Eriksson, TMI; (2016) Development of two in vitro organotypic models for the oral tumour ameloblastoma. Doctoral thesis , UCL (University College London).

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Abstract

Ameloblastoma is the most common odontogenic tumour worldwide. It is a locally invasive yet benign tumour, with bone destructive capacity. Up to 70% of cases are estimated to recur and some of these form tumours in the soft tissues surrounding the original tumour sites. There are many unanswered questions around the cellular events leading up to the growth of an ameloblastoma tumour, how ameloblastoma cells invade the bone tissue surrounding it, how the disease progresses and if there are any suitable biomarkers to potentially be used for disease diagnosis and/or prevention. This study used tissue engineering techniques to create two distinct models for ameloblastoma tumours. The first involved the development of bone-like compressed collagen constructs, which were co-cultured with ameloblastoma cells from the AM-1 cell line. These constructs were examined for cell proliferation, invasion, cell-to-cell contacts and gene expression. The second construct involved modelling AM-1 cell behaviour together with an organotypic soft tissue model, so that recurrent ameloblastoma behaviour could be investigated. For this, co-cultures of gingival fibroblasts in compressed collagen scaffolds were developed. Using this construct, it was found that AM-1 cells upregulated matrix metalloproteinase (MMP-2) expression. It was found that AM-1 cells rapidly proliferated in both constructs, and cell-to-cell interactions and some invasion were also observed. Finally, based on gene expression data obtained for the two constructs, potential therapeutic agents were tested. Application of either Alendronate or Doxycycline was found to reduce AM-1 cell survival within the models. The models developed during this project are the first to provide an organotypic in vitro setting for the examination of ameloblastoma cells. They effectively mimic the in vivo tissue by providing appropriate extracellular matrix factors and cell types. The behaviour of AM-1 cells in these models was close to that observed in in vivo tumours.

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