Synthesis of Hyaluronan by Tumour Cells – Mechanism and Implications

Abstract

Hyaluronan (HA) is a glycosaminoglycan found in the extracellular matrices of epithelial and connective tissues. It has both structural and signalling functions, triggering various cell signalling cascades, which result in adhesion, migration and invasion. It has been reported that Squamous Cell Carcinomas (SCC) of the skin, oesophagus, larynx and lung, initially experience an increase in HA production. More advanced, less differentiated lesions are subject to decreased HA expression, which correlates with nodal involvement and metastasis in high-grade laryngeal and oral SCC.

The first aim of this project was to determine the mechanism increasing HA synthesis by tumours, including which signalling pathways, Hyaluronan Synthase (HAS) enzymes and cell types are responsible. The second aim was to determine what consequences this has for different cells within the tumour in terms of phenotype.

Epithelial and tumour-associated fibroblast cell lines from oral SCC were cultured in the presence of growth factors present in the tumour microenvironment (EGF, VEGF and TGF). Levels of HAS2/3 and HA production were measured using immunocytochemistry and a quantitative assay. HAS2 production was promoted in SCC epithelial cells, which corresponded with an increase in HA production.

Regarding phenotype, the addition of HA had no effect on E-Cadherin expression, a marker of epithelial cells. However, it switched on vimentin expression, a marker of mesenchymal cells, in one well-differentiated SCC epithelial line but not in the other.

These results suggest that increased HAS2 expression in transformed epithelial cells are responsible for the increase in HA, reported in SCC. Vimentin expression may indicate that Epithelial to Mesenchymal Transition (EMT) is taking place, but this effect of HA may only occur in some SCC. Further research is needed to investigate this phenomenon.

Date of Award	2015
Original language	English
Supervisor	Ian Ellis (Supervisor), Sarah Jones (Supervisor) & Michaelina Macluskey (Supervisor)