The Role of the ET-axis and RAS in Head and Neck Cancer Progression

Head and neck squamous cell carcinoma (HNSCC) is a frequently fatal and increasingly common epithelial malignancy. Significant morbidity and mortality frequently results from the invasion of tumours into surrounding structures and local metastasis to lymph nodes. The invasion and migration of HNSCC cells is increasingly recognised to be influenced by factors derived from adjacent tumour-associated stroma. The contextual signals regulating stromal-tumour interactions, however, remain poorly understood. Here, a role for endothelin-1 (ET-1) and angiotensin II (Ang II), in promoting pro-metastatic cross-talk between head and neck cancer cells and adjacent fibroblasts is investigated.
The results of this study indicate that treatment of normal oral fibroblasts (NOFs) with ET-1 activates ADAM17 mediated release of epidermal growth factor receptor (EGFR) ligands, triggering EGFR signalling and increased migration and invasion in neighbouring HNSCC cells. ET-1 mediated paracrine transactivation of EGFR also increases cyclooxygenase-2 (COX-2) levels in the head and neck cancer cells, providing a molecular insight into the mechanisms by which the elevated levels of ET-1 observed in HNSCC may contribute to disease progression.
Evidence is also provided that Ang II stimulates migration and invasion of HNSCC via AT1R using a similar paracrine mechanism to that employed by ET-1, and also via an autocrine mechanism, acting on HNSCC cells alone. AT1R is expressed by both HNSCC cells and NOFs, but not normal oral keratinocytes (NOKs). Angiotensin 1-7 (Ang 1-7), a proteolytic product of the degradation of Ang II, is able to inhibit the stimulation of HNSCC migration by Ang II and other peptides implicated in HNSCC progression including ET-1 and bradykinin (BK). Together, these results demonstrate a novel role for the RAS in head and neck carcinogenesis and implicate Ang 1-7 as a possible novel therapeutic agent in the treatment of HNSCC.
In addition, it is shown herein that ET-1 and Ang II increase the proliferation and migration of NOFs, and induce a more contractile phenotype, key features of myofibroblast transdifferentiation, a strong indicator of poor prognosis in HNSCC. Interestingly Ang II, but not ET-1, stimulates changes in gene expression indicative of myofibroblast transdifferentiation, despite both inducing similar levels of pro-invasive paracrine signalling between oral fibroblasts and HNSCC.
The findings in this thesis provide important novel information regarding the role that the ET-axis and renin angiotensin system (RAS) play in contributing to HNSCC progression and the results collected identify potential novel targets and agents for drug therapies in the treatment of the disease.