progression. In early-stage carcinogenesis, TGF-β acts as a potent tumor suppressor, promoting apoptosis and inhibiting cell proliferation through cell cycle arrest mechanisms, notably by inducing expression of cell cycle inhibitors such as p21 and p15.

Despite these protective roles, as OSCC advances to later stages, TGF-β signaling can change course, fostering tumor growth, invasion, and metastasis. This phenomenon is often attributed to the induction of epithelial-mesenchymal transition (EMT), a process whereby tumor cells evade immune surveillance and gain migratory and invasive properties. This transition is associated with decreased expression of E-cadherin and increased production of mesenchymal markers, further highlighting the duality of TGF-β in cancer progression.

Moreover, the loss of TGF-β signaling components is strongly linked to poor prognosis in OSCC patients. Research has shown that decreased expression of TGF-β receptors correlates with heightened tumor aggression, cell migration, and reduced survival rates. Conversely, mutations in SMAD genes can eliminate the tumor-suppressive effects of TGF-β, accelerating tumor progression.

TGF-β in Salivary Adenoid Cystic Carcinoma

Salivary adenoid cystic carcinoma (SACC) stands out among salivary gland malignancies, characterized by its remarkable ability to invade perineurally and perivascularly, leading to a relatively poor prognosis and frequent recurrences. TGF-β's involvement in SACC is multifaceted, demonstrating potential both for tumor suppression and promotion. Notably, TβRIII is often repressed in SACC specimens, and its overexpression can induce apoptosis and inhibit tumor growth through modulation of NF-κB signaling pathways.

Recent research has shown that TGF-β signaling also influences apoptosis through its effects on transcription factors like RUNX3, whose downregulation is linked to SACC malignancy. Elevated levels of TGF-β cytokines promote EMT in SACC, significantly contributing to its invasive properties. Specifically, TGF-β enhances MMP-9 expression, facilitating tumor invasion and metastasis, revealing the importance of TGF-β in elucidating SACC pathophysiology and progression.

TGF-β in Keratocystic Odontogenic Tumors

Keratocystic odontogenic tumors (KCOTs) represent benign, yet recurrent, epithelial neoplasms occurring within the jaw. Although classified as benign, KCOTs possess a unique potential for malignant transformation. The involvement of TGF-β signaling in KCOTs appears to regulate epithelial behaviors related to invasiveness and proliferation. TGF-β may influence the differentiation of odontogenic epithelium, facilitating local invasiveness and contributing to the tumor microenvironment.

Mutations in key genes like PTCH1 have been implicated in the pathogenesis of KCOTs, suggesting that TGF-β signaling could interact with various pathways, including those governing odontogenic development. Elevated TGF-β1 levels in KCOTs suggest a direct correlation with the neoplastic behavior of the cysts, emphasizing the need for further exploration into its regulatory mechanisms in odontogenic tumors.

TGF-β as a Therapeutic Biomarker

The complex duality of TGF-β signaling underscores its potential as both a therapeutic target and a biomarker in oral cancers. Elevated TGF-β signaling activity has been associated with worse prognostic outcomes in patients, particularly those exhibiting aggressive cancer phenotypes. Therefore, the inhibition of TGF-β could represent a viable therapeutic approach in targeting advanced cancers.

Several strategies have been developed to antagonize TGF-β signaling, including monoclonal antibodies, small-molecule inhibitors, and engineered proteins designed to inhibit receptor activation. Preclinical studies have shown that TGF-β inhibitors can suppress tumor growth, decrease fibrosis, and enhance responses to conventional cancer treatments. However, the complexity of TGF-β signaling complicates such targeting, necessitating careful patient stratification and biomarker identification to predict therapeutic responses.

Conclusion

TGF-β signaling plays a multifaceted role in the pathophysiology of oral cancers, including OSCC, SACC, and KCOTs. Its dual functionalities as a tumor suppressor and promoter underscore the complexity of its regulatory mechanisms. Understanding these mechanisms is essential for developing targeted therapies that can harness the therapeutic potential of TGF-β while minimizing adverse effects. Ongoing research is vital for unraveling the intricacies of TGF-β signaling and its implications for the future of oral cancer therapy.