Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant disease with a 5-year survival rate of only 8%. Within the USA, PDAC is expected to become the second leading cause of cancer-related deaths by 2030. Treatment of PDAC remains a major challenge due to late diagnosis, the lack of biomarkers for early detection, and the poor response to systemic chemotherapies.
A hallmark feature of pancreatic cancer is the pronounced tumour stroma. This highly dynamic tumour compartment consists of pancreatic stellate cells, cancer associated fibroblasts (CAFs), myofibroblasts, immune and inflammatory cells, vascular cells, and extracellular matrix components such as collagen, hyaluronic acid, and SPARC. The tumour microenvironment has been extensively studied as a potential therapeutic target to improve the response to various systemic and targeted therapies. In particular, stroma depletion approaches were investigated that may increase vascularisation, drug delivery, and response to treatment. Although pre-clinical experiments suggested some efficacy (e.g. sonic hedgehog inhibition), none of these findings could be successfully translated into clinical use for patients. In contrast, recent preclinical research revealed that genetic or pharmacological ablation of CAFs resulted in more aggressive and undifferentiated tumours.
At UEG Week 2016 in Vienna, Austria, we presented data from our laboratory suggesting that CAFs are involved in drug metabolism in PDAC by storing large amounts of activated gemcitabine intracellularly. Mass spectrometry analysis of small tumour pieces distinguished between native gemcitabine, the inactivated form, and the active cytotoxic metabolite of gemcitabine. Interestingly, the activated form of gemcitabine was found to be increased 3-fold in CAFs compared to tumour cells. Since the inactive form of gemcitabine was dramatically decreased, we hypothesised that gemcitabine metabolism rather than delivery may be instrumental for the increased drug accumulation in CAFs. Indeed, a number of gemcitabine inactivating enzymes were expressed at very low levels in CAFs that explained the increase of gemcitabine metabolites in those cells. As pancreatic tumour cells are surrounded by a dense microenvironment including multiple activated fibroblasts, these cells may thus scavenge chemotherapy drugs no longer available for cancer cells.
As stromal depletion approaches may mediate adverse therapeutic effects, stromal reprogramming thus seems to be a promising novel strategy to improve chemotherapy availability and efficacy for pancreatic cancer patients. To this end, molecular engineering of CAFs that target the metabolic machinery of drug activation and inactivation may reduce the amount of active chemotherapy accumulation in CAFs and consequently shift the availability to tumour cells. Although stromal reprogramming is still highly experimental and far from clinical use, it may open new avenues to tackle chemoresistance and sensitise pancreatic cancer to standard therapies.
