Extensive desmoplasia is associated with high expression of ZEB1 in pancreatic cancer cells and cancer associated fibroblasts determine prognosis

Abstract

Background: Tumor sorrounding stroma and cancer associated fibroblast (CAFs) in particular play a major role in ductal adenocarcinoma of the pancreas (PDAC). The aim of our study was to r investigate the interaction between CAFs and PDAC cells in vitro using patient derived CAF cultures. Methods: CAFs were isolated from tumor tissue, transferred to in vitro setting and phenotypically characterized. Migration capacity and chemo-sensitivity was evaluated in a modified two-well system with established PDAC cell lines. Non-malignant fibroblast from foreskin served as controls. Paracrine interaction via chemokines was measured using elisa. Results: CAFs resemble activated pancreatic stellate cells. A strong negative effect on the therapeutic response of PDAC cells to Gemcitabine, Notch inhibition (DAPT) and nab-paclitaxel could be observed in direct co-cultures. Indirect co-culturing showed no significant effect on the chemo-sensitivity of PDAC cells but nevertheless resulted in a significant increase of IL-6 levels. PDAC cells showed a higher migration capacity when cocultured with CAFs. CAFs themselves showed a significantly higher migration capacity compared to non-malignant fibroblasts. This was further boosted in presence of PDAC cells. Conclusion: We elucidated a strong interaction between PDAC cells and CAFs, which may have a high impact on therapeutic efficiency. Paracrine inflammation response could play a pivotal role in this modification process. Further evaluation is needed to clarify this observations.