In cancer, epithelial cell de-differentiation is a feature of rapidly dividing cells under non-controlled growth and it often reflects a change in the gene expression pattern; however, the relationship between proliferation and alterations in cellular differentiation has not yet been identified. This work examined how changes in the characteristics of cells that discriminate their differentiated and proliferative states can be used to improve on current pancreatic cancer chemotherapeutic strategies. PepT1, a high substrate-capacity and low-affinity transporter system, has been suggested as an attractive drug delivery target for pancreatic cancer. Through a combination of immunological assays, PepT1 normally restricted to the apical surfaces in polarised intestinal epithelial cells, was shown to distribute at the cell membrane of non-polarised cancerous ductal cells. Anti-inflammatory or anti-cancer agents, like ibuprofen or gemcitabine, were conjugated to selected amino acids to enhance their uptake via PepT1. Studies with these conjugates demonstrated enhanced uptake into pancreatic cancer cells, AsPc-1 and HPAFII. Subsequent studies investigated how cell polarity that is typically disrupted in cancer can be modulated to affect the balance of epithelial differentiation versus proliferation. Pharmacological attenuation of YAP (c-Yes associated protein) using a β adrenergic agonist, dobutamine, increased functional tight junction (TJ) structures and diminished proliferation rates of two pancreatic cancer cells, AsPc-1 and HPAFII. Dobutamine also primed an apoptotic cell response. When given in combination with gemcitabine, dobutamine further reduced cell proliferation. Overall, these studies have provided support for using PepT1 as a method to target pancreatic cancer cells for the delivery of anti-cancer agents. Additionally, dobutamine was identified as a potential pharmacological agent to suppress the proliferation of pancreatic cancer cells by altering increasing cell programming that drives epithelial cell differentiation.
|Date of Award||16 Jan 2015|
|Supervisor||Randy Mrsny (Supervisor)|