Medicine (Austin & Northern Health) - Theses
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ItemImpact of a pregnancy-associated protein (PAPPA) on melanoma: a link between pregnancy and progression of cancer( 2016)Melanoma is the most common cancer diagnosed in pregnant women, and an aggressive course with poorer outcomes is commonly described during pregnancy or shortly after childbirth. The underlying mechanisms for this are not understood. This thesis reports that migration, invasiveness and progression of melanoma are promoted by pregnancy-associated plasma protein-A (PAPPA), a pregnancy-associated metalloproteinase produced by the placenta that increases the bioavailability of insulin-like growth factor (IGF)-1 by cleaving it from a circulating complex formed with IGF binding protein-4. The results presented in this thesis confirm that PAPPA is widely expressed by metastatic melanoma tumours and is elevated in melanoma cells exhibiting mesenchymal, invasive and label-retaining phenotypes. Notably, inhibition of PAPPA significantly reduced invasion and migration of melanoma cells in vitro and in the avian embryonic neural crest model in vivo. Treatment with PAPPA-enriched pregnancy serum enhanced the motility of melanoma cells in vitro. Furthermore, this thesis reports that IGF-1 can induce the phenotypic and functional effects of epithelial-mesenchymal transition (EMT) in melanoma cells. This study establishes a clear relationship between the pregnancy-associated protein PAPPA, melanoma, and functional effects mediated through IGF-1, providing a plausible mechanism for accelerated progression of melanoma during pregnancy. This opens the possibility of therapeutic targeting of the PAPPA/IGF-1 axis.
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ItemOrigins of heterogeneity in melanoma( 2012)The cancer stem cell hypothesis has dominated discussions of cancer cellheterogeneity in recent years; however its relevance to melanoma is controversial. This thesis presents projects outlining sources of cellular heterogeneity in melanoma in relation to three models of cancer development: the cancer stem cell model, clonal evolution, and phenotypic plasticity. A common cancer stem cell culture method, which involves supplementing serum-free media with specific growth factors, yielded a model of melanoma that was not as representative of the original tumour as standard methods. Gene expression profiling revealed a biased towards expression of neural lineage genes, which could seriously confound therapeutic target selection. In contrast metastatic melanoma cell lines and a metastatic melanoma tissue sample were found to be heterogeneous for DNA copy number abnormalities, supporting the involvement of clonal evolution in the development of melanoma heterogeneity. Finally by segregating melanoma cells based on functional heterogeneity evidence for dynamic and reversible transitions between different phenotypes was observed. Gene expression profiling of these functionally distinct subpopulations identified genes relating to epithelial-to-mesenchymal transition and inflammation as relevant to melanoma cell invasion and drug resistance, including both cytotoxic and targeted therapies. Together these results suggest that heterogeneity between the cells of a melanoma results from ongoing genetic changes as well as cell-cell and environmental interactions, and that targeting molecules representing multiple phenotypes simultaneously might be necessary to successfully treat the disease.