An Investigation of Signalling Pathways linked to Lymphatic Metastasis in Squamous Cell Carcinomas of the Head and Neck

Squamous cell carcinomas of the head and neck (SCCHN) spread predominantly by local invasion and lymphatic dissemination. The aim of this project was to learn more about the molecular mechanisms of lymphatic metastasis in this disease. EGFR is a major driver of progression, invasion and metastasis in SCCHN. Ip. addition, signalling via chemokine receptors such as CXCR4 and CCR7 and the lymphangiogenic cytokine receptor VEGFR-3 has been implicated in lymphatic metastasis. My first aim was to measure expression levels in SCCHN cell lines, determine their interactions with EGFR and the signalling pathways involved in their regulation. Most SCCHN cell lines expressed VEGF-A, -C, -D, CCR7 and CXCR4. VEGF-A expression was PI3K- and MAPK-dependent, whereas VEGF-C expression was regulated by MAPK only. Possible EGFR transactivation by CXCLl2 (CXCR4 ligand) or CCL21 (CCR7Iigand) was identified. Metastatic processes also depend on intrinsic properties of tumour cells. PI3K and PLCyl are important regulators of cell motility downstream of EGFR. In addition, Syk, a nonreceptor tyrosine kinase, has been implicated in PI3K and PLCyl signalling pathways in B-cells and chemomigration in nasopharyngeal carcinoma. Recently, an interaction between Syk and EGFR has been reported. My second aim was to explore the role of Syk in SCCHN. Syk overexpression enhanced chemomigration in vitro, whereas inhibition by piceatannol or siRNA inhibited cell migration, haptotaxis and matrix interactions; these effects were associated with changes in activation ofPLCyl or AKT. In clinical samples, high Syk expression was associated with higher risk of recurrence, was significantly correlated with worse survival and may be of prognostic value in SCCHN. Coordinated EGFR signalling regulates many key processes in lymphangiogenesis/angiogenesis and invasion that contribute to lymphatic metastasis in SCCHN. Key molecules and their integrated signaling pathways could be useful for prognosis and have the potential to provide novel therapeutic targets in SCCHN.EThOS - Electronic Theses Online ServiceGBUnited Kingdo