THE BIOLOGICAL AND CLINICAL IMPLICATIONS OF PLASMINOGEN ACTIVATION IN PANCREATIC AND LUNG CARCINOMAS

Abstract

The blood protein plasminogen circulates as an inactive precursor of the serine protease plasmin. Plasmin prevents aberrant formation of blood clots and protects individuals from vascular/tissue damage. Plasmin is also an extracellular proteolytic agent that is often exploited by malignant cancers to facilitate their escape from the confinements of the extracellular matrix. The initiation of invasion and metastasis by cancer cells has been linked to epithelial to mesenchymal transition (EMT). EMT prompts cancer cells to lose epithelial proteins and acquire versatile characteristics thereby permitting mesenchymal migration and movement. The invasive process often associates increased plasminogen activation with mesenchymal cancer cells. However, the two distinct processes of plasminogen activation and EMT are not yet functionally linked. The first objective of this dissertation was to characterize differentially-expressed components of the plasminogen activation system in lung cancer cells undergoing EMT. This objective was addressed using various models of epithelial-like and mesenchymal-like cells. Specifically, we demonstrated that the plasminogen receptor S100A10, the plasminogen activator receptor uPAR and the plasminogen activation inhibitor PAI-1 were differentially regulated in epithelial vs. mesenchymal cells. The expression and localization of these proteins modulated plasminogen activation at the cell surface. Importantly, we demonstrated that epithelial cells and not mesenchymal cells display marked levels of plasminogen activation. The second objective was to assess genes involved in plasminogen activation as potential predictors of patient outcome in non-small cell lung cancer using hierarchical clustering strategies in merged patient cohorts. We identified a list of candidate markers of which four genes (PLAUR, PLAU, ANXA2 and S100A10) emerged as strong predictors of overall survival. The third objective was to study the biological and clinical implications of S100A10 in pancreatic cancer. We showed that pancreatic carcinoma overexpressed S100A10 compared to early-stage lesions, stroma and normal tissues. S100A10 mRNA levels were also predictive of overall and recurrence-free survival in pancreatic cancer patients. The expression of S100A10 was largely driven by the oncogene KRAS and by DNA methylation of its promoter region. Together, these findings delineated a fundamental role of plasminogen activation, particularly that of S100A10 in lung and pancreatic carcinomas.