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

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...

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Bibliographic Details
Published in:	Hepatobiliary & pancreatic diseases international Vol. 17; no. 5; pp. 461 - 472
Main Authors:	Neumann, Christopher C.M., von Hörschelmann, Ellen, Reutzel-Selke, Anja, Seidel, Elisabeth, Sauer, Igor Maximilian, Pratschke, Johann, Bahra, Marcus, Schmuck, Rosa Bianca
Format:	Journal Article
Language:	English
Published:	Singapore Elsevier B.V 01-10-2018 Department of Surgery, Campus Charité Mitte \| Campus Virchow-Klinikum, Experimental Surgery, Charité-Universitatsmedizin Berlin, Berlin, Germany%Department of Surgery, Campus Charité Mitte \| Campus Virchow-Klinikum, Experimental Surgery, Charité-Universitatsmedizin Berlin, Berlin, Germany Berlin Institute of Health, Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany
Subjects:	Atroma targeted therapy Cancer associated fibroblasts Cancer-Associated Fibroblasts - drug effects Cancer-Associated Fibroblasts - pathology Cancer–stroma co-culture 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 cancer Pancreatic Neoplasms - drug therapy Pancreatic Neoplasms - pathology Risk Factors Sensitivity and Specificity Stromal Cells - drug effects Stromal Cells - pathology Tumor Cells, Cultured Tumor microenvironment Cancer–stroma co-culture Cancer associated fibroblasts Tumor microenvironment Atroma targeted therapy Pancreatic cancer
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Summary:	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. 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. 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. CAFs are highly chemoresistant. Direct cell–cell contact and high levels of IL-6 correlate with a high chemoresistance.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1499-3872
DOI:	10.1016/j.hbpd.2018.09.004