Pancreatic cancer has a dismal prognosis and is highly resistant to chemotherapy. It is now known that the extensive desmoplastic reaction, principally produced by pancreatic stellate cells (PSCs), plays a role in chemoresistance via impairment of drug delivery and the formation of a hypoxic microenvironment. Interestingly despite high concentrations of cytotoxic drugs sequestered in the stromal compartment, hypoxia and low nutrient levels, PSCs thrive and proliferate. Membrane drug transporters associated with chemoresistance and cell survival are known to be altered in pancreatic cancer, yet the expression of drug transporters in PSCs and the impact of the hypoxic microenvironment on drug transporter expression in pancreatic cancer cells, have not been examined.
Aims: i) To characterise the expression of drug transporters in PSCs; and ii) To investigate the effect of hypoxia on drug transporter expression in pancreatic cancer cells.
Methods: i) PSCs were isolated from surgically resected normal pancreas and pancreatic cancer tissue from human patients. ii) Pancreatic cancer cells (MiaPaCa-2) were exposed ± hypoxia for 48h. mRNA expression of 84 human drug transporter genes were analysed in PSCs and pancreatic cancer cells using a PCR Array and differentially regulated genes in PSCs were validated by real-time PCR.
Results: Comparison between normal and cancer-associated PSCs revealed 11 differentially regulated genes with functions relating to drug-resistance, nutrient uptake and survival. Additionally in pancreatic cancer cells exposed to hypoxia, 25 drug transporter genes, which may regulate pro-survival and chemoresistant mechanisms, were significantly altered.
Conclusions: Drug transporters are: i) expressed in PSCs and differentially regulated in cancer-associated PSCs compared to normal PSCs; and ii) altered in pancreatic cancer cells under hypoxic conditions.
Implication: Characterisation of expression and alterations of drug transporters in PSCs and pancreatic cancer cells has the potential to identify new therapeutic targets that may improve the clinical outcome of pancreatic cancer patients.