Marsh, D.J.; (2011) The αvβ6 Integrin in cancer. Doctoral thesis , UCL (University College London).

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Abstract

The epithelial restricted αvβ6 integrin is known to have minimal expression in healthy tissue and to be upregulated in cancer and healing wounds. This thesis explores the role of αvβ6 in cancer and tests the hypothesis that αvβ6 has a prognostic and therapeutic utility in cancer. Using immunohistochemistry, increased αvβ6 expression was found in nonmelanoma skin cancers (NMSC), particularly in morphoeic type basal cell carcinoma. In cell culture experiments, αvβ6 was found to activate TGF-β and promote myofibroblast differentiation, producing a tumour stroma rich in smooth muscle actin (SMA). These findings prompted a study of αvβ6 and SMA as prognostic indicators in oral squamous cell carcinoma (OSCC). A study of 282 cases of OSCC found that although αvβ6 was not a prognostic marker, patients with high SMA levels had a highly significant increased risk of disease specific mortality (HR 3.06 [CI 1.65-5.66], p<0.001). Next, the utility of αvβ6 as a target was explored through the development of a single chain antibody fragment (scFv) specific for αvβ6. The scFv was tested for the delivery of targeted magnetic fluid hyperthermia (MFH), an experimental cancer treatment based on the generation of heat by magnetic nanoparticles when placed within an alternating magnetic field. The αvβ6-specific scFv (B6.3) was manufactured and high ligand specificity confirmed on ELISA and FACS analysis. B6.3 was successfully conjugated to two alternative iron nanoparticles. In-vitro studies demonstrated increased cellular uptake of scFv-nanoparticle complexes and greater cellular toxicity on exposure to MFH compared to nanoparticles alone. In conclusion, αvβ6 is a potential target for therapy in NMSC and OSCC. SMA is found to be an independent prognostic marker in OSCC and αvβ6 identified as a proinvasive factor in morphoeic BCC. Finally, the production αvβ6 specific scFvs and use for in-vitro MFH potentiates the development of αvβ6 targeted MFH cancer therapy.

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