|dc.description.abstract||INTRODUCTION: Pancreatic Ductal Adenocarcinoma (PDAC) is an aggressive form of cancer with a high mortality rate, primarily due to lack of effective treatment options. Current therapeutic approaches are limited to surgical resection of the pancreas during early stages of the disease and to the use of non-specific chemotherapeutic drugs such as gemcitabine, neither of which has successfully improved the 5-year survival rate of PDAC. Both the lack of effective treatments and the high mortality of the disease call for the urgent need to develop new therapeutic options.
OBJECTIVES: This thesis project focuses on an endogenous inhibitor of the neuropilin 2 receptor (NRP2) called semaphorin 3F (SEMA3F) and its use as a potential new drug in the fight against pancreatic cancer. By binding the transmembrane receptor neuropilin 2 (NRP2), SEMA3F can inhibit angiogenesis and cellular proliferation. Interestingly, given its role as a guidance molecule, it is also a potent mediator of cellular repulsion. All three of these effects will be analyzed in the context of this study.
METHODS: Syngeneic pancreatic cancer cells were injected orthotopically in two separate groups of mice. One group involved the use of transgenic Nrp2-/- mice, and served as a way to analyze the absence of the receptor on the vasculature and how that affects the growth of the primary tumor and the formation of metastases in the liver. The other group received intravenous injections of SEMA3F-expressing and control adenovirus, and served to explore the effect of SEMA3F as a potential therapy against the growth of the primary tumor in the pancreas and distant metastases in the liver.
RESULTS: We observed a decrease in pancreatic tumor and metastatic growth in the absence of Nrp2 in our transgenic mouse model compared to the WT control. Mice injected with SEMA3F-expressing adenovirus also showed a decrease in primary tumor growth as well as a reduction in the formation of metastases in the liver compared to the control.
CONCLUSION: Nrp2 mediates angiogenesis in pancreatic cancer, which facilitates the growth of the primary tumor as well as the formation of metastases. Our results indicate that the anti-angiogenic, anti-proliferative and repulsive actions of SEMA3F could be used to develop an effective treatment option for PDACpancreatic ductal adenocarcinoma.||en_US