Eliane Angst1, Howard A Reber, Oscar J Hines, Guido Eibl. 1. Hirshberg Laboratories for Pancreatic Cancer Research, CURE, Digestive Diseases Research Center, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA.
Abstract
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-1beta 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-1beta stimulated expression of cyclooxygenase-2 and prostaglandin E(2) 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-1beta-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.
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-1beta 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-1beta stimulated expression of cyclooxygenase-2 and prostaglandin E(2) 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-1beta-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.
Authors: O N Tucker; A J Dannenberg; E K Yang; F Zhang; L Teng; J M Daly; R A Soslow; J L Masferrer; B M Woerner; A T Koki; T J Fahey Journal: Cancer Res Date: 1999-03-01 Impact factor: 12.701
Authors: A Bellocq; M Antoine; A Flahault; C Philippe; B Crestani; J F Bernaudin; C Mayaud; B Milleron; L Baud; J Cadranel Journal: Am J Pathol Date: 1998-01 Impact factor: 4.307
Authors: I Esposito; M Menicagli; N Funel; F Bergmann; U Boggi; F Mosca; G Bevilacqua; D Campani Journal: J Clin Pathol Date: 2004-06 Impact factor: 3.411
Authors: Sanjeev Banerjee; Asfar S Azmi; Subhash Padhye; Marjit W Singh; Jubaraj B Baruah; Philip A Philip; Fazlul H Sarkar; Ramzi M Mohammad Journal: Pharm Res Date: 2010-04-27 Impact factor: 4.200
Authors: Andrea Schmidt; James Sinnett-Smith; Steven Young; Hui-Hua Chang; O Joe Hines; David W Dawson; Enrique Rozengurt; Guido Eibl Journal: Surgery Date: 2017-02-20 Impact factor: 3.982
Authors: Hiroki Takahashi; Monica C Chen; Hung Pham; Eliane Angst; Jonathan C King; Jenny Park; Ethan Y Brovman; Hideyuki Ishiguro; Diane M Harris; Howard A Reber; Oscar J Hines; Anna S Gukovskaya; Vay Liang W Go; Guido Eibl Journal: Biochim Biophys Acta Date: 2011-05-10
Authors: Kenneth H Yu; Mark Ricigliano; Manuel Hidalgo; Ghassan K Abou-Alfa; Maeve A Lowery; Leonard B Saltz; Joseph F Crotty; Kristen Gary; Brandon Cooper; Rena Lapidus; Mariola Sadowska; Eileen M O'Reilly Journal: Clin Cancer Res Date: 2014-08-08 Impact factor: 12.531
Authors: Anita L Ray; Kiersten L Berggren; Sebastian Restrepo Cruz; Gregory N Gan; Ellen J Beswick Journal: Int J Cancer Date: 2017-12-12 Impact factor: 7.396
Authors: Alice Nomura; Vineet K Gupta; Patricia Dauer; Nikita S Sharma; Vikas Dudeja; Nipun Merchant; Ashok K Saluja; Sulagna Banerjee Journal: Mol Cancer Res Date: 2017-09-28 Impact factor: 5.852