David Greenhalgh - Overview

The incidence of melanoma, one of the most morbid of human cancers and squamous cell carcinoma, one of the most common, is steadily rising, both associated with increased sun exposure. Thus, development of models designed to identify the genes which cause cancer, investigate their synergism, determine when they become causal and thereby accurately mimic the multistage nature of human skin cancers, is highly desirable. Human tumorigenesis proceeds via acquisition of discrete synergistic mutations in the genome that transform a normal cell, through preneoplastic and premalignant intermediaries, to malignancy. The mouse skin model of multistage carcinogenesis, with its well defined and distinct pathology associated with the stages of initiation, promotion and malignant conversion is ideally suited to combine with transgenic technology and develop models to study the underlying molecular mechanism. Towards this end we have recently established a Transgenic Skin Group, with a newly refurbished laboratory. In tissue culture [living skin equivalents] and via transgenic oncogene overexpression or tumour suppressor gene knockout, skin systems can be exploited to identify which genes cause initial pre-neoplastic events, analyse the gene groups which then cooperate to give rise to overt but benign tumours and finally determine the molecular events that convert a benign tumour cell to malignancy. Gene expression can now be restricted to epidermal keratinocytes or melanocytes employing a variety of targeting vectors, creating highly accessible models that allow macroscopic observation of neoplastic events and which possess added value in that analysis of transgenic, yet normal skin provides insights on gene function in normal physiology and/or alternate disease. As a further refinement to study gene mutations in vivo, an inducible gene switch system based has been developed that allows focal induction of transgene expression or ablation, in subsets of cutaneous cells, at times dictated by the investigator following application of an inducer hormone. Collectively, these skin models directly test causal, stage-specific neoplastic mechanisms and resultant phenotypes may provide a highly relevant translational cancer research systems to stringently evaluate generic or tailored treatment modalities, including gene therapy, prior to clinical trials.