Mast Cell-Tumor Cell Interactions in OSCC: Genetic and microRNA Insights

Abstract

Oral squamous cell carcinoma (OSCC) is the most prevalent malignancy of the head and neck area, marked by its virulence and lethality. Emerging research has focused on the important role of the tumor microenvironment in OSCC development, more specifically the communication between mast cells and tumor cells. Mast cells, which have been involved in inflammatory reactions, have been reported to play a role in both tumor-supporting and tumor-repressing functions. Rising evidence indicates that the interaction between mast cells and tumor cells impacts gene and microRNA (miRNA) expression profiles, in turn, modulating tumor growth, angiogenesis, and immune escape. The molecular mechanisms of mast cell-tumor cell interactions, with particular reference to the involved genes and miRNAs, are discussed in this review. Elucidating these molecular pathways may open new avenues for the treatment of OSCC and more accurate prognostic markers.

Introduction

Oral squamous cell carcinoma (OSCC) is responsible for over 90% of oral cancers and continues to be a significant global health issue. OSCC patients' prognosis, despite the advances made in surgical and adjuvant treatments, continues to be poor because of its extremely high invasive, metastatic, and recurrence rates. One of the novel fields of investigation in OSCC is the tumor microenvironment, which represents an active interplay between the tumor cells and different stromal elements, such as immune cells, fibroblasts, and endothelial cells.

Mast cells, once primarily associated with allergic responses, have been found to play a key role in the tumor microenvironment as important mediators. Their occurrence in OSCC tissues is associated with tumor aggressiveness, angiogenesis, and immune modulation. Through the release of a diverse array of bioactive mediators, mast cells regulate several tumor biological processes such as proliferation, apoptosis, and metastasis. Notably, mast cells may regulate the gene expression and miRNA profile of tumor cells, which results in modified oncogenic signaling pathways. The review presents an extensive overview of the gene and miRNA expression alterations developed during interactions between mast and tumor cells in OSCC and elaborates on their possible clinical implications.

Mast Cells in the Tumor Microenvironment

Mast cells are immune cells derived from the bone marrow that live in connective tissues and mucosal surfaces, where they are crucial for inflammatory responses. Their actions are largely mediated by the secretion of histamine, proteases, cytokines, and growth factors. In cancer, mast cells have dual functions, acting either as tumor promoters or suppressors, depending on the nature of the tumor and microenvironmental conditions.

In OSCC, mast cells are more localized in peritumoral and intratumoral areas. Their density was found to have been correlated with tumor angiogenesis and progression in a positive manner. Mast cells release proangiogenic factors like vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and tumor necrosis factor-alpha (TNF-α), which assist in the development of new blood vessels for the maintenance of tumor growth. In addition, mast cells also release proteases like tryptase and chymase, which break down the extracellular matrix and promote tumor invasion and metastasis.

Gene Expression Profiles Associated with Mast Cell-Tumor Cell Interactions

Several studies have demonstrated that mast cells influence gene expression profiles in OSCC cells, leading to the activation of oncogenic pathways. The key genes that are modulated through mast cell-tumor cell interactions include:

1. VEGF (Vascular Endothelial Growth Factor) – Upregulated in OSCC cells in response to mast cell-derived mediators, VEGF enhances angiogenesis and promotes tumor progression.

2. MMPs (Matrix Metalloproteinases) – Increased expression of MMP-9 and MMP-2 facilitates extracellular matrix degradation, promoting tumor invasion and metastasis.

3. COX-2 (Cyclooxygenase-2) – Overexpression of COX-2 contributes to inflammation-induced carcinogenesis and has been linked to increased mast cell infiltration in OSCC tissues.

4. TNF-α and IL-6 (Interleukin-6) – These inflammatory cytokines, secreted by mast cells, activate NF-κB signaling, which enhances OSCC cell proliferation and survival.

5. CD44 – A stem cell marker associated with OSCC progression and metastasis, CD44 expression is upregulated in the presence of mast cells, indicating a role in cancer stem cell maintenance.

MicroRNA Expression Alterations in Mast Cell-Tumor Interactions

MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression post-transcriptionally. Several miRNAs have been identified as critical regulators in OSCC progression, and their expression is influenced by mast cell interactions.

1. miR-21 – Upregulated in OSCC and associated with poor prognosis, miR-21 is induced by mast cell-derived cytokines and promotes tumor cell survival and chemoresistance.

2. miR-34a – A tumor-suppressor miRNA that is downregulated in OSCC, miR-34a is negatively influenced by mast cell-tumor interactions, leading to enhanced epithelial-to-mesenchymal transition (EMT) and tumor invasion.

3. miR-155 – Induced by inflammatory signals from mast cells, miR-155 plays a role in immune evasion and tumor-associated inflammation in OSCC.

4. miR-125b – Downregulated in OSCC, miR-125b loss contributes to increased cell proliferation and resistance to apoptosis.

5. miR-200 family – These miRNAs regulate EMT and metastasis, and their expression is influenced by mast cell-secreted factors.

Clinical Implications and Therapeutic Targeting

The influence of mast cells on gene and miRNA expression in OSCC suggests potential therapeutic strategies targeting mast cell-tumor cell interactions. Some of these strategies include:

1. Mast Cell Stabilizers: Drugs such as cromolyn and ketotifen, which inhibit mast cell degranulation, may reduce tumor-promoting effects mediated by mast cells.

2. VEGF Inhibitors: Targeting VEGF signaling with agents like bevacizumab may counteract mast cell-induced angiogenesis in OSCC.

3. COX-2 Inhibitors: Nonsteroidal anti-inflammatory drugs (NSAIDs) such as celecoxib have shown potential in reducing mast cell-mediated tumor inflammation.

4. miRNA-Based Therapies: Restoring the expression of tumor-suppressor miRNAs (e.g., miR-34a) or inhibiting oncogenic miRNAs (e.g., miR-21) could offer a novel therapeutic approach.

Future Directions

Although significant progress has been made in understanding mast cell-tumor cell interactions in OSCC, several gaps remain. Future research should focus on:

1. Elucidating the precise signaling pathways linking mast cell mediators to gene and miRNA expression changes in OSCC.

2. Investigating patient-specific variations in mast cell infiltration and their prognostic implications.

3. Developing targeted therapies that specifically modulate mast cell functions without impairing their beneficial immune responses.

Conclusion

The interaction between tumor cells and mast cells in OSCC is a multi-faceted process with many signaling pathways and genetic regulatory systems. Through their effects on gene and miRNA expression, mast cells are involved in tumor development, invasion, and immune evasion. Elucidation of these molecular interactions reveals new therapeutic strategies and personalized treatment modalities for OSCC. Inhibition of mast cell-dependent mechanisms may enhance existing treatment options and patient outcomes in OSCC treatment.

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