Chemokine-Cytokine Networks in the Head and Neck Tumor Microenvironment

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.

Keywords: angiogenesis; apoptosis; chemokines; cytokines; head and neck squamous cell carcinomas; immune evasion; invasion; metastasis; response to therapy; tumor microenvironment.

Figure 1

Chemokine and cytokine-mediated crosstalk in head and neck squamous cell carcinoma (HNSCC) tumor micro-environment (TME). Cytokines and chemokines secreted by a variety of stromal cells affect tumor cell growth, proliferation & metastasis in many ways. By inducing immune-suppressive TME, they promote immune evasion and metastasis. Many chemokines and cytokines help degrade extracellular matrix (ECM) proteins, induce angiogenesis, and thereby promote invasion and metastasis.

Figure 2

Deregulated chemokines and cytokines in HNSCC. The heat maps showing deregulated expression of (A) chemokines and, (B) cytokines in HNSCC patients. The heat maps were constructed through data mining in the HNSCC TCGA database by using the UCSC Xena browser (http://xena.ucsc.edu (accessed on 9 February 2021)) (adjacent normal, n = 44, tumor tissue, n = 518 and metastatic = 02) samples).

Figure 3

Cytokines/Chemokines activate signaling pathways. Chemokines/cytokines via transmembrane protein GPCR activate an array of signaling pathways like PI3K/AKT/mTOR, JAK/STAT, RAS/RAF, integrin mediates SRC/FAK and Rho/RAC. Deregulation of these signaling pathways is known to promote initiation, progression, and metastasis in HNSCC.