Abstract
Head and neck squamous cell carcinomas (HNSCCs) are aggressive diseases with a dismal patient prognosis. Despite significant advances in treatment modalities, the five-year survival rate in patients with HNSCC has improved marginally and therefore warrants a comprehensive understanding of the HNSCC biology. Alterations in the cellular and non-cellular components of the HNSCC tumor micro-environment (TME) play a critical role in regulating many hallmarks of cancer development including evasion of apoptosis, activation of invasion, metastasis, angiogenesis, response to therapy, immune escape mechanisms, deregulation of energetics, and therefore the development of an overall aggressive HNSCC phenotype. Cytokines and chemokines are small secretory proteins produced by neoplastic or stromal cells, controlling complex and dynamic cell–cell interactions in the TME to regulate many cancer hallmarks. This review summarizes the current understanding of the complex cytokine/chemokine networks in the HNSCC TME, their role in activating diverse signaling pathways and promoting tumor progression, metastasis, and therapeutic resistance development.
Highlights
Head and neck squamous cell carcinoma (HNSCC) is a very aggressive disease with a dismal prognosis
Cytokines/chemokines and growth factors like epidermal growth factor (EGF), IL-1α, IL-1β, IL-6, IL-8, tumor necrosis factor-α (TNF-α), TGF-β, RANTES (CCL5), fibroblast growth factor (FGF), monocyte chemo-attractant protein 1 (MCP-1), tumor necrosis factor (TNF), family granulocyte-macrophage colony-stimulating factor (GM-CSF), vascular endothelial growth factor (VEGF), and hepatocyte growth factor (HGF), are upregulated in the HNSCC tumor micro-environment (TME) and are involved in the progression and metastasis [18,19]. These cytokines and chemokines induce cellular transformation [20], control autocrine or paracrine communication within and between the individual cells in the TME [21], and play diverse roles in the HNSCC by controlling processes not limited to Epithelial–Mesenchymal Transition (EMT), anoikis resistance, invasion and metastasis, angiogenesis and development of therapeutic resistance [22], contributing to the development of aggressive HNSCC tumors
Though TGF-β is suppressive in function, migration inhibitory factor (MIF) helps recruit neutrophils to the TME and promotes invasion and metastasis by producing ROS, MMP9 and, VEGF expression [39]
Summary
Head and neck squamous cell carcinoma (HNSCC) is a very aggressive disease with a dismal prognosis. Cytokines/chemokines and growth factors like epidermal growth factor (EGF), IL-1α, IL-1β, IL-6, IL-8, TNF-α, TGF-β, RANTES (CCL5), fibroblast growth factor (FGF), monocyte chemo-attractant protein 1 (MCP-1), tumor necrosis factor (TNF), family granulocyte-macrophage colony-stimulating factor (GM-CSF), vascular endothelial growth factor (VEGF), and hepatocyte growth factor (HGF), are upregulated in the HNSCC tumor micro-environment (TME) and are involved in the progression and metastasis [18,19] These cytokines and chemokines induce cellular transformation [20], control autocrine or paracrine communication within and between the individual cells in the TME [21], and play diverse roles in the HNSCC by controlling processes not limited to Epithelial–Mesenchymal Transition (EMT), anoikis resistance, invasion and metastasis, angiogenesis and development of therapeutic resistance [22], contributing to the development of aggressive HNSCC tumors. These cytokines and chemokines create an immunosuppressive TME and help evade anti-tumor immune response [21]
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