title: Aspirin counteracts cancer stem cell features, desmoplasia and gemcitabine resistance in pancreatic cancer.
abstract: Pancreatic ductal adenocarcinoma (PDA) is characterized by an extremely poor prognosis. An inflammatory microenvironment triggers the pronounced desmoplasia, the selection of cancer stem-like cells (CSCs) and therapy resistance. The anti-inflammatory drug aspirin is suggested to lower the risk for PDA and to improve the treatment, although available results are conflicting and the effect of aspirin to CSC characteristics and desmoplasia in PDA has not yet been investigated. We characterized the influence of aspirin on CSC features, stromal reactions and gemcitabine resistance. Four established and 3 primary PDA cell lines, non-malignant cells, 3 patient tumor-derived CSC-enriched spheroidal cultures and tissues from patients who did or did not receive aspirin before surgery were analyzed using MTT assays, flow cytometry, colony and spheroid formation assays, Western blot analysis, antibody protein arrays, electrophoretic mobility shift assays (EMSAs), immunohistochemistry and in vivo xenotransplantation. Aspirin significantly induced apoptosis and reduced the viability, self-renewal potential, and expression of proteins involved in inflammation and stem cell signaling. Aspirin also reduced the growth and invasion of tumors in vivo, and it significantly prolonged the survival of mice with orthotopic pancreatic xenografts in combination with gemcitabine. This was associated with a decreased expression of markers for progression, inflammation and desmoplasia. These findings were confirmed in tissue samples obtained from patients who had or had not taken aspirin before surgery. Importantly, aspirin sensitized cells that were resistant to gemcitabine and thereby enhanced the therapeutic efficacy. Aspirin showed no obvious toxic effects on normal cells, chick embryos or mice. These results highlight aspirin as an effective, inexpensive and well-tolerated co-treatment to target inflammation, desmoplasia and CSC features PDA.
authors.affiliation: Molecular OncoSurgery, University of Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.|Section Surgical Research, University of Heidelberg, Heidelberg, Germany.|Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.|Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, Xiamen, China.
authors.forename: Yiyao
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Molecular OncoSurgery, University of Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.|Section Surgical Research, University of Heidelberg, Heidelberg, Germany.|Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.affiliation: Molecular OncoSurgery, University of Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.|Section Surgical Research, University of Heidelberg, Heidelberg, Germany.|Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Pei
authors.initials: P
authors.lastname: Fan
authors.affiliation: Molecular OncoSurgery, University of Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.|Section Surgical Research, University of Heidelberg, Heidelberg, Germany.|Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bauer
authors.affiliation: Molecular OncoSurgery, University of Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.|Section Surgical Research, University of Heidelberg, Heidelberg, Germany.|Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Jury
authors.initials: J
authors.lastname: Gladkich
authors.affiliation: Section Surgical Research, University of Heidelberg, Heidelberg, Germany.|Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Eduard
authors.initials: E
authors.lastname: Ryschich
authors.affiliation: Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Alexandr V
authors.initials: AV
authors.lastname: Bazhin
authors.affiliation: Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Nathalia A
authors.initials: NA
authors.lastname: Giese
authors.affiliation: Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Strobel
authors.affiliation: Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Thilo
authors.initials: T
authors.lastname: Hackert
authors.affiliation: Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Ulf
authors.initials: U
authors.lastname: Hinz
authors.affiliation: Molecular OncoSurgery, University of Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.|Section Surgical Research, University of Heidelberg, Heidelberg, Germany.|Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Gross
authors.affiliation: Section Surgical Research, University of Heidelberg, Heidelberg, Germany.|Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Franco
authors.initials: F
authors.lastname: Fortunato
authors.affiliation: Molecular OncoSurgery, University of Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.|Section Surgical Research, University of Heidelberg, Heidelberg, Germany.|Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Herr
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001241:Aspirin / Q000008:administration & dosage / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000378:metabolism; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002642:Chick Embryo; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D014408:Biomarkers, Tumor; D003841:Deoxycytidine; D001241:Aspirin; D000093542:Gemcitabine
keywords: cancer stem cells; novel therapeutics; pancreatic cancer
references.citation: Langenbecks Arch Surg. 2013 Oct;398(7):989-96
references.pmid: 23989613
references.citation: Cancer Cell. 2014 Jun 16;25(6):711-2
references.pmid: 24937454
references.citation: Environ Toxicol Pharmacol. 2005 Nov;20(3):501-5
references.pmid: 21783632
references.citation: Cancer Invest. 2013 Feb;31(2):97-102
references.pmid: 23245395
references.citation: Oncotarget. 2014 Mar 30;5(6):1621-34
references.pmid: 24742583
references.citation: J Clin Invest. 2007 Jan;117(1):50-9
references.pmid: 17200706
references.citation: N Engl J Med. 2005 Jan 20;352(3):238-44
references.pmid: 15659723
references.citation: J Clin Invest. 2007 Jun;117(6):1502-13
references.pmid: 17525799
references.citation: Stem Cells Dev. 2009 Jan-Feb;18(1):17-25
references.pmid: 18573038
references.citation: Gut. 2009 Jul;58(7):949-63
references.pmid: 18829980
references.citation: Science. 1994 Aug 12;265(5174):956-9
references.pmid: 8052854
references.citation: Gastroenterology. 2009 Sep;137(3):1102-13
references.pmid: 19501590
references.citation: Oncogene. 2003 May 22;22(21):3243-51
references.pmid: 12761494
references.citation: FASEB J. 2008 Mar;22(3):659-61
references.pmid: 17942826
references.citation: J Natl Cancer Inst. 2004 Jan 7;96(1):22-8
references.pmid: 14709735
references.citation: Pancreatology. 2004;4(6):567-86
references.pmid: 15550766
references.citation: Lancet. 2011 Jan 1;377(9759):31-41
references.pmid: 21144578
references.citation: Cancer Res. 1956 Aug;16(7):589-94
references.pmid: 13356282
references.citation: Gut. 2006 Jan;55(1):115-22
references.pmid: 16118353
references.citation: Cell Stem Cell. 2007 Sep 13;1(3):313-23
references.pmid: 18371365
references.citation: Int J Cancer. 2014 Feb 1;134(3):519-29
references.pmid: 23852449
references.citation: J Natl Cancer Inst. 2002 Aug 7;94(15):1168-71
references.pmid: 12165642
references.citation: Cell. 2004 Aug 6;118(3):285-96
references.pmid: 15294155
references.citation: Nat Rev Clin Oncol. 2012 May;9(5):259-67
references.pmid: 22473097
references.citation: Gut. 2010 May;59(5):630-7
references.pmid: 19880966
references.citation: J Physiol Pharmacol. 2010 Oct;61(5):619-28
references.pmid: 21081806
references.citation: N Engl J Med. 1997 Apr 10;336(15):1066-71
references.pmid: 9091804
references.citation: Nature. 2001 May 17;411(6835):375-9
references.pmid: 11357145
references.citation: Gut. 2014 Nov;63(11):1755-9
references.pmid: 24488498
references.citation: Gastroenterology. 2011 Dec;141(6):2218-2227.e5
references.pmid: 21864475
references.citation: Nature. 1998 Nov 5;396(6706):77-80
references.pmid: 9817203
references.citation: Clin Res Hepatol Gastroenterol. 2014 Oct;38(5):570-6
references.pmid: 25130796
references.citation: Science. 2009 Jun 12;324(5933):1457-61
references.pmid: 19460966
references.citation: Cancer Epidemiol Biomarkers Prev. 2014 Jul;23(7):1254-63
references.pmid: 24969230
references.citation: Best Pract Res Clin Gastroenterol. 2008;22(1):65-73
references.pmid: 18206813
references.citation: J Surg Res. 2012 Jan;172(1):29-39
references.pmid: 21683373
references.citation: Adv Exp Med Biol. 1977;88:47-59
references.pmid: 303453
references.citation: Pol J Pharmacol. 1996 Nov-Dec;48(6):609-13
references.pmid: 9112701
references.citation: Proc Natl Acad Sci U S A. 2007 Oct 2;104(40):15852-7
references.pmid: 17890319
references.citation: Cancer. 2005 Jun 15;103(12):2485-90
references.pmid: 15861417
references.citation: Cancer Res. 2008 Feb 1;68(3):918-26
references.pmid: 18245495
references.citation: Int J Cancer. 2014 May 15;134(10):2489-503
references.pmid: 24615157
references.citation: Med Sci Monit. 2004 Jun;10(6):BR175-9
references.pmid: 15173663
references.citation: Nature. 2006 Aug 17;442(7104):742-3
references.pmid: 16915262
references.citation: Rev Hist Pharm (Paris). 2007 Jul;55(354):209-16
references.pmid: 18175528