Date of Graduation
Doctor of Philosophy (PhD)
Craig D. Logsdon
Robert Bast Jr.
Pancreatic ductal adenocarcinoma (PDAC) is a disease characterized by a dismal prognosis with a 5-year survival rate of 7%. A unique hallmark of this disease is an abundant desmoplastic reaction that can account for up to 90% of the solid tumor volume. Key components of the PDAC stroma include the extracellular matrix (ECM) rich in collagen type I and III, activated pancreatic stellate cells (PSCs) and inflammatory cells such as neutrophils and macrophages. The main line of evidence has suggested a pro-tumorigenic role for the PDAC stroma as it has been shown to help enhance tumor growth, invasive potential and drug resistance. Recent reports however, have challenged these findings and shown that the stroma offered protection from tumor growth. Given the extensive presence of stroma and its presumed roles in PDAC, characterization of the function of molecules that can alter stromal composition is warranted. LCN2 is a molecule that has been confirmed to be differentially expressed in PDAC. Attempts to investigate its biological function in PDAC have unfortunately led to conflicting results. In this study, we examined the effect of LCN2 depletion on tumor growth in a syngeneic orthotopic model of PDAC. We report that LCN2 depletion delayed tumor growth, decreased changes in stromal composition, and diminished inflammatory cell infiltration leading to increased survival. In addition, we examined the role of LCN2 and its specific receptor SLC22A17 in human PSCs. We revealed for the first time that hPSCs don’t produce LCN2, but do express LCN2 receptors. Moreover, ectopic LCN2 promoted hPSCs to produce inflammatory factors in a receptor-mediated manner. Finally, because LCN2 is involved in iron transport, we showed that LCN2’s effects on hPSCs were also mediated by changes in iron levels. Overall, our results suggest a model for LCN2 function in the regulation of the tumor microenvironment and shown its ability to promote tumor growth in PDAC.
pancreatic cancer, lipocalin 2, inflammation, microenvironment, stellate cells
Available for download on Saturday, April 29, 2017