Background
Pancreatic cancer is a very aggressive malignancy and efficient therapeutic options
are still largely lacking. The importance of interactions between tumor cells and
surrounding stromal elements, eg, mononuclear cells, for chemoresistance have been
increasingly recognized. In addition, cyclooxygenase-2 is thought to be an important
mediator of chemoresistance in several malignancies. The aim of this study was to
explore the role of mononuclear cells in pancreatic cancer chemoresistance.
Methods
Human histiocytic lymphoma U937 cells were differentiated into macrophage-like cells.
The effect of U937-conditioned medium on drug-induced pancreatic cancer cell apoptosis
was measured by enzyme-linked immunosorbent assay. The contributions of interleukin-1β
and cyclooxygenase-2 were evaluated by specific receptor antagonists and inhibitors.
The importance of the extracellular signal-regulated kinase (ERK1/2) pathway also
was determined.
Results
U937-conditioned culture medium protected pancreatic cancer cells from drug-induced
apoptosis. This protective effect was abolished by an interleukin-1 receptor antagonist
and cyclooxygenase-2 inhibitor. U937-conditioned medium and interleukin-1β stimulated
expression of cyclooxygenase-2 and prostaglandin E2 production in pancreatic cancer cells, which was mediated by activation of the ERK1/2
pathway. Transfection of pancreatic cancer cells with cyclooxygenase-2 increased resistance
to drug-induced cell death.
Conclusions
Mononuclear cells protect pancreatic cancer cells from drug-induced apoptosis in vitro
by interleukin-1β–mediated expression of cyclooxygenase-2 and production of prostaglandins.
This study highlights the importance of tumor-host interactions in pancreatic cancers
and may provide the basis for novel therapeutic approaches to sensitize pancreatic
cancers to chemotherapeutic agents.
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Article info
Publication history
Published online: June 06, 2008
Accepted:
March 3,
2008
Footnotes
Supported in part by research grants from the CURE: Digestive Diseases Research Center Pilot and Feasibility Studies (Center: P30 DK041301); the Hirshberg Foundation for Pancreatic Cancer Research (H.A.R.); the UCLA Center for Excellence in Pancreatic Diseases (P01 AT003960); the Swiss Scientific Foundation (PBZHB-117008 to E.A.); and the National Institutes of Health (R01 CA104027 and R01 CA122042 to G.E.).
Identification
Copyright
© 2008 Mosby, Inc. Published by Elsevier Inc. All rights reserved.
