The role of SPARC in pancreatic cancer

Mintzia, Christina Evangelina (2011) The role of SPARC in pancreatic cancer. (MSc(R) thesis), Kingston University, .


Pancreatic cancer is a highly aggressive disease with generally poor prognosis. This is due in part to late presentation and frequent drug resistance. Gemcitabine chemotherapy is the standard first-line treatment for pancreatic cancer. The development of an invasive pancreatic cancer is thought to be dependent on the interaction between malignant cells and stromal fibroblasts. SPARC, also known as osteonectin, is a matricellular protein that interacts with components of the extracellular matrix (ECM) and can modulate cell growth and migration. It is expressed by both tumour and stromal cells and is thought to play a role in the tumour-stromal interaction. A recent study by Toshimitsu et al (2006) suggested that expression ofSPARC in YPK-l pancreatic cancer cell line is regulated by Gemcitabine treatment. The aim of this project is to test this hypothesis that drug resistance is associated with the level of SPARC expression in pancreatic cancer cells. In this study, SPARC mRNA expression was examined in four pancreatic cancer cells lines (AsPC, Panc-l , PT-4S and Capan-l), before and after Gemcitabine treatment, at 0.01, 0.1 and 1.0 [mu]g/ml, at 24 and 48 hours (control and treated cells). Results showed that although 1.0 [mu]g/ml Genicitabine increased SP ARC expression at 48 hours in all four cell lines, the difference over control cells is variable and not statistically significant. The greatest change was observed in Panc-l cells, with on average a S-fold increase in SPARC expression at 48 hours using 1.0 [mu]g/ml Gemcitabine. In Panc-l cells, the Gemcitabine dose range was therefore extended to include 2.0, 5.0 and 10.0 [mu]g/ml, The highest Gemcitabine concentration induced a S-fold increase in SPARC expression at 48 hours. However, although these results demonstrate that SPARC expression can be elevated by Gemcitabine treatment, no overall association was observed between SPARC induction and drug resistance of the different cell lines, as determined by growth curves. Instead, high basal SP ARC expression appears to be associated with poor growth characteristics in anchorage-independent cell culture. Therefore, this could suggest that cancer cells expressing low levels of SP ARC may demonstrate a more aggressive phenotype and capacity for anchorage-independent growth.

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