The tumor microenvironment contribution to development, growth, invasion and metastasis of head and neck squamous cell carcinomas

Abstract

Head and neck squamous cell carcinoma (HNSCC) is a complex tissue that contains tumor cells and the surrounding stroma, which is populated by different types of mesenchymal cells and the extracellular matrix (ECM). Collectively, they are referred to as the tumor microenvironment (TME). Recent studies have shown that TME has a more profound influence on the growth and metastasis of HNSCC than was previously appreciated. Because carcinoma-associated fibroblasts (CAFs) are frequently observed in the stroma of the tumor, this review focuses on the potential role of tumor-CAFs interactions in progression of HNSCC. Tumor-CAFs crosstalk enhances the production of growth factors, cytokines, chemokines, matrix metalloproteinases (MMPs), and inflammatory mediators, which eventually facilitates tumor growth. In fact, factors and cells that do not support tumor growth are usually down regulated or mitigated in TME. Therefore TME may determine the fate of the tumors at the site of invasion and metastasis. For tumor cells that survive at these sites, stromal activation may serve to establish a supportive tumor stroma, fostering the outgrowth of the metastatic cells. The concept of tumor-stromal interactions and microenvironmental niche has profound consequences in tumor growth and metastasis and therefore, it's understanding will open up new strategies for the diagnosis, prognosis and therapy of HNSCC.

Keywords: CCL12.; CXCR4; Cancer associated fibroblasts (CAFs); Cycloxygenase-2 (COX-2); Head and neck cancer; Matrix metalloproteinases (MMPs).

Figure 1

Cell cycle deregulation in HNSCC. Normally, the cell cylcle is regulated by complexes of cyclins and cyclin-dependent kinases (CDKs). pRb binds to and inactivated E2F transcription factor, which induces in the expression of S phase genes. The CDK2-cyclin E complex phosphorylated Rb and causing release of E2F. In response to a mitogenic signal such as MAPK activation, the cyclin D1-CDK4/6 complex is activated. Activation of receptor tyrosine kinase (RTK) by mitogens can signal through ERK/MAPK and PI3 K pathways. AKT is a major downstream of PI3K. AKT prevents apoptosis by acting through different pathways. It could inactivate the apoptotic protein (BAD). The p16 and p 27 proteins are the inhibitors of cyclin D1-CDK4/6 and CDK2-cyclin E complexes, respectively. The p53 is another key protein, involving in the response of DNA damage. Deregulation of cell cycle-regulating proteins was observed in HNSCC. E6 and E7 proteins from human papillomavirus (HPV) could inactivate p53 and pRb functions, respectively. Activation of cyclin D1 and the RTK commonly occur in HNSCC.

Figure 2

The tumor microenvironment (TME). TME comprises different stromal cells in addition to tumor cells. These include vascular or lymphatic endothelial cells, supporting pericytes, fibroblasts, and both innate and adaptive infiltrating immune cells. Moreover, TME contains non-cellular components, including extracellular matrixes, growth factors, proteases, protease inhibitors and other signaling molecules that play important roles in stromal reactions in TME.

Figure 3

COX and LOX in HNSCC. COXs and LOXs stimulate proliferation, inhibit apoptosis, induce angiogenesis, and enhance invasion and metastasis in HNSCC. Key proteins including MAPKs, PKC, Bcl-2, PPARs (peroxisome proliferator-activated receptors), VEGF and MMPs involve in downstream effects of COXs and LOXs.

Figure 4

Tumor-stromal interactions in HNSCC. Tumor-stromal crosstalk leads to the overexpression of growth factors sustaining tumor growth, angiogenic factors promoting angiogenesis, and proteolytic enzymes enhancing the degradation of extracellular matrixes. These autocrine and paracrine factors facilitate tumor cell invasion and finally metastasis.