Role of myofibroblasts in innate chemoresistance of pancreatic carcinoma—Epigenetic downregulation of caspases

We recently reported on continuous tumor–stroma interactions essentially contributing to chemoresistance of pancreatic ductal adenocarinoma (PDAC) cells. As demonstrated here, long‐term coculture with pancreatic myofibroblasts representing the main stromal compartment of PDAC resulted in a chemoresi...

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Bibliographic Details
Published in:International journal of cancer 2008-10, Vol.123 (8), p.1751-1760
Main Authors: Müerköster, Susanne Sebens, Werbing, Veronika, Koch, Dorothee, Sipos, Bence, Ammerpohl, Ole, Kalthoff, Holger, Tsao, Ming‐Sound, Fölsch, Ulrich R., Schäfer, Heiner
Format: Article
Language:English
Subjects:
Animals
Antineoplastic agents
Apoptosis - drug effects
Apoptosis - genetics
Azacitidine - analogs & derivatives
Azacitidine - pharmacology
Biological and medical sciences
Carcinoma, Pancreatic Ductal - drug therapy
Carcinoma, Pancreatic Ductal - enzymology
Carcinoma, Pancreatic Ductal - genetics
Carcinoma, Pancreatic Ductal - pathology
Caspases - biosynthesis
Caspases - genetics
Cell Line, Tumor
Cell Nucleus - enzymology
chemoresistance
Chemotherapy
Coculture Techniques
Deoxycytidine - analogs & derivatives
Deoxycytidine - pharmacology
DNA (Cytosine-5-)-Methyltransferase 1
DNA (Cytosine-5-)-Methyltransferases - biosynthesis
DNA (Cytosine-5-)-Methyltransferases - metabolism
Down-Regulation
Drug Resistance, Neoplasm
Epigenesis, Genetic
epigenetic gene silencing
Etoposide - pharmacology
Female
Fibroblasts - enzymology
Fibroblasts - pathology
Humans
Medical sciences
Mice
Mice, SCID
myofibroblasts
pancreatic cancer
Pancreatic Neoplasms - drug therapy
Pancreatic Neoplasms - enzymology
Pancreatic Neoplasms - genetics
Pancreatic Neoplasms - pathology
Pharmacology. Drug treatments
STAT1 Transcription Factor - biosynthesis
STAT1 Transcription Factor - genetics
Transfection
Tumors
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Summary:We recently reported on continuous tumor–stroma interactions essentially contributing to chemoresistance of pancreatic ductal adenocarinoma (PDAC) cells. As demonstrated here, long‐term coculture with pancreatic myofibroblasts representing the main stromal compartment of PDAC resulted in a chemoresistant phenotype in the pancreatic ductal epithelial cell line H6c7 as well as in the chemosensitive PDAC cell line T3M4. This involved a reduced expression of caspases and the caspase inducing transcription factor STAT1, both caused by diminished gene transcription. The DNA‐methylation inhibitor 5‐azadeoxycytidine enhanced caspase and STAT1 expression in cocultured H6c7 and T3M4 cells along with an increased chemosensitivity, indicating a role for CpG DNA‐hypermethylation in the downregulation of these crucial apoptosis mediators. Cocultured H6c7 and T3M4 cells exhibited elevated nuclear levels of DNA‐methyltransferase‐1 (DNMT1). Silencing of DNMT1 expression by siRNA increased expression of caspases and STAT1 and restored chemosensitivity. In SCID mice, tumors arising from coinoculated T3M4 cells and myofibroblasts (co‐tumors) responded less towards chemotherapy than mono‐tumors, exhibiting decreased apoptosis, no remission and reduced expression of caspases and STAT1. These data underscore the role of myofibroblasts in chemoresistance of PDAC and point to the importance of caspases as central target structures of epigenetic regulation in this scenario. Furthermore, an activated microenvironment might apparently promote the manifestation of chemoresistance already in premalignant precursor cells at early stages of PDAC tumorigenesis. © 2008 Wiley‐Liss, Inc.
ISSN:0020-7136
1097-0215
DOI:10.1002/ijc.23703