TUMOUR PROGRESSION OF CUTANEOUS SQUAMOUS CELL CARCINOMA: RESPONSE TO CHEMOTHERAPEUTICS AND REGULATION OF THE EPITHELIAL-MESENCHYMAL TRANSITION PROCESS

Although most of the cutaneous squamous cell carcinomas (SCCs) can be cured, a subset of patients develops advanced disease, with high risk for metastasis.  The induction of invasion and metastasis by epithelial-mesenchymal transition, as well as the failure to eliminate the (metastatic) cancer cells due to resistance to therapy plays a major role in the lethal outcome of advanced cutaneous squamous cell carcinoma. EMT and chemoresistance, 2 important hallmarks of tumour progression are studied in this thesis.
In the first part of the thesis we demonstrate in an isogenic skin cancer progression model, that the more advanced cutaneous squamous cell carcinoma cells, which lose their sensitivity to the genotoxic chemotherapeutic agent cisplatin, remain sensitive to hydrogen peroxide or photodynamic therapy. Both induce major oxidative stress; indicating that the cell death sensitivity in this model of progressive cutaneous squamous cell carcinoma is dependent on the kind of stress. Thisdifferential sensitivity could have implications for the treatment of advanced cSCC.In the second part of the thesis we studied EMT, a process involving loss of intercellular adhesion, and acquisition of increased migration and invasion potential, which is required for tumour invasion and dissemination to occur. Using both the previous studied isogenic cellular model of cSCC progression and an in vivo model of skin samples of skin cancer patients arranged in a tissue microarray of patientmatched normal epidermis adjacent to cSCC, of cSCC in situ and ofinvasive cSCC, we found a significant upregulation of the EMT process in primary invasive cSCC, as compared to normal skin and/or cSCC in situ. This upregulation of EMT was paralleled with AKT activation. Pharmacological AKT inhibition in the isogenic tumour progression model in vitro, suppresses migration and invasion.
Altogether, our results provide evidence for the use of a more oxidative stress inducing chemotherapeutic, while AKT may serve as a therapeutic target to avoid dissemination of cSCC cells.