Tumor-stromal cross-talk modulating the therapeutic response in pancreatic cancer

Hepatobiliary Pancreat Dis Int. 2018 Oct;17(5):461-472. doi: 10.1016/j.hbpd.2018.09.004. Epub 2018 Sep 7.

Abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant solid tumor with a dismal prognosis. The stroma component makes up to 90% of the tumor mass and is thought to be one of the main reasons for the tumor's high chemoresistance. Cancer associated fibroblasts (CAFs) have previously been identified to be the key stromal players. This is the first time we provide detailed in vitro experiments investigating tumor-stromal interactions when exposed to three well-known chemotherapeutic agents.

Methods: Monocultures, indirect and direct co-cultures of two PDAC cell lines (AsPC and Panc-1) and six primary patients derived CAFs were treated with gemcitabine, nab-paclitaxel and the γ-secretase-inhibitor (GSI) DAPT. The cell viability of each component was measured with XTT. Finally, IL-6 concentrations of the supernatants were analyzed.

Results: On the contrary to PDAC cell lines, CAF monocultures hardly responded to any treatment which suggested that stroma (CAFs) itself is more resistant to standard chemo-treatments than the epithelial cancer cells. Moreover, only a weak chemotherapeutic response was observed in direct co-cultures of cancer cells with CAFs. A change in the morphology of direct co-cultures was accompanied with the chemoresistance. CAFs were observed to build cage-like structures around agglomerates of tumor cells. High levels of IL-6 were also associated with a reduced response to therapy. Indirect co-cultures make the tumor-stromal interaction more complex.

Conclusions: CAFs are highly chemoresistant. Direct cell-cell contact and high levels of IL-6 correlate with a high chemoresistance.

Keywords: Atroma targeted therapy; Cancer associated fibroblasts; Cancer–stroma co-culture; Pancreatic cancer; Tumor microenvironment.

MeSH terms

  • Cancer-Associated Fibroblasts / drug effects*
  • Cancer-Associated Fibroblasts / pathology
  • Carcinoma, Pancreatic Ductal / drug therapy*
  • Carcinoma, Pancreatic Ductal / pathology*
  • Cell Survival / drug effects
  • Coculture Techniques
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / pharmacology
  • Female
  • Humans
  • Male
  • Paclitaxel / pharmacology*
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / pathology*
  • Risk Factors
  • Sensitivity and Specificity
  • Stromal Cells / drug effects
  • Stromal Cells / pathology
  • Tumor Cells, Cultured

Substances

  • Deoxycytidine
  • gemcitabine
  • Paclitaxel