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ID: 686 (Conflict of Interest: K)

Die Interaktion von Tumor und Stroma über die IL-17B / RB-Achse beeinflusst das metastatische Potenzial des Pankreasgang-Adenokarzinoms

J.Li, Y.Zhao, C. J.Bruns, F.Popp
Uniklinik Köln, Köln

Einleitung

Pancreatic stellate cells (PSCs) produce collagenous stroma in pancreatic ductal adenocarcinoma (PDAC) and interact with tumor cells as well as with immune cells. PSCs form a tumorigenic microenvironment thus they play an important role in pancreatic cancer progression and possibly resistance to chemotherapy. IL-17RB is a negative predictive marker in pancreatic cancer and several other tumor entities. Mechanistically, a positive autocrine feedback loop of IL-17 and IL-17RB in tumor cells promotes metastasis. Because PSCs also express IL-17RB our aim is to elucidate if tumor cells communicate with PSCs through IL-17B to promote pancreatic cancer progression.

Material und Methoden

Methods:First, we detected IL-17RB expression in human PDAC tissue samples by immunohistochemistry and flow cytometry analysis, respectively. Primary PSCs were isolated from wild type C56/BL6 mice and human pancreas, as well as from pancreatic cancer samples. Co-culture of PSCs with PDAC tumor cells was performed in a 3D culture model and by indirect co-culture assays. Tumor cell migration, metastatic related cytokines and stemness markers were analyzed using ELISA, Western blot and FACS respectively. The stemness of cancer cells was also detected by sphere formation and soft-agar colony formation assay in vitro. Overexpression of IL-17RB was induced in the human PSCs cell line RLT-PSC. 

Ergebnisse

High expression levels of IL-17RB were detectable in human PDAC. IL-17RB expression was also localized in the stroma. Tumor cell lines with high metastatic potential express more IL17B compared to low metastatic tumor cells. Co-culture of murine PSC with tumor cells results in PSC activation and sensitivity to IL-17B. In response to IL17B stimulation, PSCs produce increased levels of CCL5, CXCL12 and MMP9. Co-culture with PSC increases the stemness marker CD44, sphere formation rate and colony formation capacity of tumor cells.

Schlussfolgerung

The IL17B/RB axis is involved in interaction between PDAC and PSCs. IL-17B stimulation of PSC results in the secretion of pro-tumorigenic factors. PSCs contribute to sustain tumor stemness and thus might contribute to chemotherapy resistance. Pharmacological blocking of the IL-17B/RB axis could modify the tumor-stroma interaction in a beneficial way and might serve as an adjuvant therapy for PDAC.