1. Chemotherapy-Induced Inflammatory Gene Signature and Protumorigenic Phenotype in Pancreatic CAFs via Stress-Associated MAPK.
- Author
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Toste PA, Nguyen AH, Kadera BE, Duong M, Wu N, Gawlas I, Tran LM, Bikhchandani M, Li L, Patel SG, Dawson DW, and Donahue TR
- Subjects
- Animals, Cancer-Associated Fibroblasts drug effects, Cancer-Associated Fibroblasts metabolism, Carcinoma, Pancreatic Ductal genetics, Carcinoma, Pancreatic Ductal metabolism, Cell Line, Tumor, Cell Movement, Cell Proliferation, Culture Media, Conditioned, Deoxycytidine pharmacology, Gene Expression Profiling, Gene Expression Regulation, Neoplastic drug effects, Humans, Mice, Neoplasm Transplantation, Oligonucleotide Array Sequence Analysis, Pancreatic Neoplasms genetics, Pancreatic Neoplasms metabolism, Tumor Cells, Cultured metabolism, Gemcitabine, Cancer-Associated Fibroblasts cytology, Carcinoma, Pancreatic Ductal pathology, Deoxycytidine analogs & derivatives, Inflammation genetics, MAP Kinase Signaling System drug effects, Pancreatic Neoplasms pathology, Tumor Cells, Cultured cytology
- Abstract
Unlabelled: Pancreatic ductal adenocarcinoma (PDAC) has a characteristically dense stroma comprised predominantly of cancer-associated fibroblasts (CAF). CAFs promote tumor growth, metastasis, and treatment resistance. This study aimed to investigate the molecular changes and functional consequences associated with chemotherapy treatment of PDAC CAFs. Chemoresistant immortalized CAFs (R-CAF) were generated by continuous incubation in gemcitabine. Gene expression differences between treatment-naïve CAFs (N-CAF) and R-CAFs were compared by array analysis. Functionally, tumor cells (TC) were exposed to N-CAF- or R-CAF-conditioned media and assayed for migration, invasion, and viability in vitro Furthermore, a coinjection (TC and CAF) model was used to compare tumor growth in vivo R-CAFs increased TC viability, migration, and invasion compared with N-CAFs. In vivo, TCs coinjected with R-CAFs grew larger than those accompanied by N-CAFs. Genomic analysis demonstrated that R-CAFs had increased expression of various inflammatory mediators, similar to the previously described senescence-associated secretory phenotype (SASP). In addition, SASP mediators were found to be upregulated in response to short duration treatment with gemcitabine in both immortalized and primary CAFs. Inhibition of stress-associated MAPK signaling (P38 MAPK or JNK) attenuated SASP induction as well as the tumor-supportive functions of chemotherapy-treated CAFs in vitro and in vivo These results identify a negative consequence of chemotherapy on the PDAC microenvironment that could be targeted to improve the efficacy of current therapeutic regimens., Implications: Chemotherapy treatment of pancreatic cancer-associated fibroblasts results in a proinflammatory response driven by stress-associated MAPK signaling that enhances tumor cell growth and invasiveness. Mol Cancer Res; 14(5); 437-47. ©2016 AACR., (©2016 American Association for Cancer Research.)
- Published
- 2016
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