The Effects Of Omega-3 Polyunsaturated Fatty Acids On Pancreatic Cancer And Pancreatic Stellate Cells In Vitro
thesisposted on 2019-12-06, 09:31 authored by Jonathan T. C. Haqq
Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant disease with a very poor prognosis. The tumour environment has been demonstrated to consist of an abundance of stroma containing many cells but predominantly pancreatic stellate cells (PSCs). Recent research has focused on understanding the interaction between PSCs and PDAC cells in vitro and in vivo. Omega-3 fatty acids have shown clinical benefit in PDAC, and their potential for mechanistic efficacy is under investigation.
Methods: Here, we investigated the efficacy of docosahexanoic acid (DHA), eicosapentanoic acid (EPA) and the DHA/EPA combination (Lipidem™) alone and in combination with gemcitabine in pancreatic cancer and a pancreatic stellate cell line. Cells were cultured 2-dimensionally and in a 3-dimensional organotypic co-culture.
Results: Pancreatic stellate cells showed a dose dependant reduction in proliferation with omega-3 fatty acids in particular LipidemTM and there was G1 cell cycle arrest. This effect may have been mediated by the downregulation of cytokine receptor PDGFR which is responsible for the proliferative pathway. Pancreatic stellate cells are necessary for PDAC invasion into the underlying extracellular matrix in an organotypic co-culture model. LipidemTM treatment decreased the invasive of pancreatic cancer cells in monoculture and in co-culture and this was reflected by downregulation of the cytokine ß-catenin. Markers of migration and extracellular matrix synthesis were also downregulated by treatments with omega-3 fatty acids.
Conclusion: Omega-3 fatty acids in particular the compound LipidemTM exerts anti proliferative effects on pancreatic cancer and pancreatic stellate cells and this is mediated by downregulation of the PDGF proliferative pathway. The omega-3 fatty acids also downregulate cytokines involved in epithelial mesenchymal transition and further research with different cell lines and strains in various clinically relevant models is needed to validate the mechanistic effects of omega-3 fatty acids on the pancreatic tumour microenvironment.
Supervisor(s)Ashley Dennison; Giuseppe Garcea; Lynne Howells
Date of award2019-11-22
Author affiliationDepartment of Cancer Studies
Awarding institutionUniversity of Leicester