Phenotypic profile and role of cancer stem cells in uveal melanoma

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Uveal melanoma (UM) is the most common primary intraocular malignancy occurring in adults. Despite successful treatment of the primary tumour approximately 50% of patients develop liver metastases. Typically, liver metastases are detected 1-3 years after ocular treatment. Sometimes the metastasis appears 10 or even 20 years after primary tumour treatment. The reason for such latency is yet to be understood. One hypothesis is that a subset of stem-like cancer cells remain dormant and are reactivated after many years. They then proliferate and give rise to the bulk of the tumour. Cancer stem cells (CSCs) are cells with the capacity to divide asymmetrically to produce another CSC and a daughter cell that gives rise to the bulk of the tumour. In addition to the key properties of CSCs of self-renewal and differentiation, they also possess features that enable them to generate, maintain, enhance tumour growth and resist conventional therapy. These include expression of putative stem cell markers, activation of embryonic signalling pathways, anoikis resistance/anchorage independent growth, dye/drug efflux, and the ability to change their metabolic signature among others. The aims of this thesis were to identify CSCs in UM, particularly their phenotypic profile and role in this disease. To this end, I examined the expression of CSC and adhesion markers in normal choroidal melanocytes (NCM), UM cell lines and in primary UM cells (PUM) grown in adherent and non-adherent culture conditions. Several CSC markers; CD166, Nestin and CD271 were upregulated in high metastatic risk PUM compared with low metastatic risk PUM and NCM. Cells surviving anoikis showed increased expression of these markers. A tumour migration assay showed that a CD166high subpopulation isolated from a UM cell line had higher migratory capacity compared to the CD166low population. The data generated in this section identified putative CSC markers in UM. The results of this thesis also showed that neural crest (NC) developmental/embryonic markers are expressed in UM, suggesting that these primitive pathways may be reactivated in this tumour. Detailed investigations of Nestin, a neural stem cell marker in UM patient tissue showed that increased expression of Nestin significantly correlates with known poor prognostic factors, such as epithelioid cell morphology, high mitotic count, the presence of closed connective loops, monosomy 3 and polysomy 8q. Nestin is also expressed in metastatic UM (MUM), which together with previous studies showing Nestin expression in circulating tumour cells, suggests that Nestin may be used as a biomarker in high-risk UM patients for early detection of disseminated disease.

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