Gemcitabine Recruits M2-Type Tumor-Associated Macrophages into the Stroma of Pancreatic Cancer.
Journal
Translational oncology
ISSN: 1936-5233
Titre abrégé: Transl Oncol
Pays: United States
ID NLM: 101472619
Informations de publication
Date de publication:
Mar 2020
Mar 2020
Historique:
received:
02
10
2019
revised:
14
01
2020
accepted:
17
01
2020
pubmed:
8
3
2020
medline:
8
3
2020
entrez:
8
3
2020
Statut:
ppublish
Résumé
Pancreatic ductal adenocarcinoma (PDAC) is a very lethal disease that can develop therapy resistance over time. The dense stroma in PDAC plays a critical role in tumor progression and resistance. How this stroma interacts with the tumor cells and how this is influenced by chemotherapy remain poorly understood. The backbone of this study is the parallel transcriptome analysis of human tumor and mouse stroma in two molecular and clinical representative patient-derived tumor xenografts models. Mice (8 animals per group) were treated for 4 weeks with gemcitabine or control. We studied tumor growth, RNA expression in the stroma, tumor-associated macrophages (TAMs) with immunofluorescence, and cytokines in the serum. A method for parallel transcriptome analysis was optimized. We found that the tumor (differentiation, gene expression) determines the infiltration of macrophages into the stroma. In aggressive PDAC (epithelial-to-mesenchymal transition high), we find more M2 polarized TAMs and the activation of cytokines and growth factors (TNFα, TGFβ1, and IL6). There are increased stromal glycolysis, reduced fatty acid oxidation, and reduced mitochondrial oxidation (tricarboxylic acid cycle and oxidative phosphorylation). Treatment with gemcitabine results in a shift of innate immune cells, especially additional infiltration of protumoral M2 TAMs (P < .001) and metabolic reprogramming. Gemcitabine treatment of PDAC xenografts stimulates a protumoral macrophage phenotype, and this, in combination with a shift of the tumor cells to a mesenchymal phenotype that we reported previously, contributes to tumor progression and therapeutic resistance. Targeting M2-polarized TAMs may benefit PDAC patients at risk to become refractory to current anticancer regimens.
Sections du résumé
BACKGROUND
BACKGROUND
Pancreatic ductal adenocarcinoma (PDAC) is a very lethal disease that can develop therapy resistance over time. The dense stroma in PDAC plays a critical role in tumor progression and resistance. How this stroma interacts with the tumor cells and how this is influenced by chemotherapy remain poorly understood.
METHODS
METHODS
The backbone of this study is the parallel transcriptome analysis of human tumor and mouse stroma in two molecular and clinical representative patient-derived tumor xenografts models. Mice (8 animals per group) were treated for 4 weeks with gemcitabine or control. We studied tumor growth, RNA expression in the stroma, tumor-associated macrophages (TAMs) with immunofluorescence, and cytokines in the serum.
RESULTS
RESULTS
A method for parallel transcriptome analysis was optimized. We found that the tumor (differentiation, gene expression) determines the infiltration of macrophages into the stroma. In aggressive PDAC (epithelial-to-mesenchymal transition high), we find more M2 polarized TAMs and the activation of cytokines and growth factors (TNFα, TGFβ1, and IL6). There are increased stromal glycolysis, reduced fatty acid oxidation, and reduced mitochondrial oxidation (tricarboxylic acid cycle and oxidative phosphorylation). Treatment with gemcitabine results in a shift of innate immune cells, especially additional infiltration of protumoral M2 TAMs (P < .001) and metabolic reprogramming.
CONCLUSIONS
CONCLUSIONS
Gemcitabine treatment of PDAC xenografts stimulates a protumoral macrophage phenotype, and this, in combination with a shift of the tumor cells to a mesenchymal phenotype that we reported previously, contributes to tumor progression and therapeutic resistance. Targeting M2-polarized TAMs may benefit PDAC patients at risk to become refractory to current anticancer regimens.
Identifiants
pubmed: 32145636
pii: S1936-5233(19)30540-6
doi: 10.1016/j.tranon.2020.01.004
pmc: PMC7058407
pii:
doi:
Types de publication
Journal Article
Langues
eng
Pagination
100743Informations de copyright
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.
Références
Br J Cancer. 2017 Nov 21;117(11):1583-1591
pubmed: 29065107
Cancers (Basel). 2018 Jan 03;10(1):
pubmed: 29301364
Breast Cancer Res. 2008;10(6):R105
pubmed: 19087274
Biomed Pharmacother. 2018 Dec;108:618-624
pubmed: 30243096
Cancer Lett. 2018 Jan 28;413:102-109
pubmed: 29111350
Curr Opin Immunol. 2010 Apr;22(2):231-7
pubmed: 20144856
Breast Cancer Res. 2016 Aug 11;18(1):84
pubmed: 27515302
Endoscopy. 2016 Nov;48(11):1016-1022
pubmed: 27626319
Immunol Cell Biol. 2014 Jul;92(6):543-52
pubmed: 24662521
Oncogene. 2014 Jun 5;33(23):2956-67
pubmed: 23851493
Cell Mol Life Sci. 2019 Apr;76(8):1447-1458
pubmed: 30747250
Front Physiol. 2013 Nov 01;4:318
pubmed: 24198790
Biochim Biophys Acta. 2012 Aug;1826(1):170-8
pubmed: 22521638
Cell. 2011 Mar 4;144(5):646-74
pubmed: 21376230
J Natl Cancer Inst. 2015 Jan 31;107(2):
pubmed: 25638248
Adv Drug Deliv Rev. 2016 Apr 1;99(Pt B):180-185
pubmed: 26621196
J Control Release. 2016 Feb 10;223:165-177
pubmed: 26742942
Cancer Discov. 2015 Jan;5(1):52-63
pubmed: 25361845
Cancer Lett. 2017 Apr 10;391:38-49
pubmed: 28093284
Theranostics. 2017 Sep 26;7(17):4276-4288
pubmed: 29158825
Biochim Biophys Acta. 2014 Sep;1841(9):1329-35
pubmed: 24960101
Am J Transl Res. 2019 Feb 15;11(2):765-779
pubmed: 30899378
BMC Cancer. 2016 Aug 12;16:632
pubmed: 27520560
Nature. 2015 Nov 26;527(7579):525-530
pubmed: 26560028
Cell Immunol. 2017 Jun;316:1-10
pubmed: 28433198
Cancer Cell. 2013 Feb 11;23(2):249-62
pubmed: 23410977
Cancer Immunol Immunother. 2005 Sep;54(9):915-25
pubmed: 15782312
Cancer Cell. 2013 Mar 18;23(3):277-86
pubmed: 23518347
J Innate Immun. 2014;6(6):716-26
pubmed: 25138714
Clin Cancer Res. 2014 Apr 15;20(8):2192-204
pubmed: 24563479
Eur J Cancer. 2014 Jul;50(11):1900-8
pubmed: 24835032
Sci Rep. 2017 Dec 4;7(1):16878
pubmed: 29203879
Invest New Drugs. 2013 Jun;31(3):760-8
pubmed: 22907596
Nat Cell Biol. 2017 May;19(5):518-529
pubmed: 28414315
Cell Death Dis. 2018 Apr 18;9(5):453
pubmed: 29670110
J Exp Clin Cancer Res. 2016 Feb 16;35:33
pubmed: 26879926
Nat Rev Urol. 2013 Aug;10(8):441-51
pubmed: 23857181
Trends Immunol. 2012 Mar;33(3):119-26
pubmed: 22277903
Int J Cancer. 2014 Aug 15;135(4):843-61
pubmed: 24458546
Int J Oncol. 2015 Mar;46(3):1109-20
pubmed: 25502147
Biochim Biophys Acta Gen Subj. 2017 Feb;1861(2):296-306
pubmed: 27750041
Cancer Res. 2006 Dec 1;66(23):11238-46
pubmed: 17114237
Cell Rep. 2017 Aug 15;20(7):1654-1666
pubmed: 28813676
Front Immunol. 2015 May 05;6:212
pubmed: 25999950
Gut. 2019 Oct;68(10):1872-1883
pubmed: 30580251
Nat Rev Drug Discov. 2012 Feb 03;11(3):215-33
pubmed: 22301798
Cytokine. 2017 Jan;89:194-200
pubmed: 26868086
Nat Med. 2011 Apr;17(4):500-3
pubmed: 21460848
Nature. 2002 Dec 19-26;420(6917):860-7
pubmed: 12490959
Lab Invest. 2013 Jul;93(7):844-54
pubmed: 23752129
Cancer Res. 2005 Apr 15;65(8):3437-46
pubmed: 15833879
Connect Tissue Res. 2015;56(5):403-13
pubmed: 26291767
J Immunol Res. 2016;2016:6031486
pubmed: 27376091
Clin Cancer Res. 2012 Aug 15;18(16):4266-76
pubmed: 22896693
Cell Metab. 2019 Jun 4;29(6):1390-1399.e6
pubmed: 30827862
Nature. 2005 Jun 9;435(7043):752-3
pubmed: 15944689
Am J Transl Res. 2012;4(4):376-89
pubmed: 23145206
J Clin Invest. 2012 Mar;122(3):787-95
pubmed: 22378047
Eur J Immunol. 2016 Jan;46(1):13-21
pubmed: 26643360
Elife. 2017 Oct 05;6:
pubmed: 28980940
Cell Immunol. 2018 Aug;330:54-59
pubmed: 29395037
Hepatobiliary Pancreat Dis Int. 2014 Aug;13(4):371-80
pubmed: 25100121
Nat Rev Cancer. 2004 Jan;4(1):71-8
pubmed: 14708027
BMC Cancer. 2012 Jan 24;12:35
pubmed: 22273460
Autophagy. 2018;14(8):1335-1346
pubmed: 29940792
BMC Genomics. 2018 Jan 5;19(1):19
pubmed: 29304755
Cancer Lett. 2016 Oct 10;381(1):211-6
pubmed: 26708507
Bioinformatics. 2012 Jun 15;28(12):i172-8
pubmed: 22689758