Introduction

Oral cancer is a significant global health issue, with a complex, multistep process involving numerous genetic and environmental factors contributing to its development. Potentially malignant disorders (PMD) of the oral cavity represent a substantial percentage of oral tumors, with progression rates varying widely from 5% to 85%. Despite the relative accessibility of the oral cavity for clinical examination, current diagnostic methods often fail to accurately predict which lesions will progress to malignancy. This highlights the pressing need for reliable biological markers to supplement traditional histodiagnosis. Vimentin, an intermediate filament protein, has emerged as a candidate prognostic biomarker in oral cancer due to its aberrant expression in premalignant lesions and its substantial role in cancer progression.

Fig. 1 The biomarker potential of vimentin (Mogre S.; et al. 2022).

The Cytoskeleton and Intermediate Filaments

The cytoskeleton is an intricate network composed of microfilaments, intermediate filaments (IF), and microtubules, functioning dynamically to provide structural support and regulate cellular activities. Among these, intermediate filaments, including vimentin, play critical roles in various cellular functions such as cell division, motility, and stress resistance. Vimentin, a type III intermediate filament, is predominantly found in mesenchymal cells but also appears in endothelial cells, macrophages, neutrophils, and lymphocytes.

Structurally, intermediate filament proteins have a central α-helical rod domain flanked by non-α-helical N- and C-terminal domains known as the head and the tail. The vimentin monomer assembles into a homodimer, which can further form tetramers and octamers, providing structural integrity and facilitating various cellular processes.

Vimentin's Role in Cellular Functions

Vimentin is integral to wound healing, controlling fibroblast proliferation, collagen accumulation, and epithelial-mesenchymal transition (EMT). It also influences cell adhesion, migration, invasion, and stemness regulation. Its expression is widespread in various tissues, where it contributes to both physiological and pathophysiological processes. Vimentin's upregulation has been linked to conditions like mammary gland development, glial function, angiogenesis, and nerve myelination.
Moreover, vimentin interacts with the extracellular matrix to promote cell motility and participates in protecting cells against misfolded proteins. While primarily intracellular, vimentin is also present on cell surfaces and in the extracellular matrix, regulating proliferation, apoptosis, and differentiation. Its role in aging, oxidative stress, and adaptability to pathological conditions further highlights its potential as a drug target and clinical biomarker.

Aberrant Expression of Vimentin in Premalignant Oral Lesions

Vimentin expression changes markedly between normal and cancerous tissues in various organs, including the prostate, gastrointestinal tract, breast, and lung. Overexpression of vimentin correlates with a more metastatic and invasive phenotype in these cancers. In the context of oral lesions, elevated vimentin expression has been documented in premalignant conditions like leukoplakia and submucous fibrosis, as well as in primary keratinocyte cultures derived from these tissues. The level of vimentin expression tends to be higher in clinically non-homogenous leukoplakia compared to homogeneous leukoplakia, correlating statistically with the degree of disease progression.

Role of Vimentin in Oral Cancer Progression

Studies indicate a significant correlation between vimentin expression and several prognostic factors of oral squamous cell carcinoma (OSCC), including tumor size, clinical stage, lymph node metastasis, local recurrence, and patient survival. High vimentin levels are often associated with increased malignancy. Mechanistically, vimentin overexpression promotes epithelial-mesenchymal transition (EMT) and stemness-related changes, which contribute to tumor progression. Knockdown studies further highlight vimentin's role in maintaining a dedifferentiated state and modulating the expression of cytokeratins through pathways involving ΔNp63 and β4 integrin.

Vimentin in Late Stages of Oral Cancer

Higher vimentin expression is notably associated with poor prognosis in advanced stages of OSCC. As a driver towards stemness-related signatures, increased vimentin levels are frequently observed in late-stage tumors and correlated with enhanced migratory and invasive capabilities. Additionally, TGFβ1-induced upregulation of vimentin further supports its role in driving EMT and cancer progression.

Vimentin in Angiogenesis

Vimentin contributes to angiogenesis by promoting endothelial tube formation and stabilizing cell-matrix adhesions. In OSCC, vimentin, along with VE-cadherin and CD44, plays a role in vasculogenic mimicry formation, enhancing metastatic potential. Elevated vimentin in angiopoietin 2-high OSCC cells is associated with increased migration, invasion, and angiogenesis, further linking vimentin to cancer progression.

Vimentin and Endothelial Tube Formation

Vimentin's role in endothelial tube formation is crucial for the development of new blood vessels, a process essential for tumor growth and metastasis. By stabilizing cell-matrix adhesions, vimentin facilitates the formation of vascular structures that supply nutrients and oxygen to the tumor, promoting its growth and survival.

Vasculogenic Mimicry in OSCC

Vasculogenic mimicry, the formation of blood vessel-like structures by cancer cells, is a phenomenon observed in aggressive tumors, including OSCC. Vimentin's involvement in this process highlights its contribution to the enhanced metastatic potential of these cancers. Targeting vimentin could disrupt vasculogenic mimicry, potentially limiting tumor growth and spread.

Vimentin in Recurrence and Therapy Resistance

Elevated vimentin expression is linked to poor prognosis, recurrence, distant metastasis, and lower disease-free survival in various cancers. In OSCC, vimentin expression at the invasive front correlates with local recurrence. Studies suggest that vimentin may predict advanced disease and therapy resistance, particularly in chemoradiotherapy-resistant OSCC. EMT drivers, cancer stem cell properties, and miRNA deregulation contribute to drug resistance, with vimentin playing a pivotal role.

Vimentin and Local Recurrence

The presence of vimentin at the invasive front of tumors is associated with an increased risk of local recurrence. This suggests that vimentin-expressing cells are more likely to survive initial treatments and contribute to tumor regrowth. Monitoring vimentin expression in resected tumor margins could provide insights into the likelihood of recurrence and inform post-surgical treatment strategies.

Vimentin and Therapy Resistance

Vimentin's role in therapy resistance is multifaceted, involving EMT, cancer stem cell properties, and miRNA deregulation. EMT-associated changes, driven by vimentin, contribute to resistance to conventional therapies, including chemotherapy and radiotherapy. Cancer stem cells, regulated in part by vimentin, are known for their ability to resist treatment and drive tumor recurrence. Additionally, miRNAs that target vimentin expression may influence therapy response, highlighting the need for integrated approaches to overcome resistance.

Conclusion

Vimentin has emerged as a promising prognostic biomarker in oral cancer, with its expression levels correlating with various aspects of cancer progression, metastasis, angiogenesis, recurrence, and therapy resistance. Understanding the regulatory mechanisms and functional roles of vimentin in oral cancer can provide insights into its potential as a therapeutic target. Future studies should focus on elucidating the precise mechanisms by which vimentin contributes to oral carcinogenesis and exploring its clinical applications in diagnosis, prognosis, and treatment.