Development of in vitro and in vivo models of uveal melanoma


Shahidipour, H (2016) Development of in vitro and in vivo models of uveal melanoma. PhD thesis, University of Liverpool.

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Abstract

Uveal melanoma (UM) is the most common primary intraocular cancer of the eye in adults. Despite successful treatment of the primary tumour, approximately half of patients diagnosed with UM will develop metastases. To date, treatments for metastatic UM have had only limited effect, hence prognosis remains poor. Metastatic UM occurs predominantly in the liver. The mechanisms responsible for this remain largely unknown. Investigations into the molecular and cellular processes underlying UM development and metastasis are essential to develop therapeutic approaches directed against dissemination of this disease. In vitro and in vivo models play a crucial role in basic and translational oncology research. The scope of the work presented in this thesis was to develop innovative and clinically relevant in vitro and in vivo preclinical models that reproduce various aspects of metastatic processes in UM. In Chapter 2, primary UM cells were used to establish 3D tumour spheroids which retained many morphological and molecular characteristics of the original tumour. These 3D tumour spheroids more accurately mimic the 3D in vivo environment in which cancer cells reside and as a result can be used in co-culture assays, drug assays, and further transferred to an animal model to examine metastatic progression. Chapter 3 outlined one such in vivo model; the chick embryo. This model represents an accessible and economical in vivo model that has long been used in developmental biology. A panel of UM cell lines that represent the characteristic genetic and morphological profile in UM were used to form tumour nodules on the chorioallantoic membrane (CAM) and metastatic colonisation in internal organs following intravenous injection. Cells predominantly homed to the chick embryo eye spreading widely within the uveal tract, and to the liver, representative of the disease in patients allowing for a better understanding in the spread of this disease. Furthermore, cell lines forming tumour nodules on the CAM can be further used to assess candidate therapeutic drugs in an in vivo setting. Chapter 4 aimed to investigate such drug candidates by assessing the effects of targeted clinical inhibitors on UM cell lines. One particular inhibitor, the bromodomain PPI inhibitor JQ1, caused cell cycle arrest in two UM cell lines paving the way for many further insightful investigations. The models established in this thesis represent valuable, inexpensive and rapid in vitro and in vivo systems that can improve our understanding of the metastatic process in UM and provide a platform for the preliminary testing of potential new agents to aid molecular-based cancer therapy.

Item Type: Thesis (PhD)
Divisions: Faculty of Health and Life Sciences
Depositing User: Symplectic Admin
Date Deposited: 13 Dec 2016 08:54
Last Modified: 19 Jan 2023 07:25
DOI: 10.17638/03004584
Supervisors:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3004584
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