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Translational oncology
Mar, 2020;13 (3): 100743.

Gemcitabine Recruits M2-Type Tumor-Associated Macrophages into the Stroma of Pancreatic Cancer.

Ashenafi Bulle, Jeroen Dekervel, Lise Deschuttere, David Nittner, Louis Libbrecht, Rekin's Janky, Stéphane Plaisance, Baki Topal, An Coosemans, Diether Lambrechts, Eric Van Cutsem, Chris Verslype, Jos van Pelt
Author Information
  1. Ashenafi Bulle: Laboratory of Clinical Digestive Oncology, Department of Oncology, KU Leuven & University Hospitals Leuven and Leuven Cancer Institute (LKI), Leuven, Herestraat 49, 3000 Leuven, Belgium.
  2. Jeroen Dekervel: Laboratory of Clinical Digestive Oncology, Department of Oncology, KU Leuven & University Hospitals Leuven and Leuven Cancer Institute (LKI), Leuven, Herestraat 49, 3000 Leuven, Belgium.
  3. Lise Deschuttere: Laboratory of Clinical Digestive Oncology, Department of Oncology, KU Leuven & University Hospitals Leuven and Leuven Cancer Institute (LKI), Leuven, Herestraat 49, 3000 Leuven, Belgium.
  4. David Nittner: Histopathology Expertise Center, VIB-KU Leuven Center for Cancer Biology, VIB, and Department of Oncology, KU Leuven, 3000 Leuven, Belgium.
  5. Louis Libbrecht: Department of Pathology, University Hospital Saint-Luc, Hippokrateslaan 10, 1200 Sint-Lambrechts-Woluwe, Belgium.
  6. Rekin's Janky: VIB Nucleomics Core, VIB, Herestraat 49, 3000 Leuven, Belgium.
  7. Stéphane Plaisance: VIB Nucleomics Core, VIB, Herestraat 49, 3000 Leuven, Belgium.
  8. Baki Topal: Department of Abdominal Surgery, University Hospitals KU Leuven, Herestraat 49, 3000 Leuven, Belgium.
  9. An Coosemans: Department of Oncology, Leuven Cancer Institute, Laboratory of Tumor Immunology and Immunotherapy, ImmunOvar Research Group, Catholic University of Leuven, Leuven, Belgium; Department of Obstetrics and Gynecology, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium.
  10. Diether Lambrechts: Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium and Center for Cancer Biology, VIB, Herestraat 49, 3000 Leuven, Belgium.
  11. Eric Van Cutsem: Laboratory of Clinical Digestive Oncology, Department of Oncology, KU Leuven & University Hospitals Leuven and Leuven Cancer Institute (LKI), Leuven, Herestraat 49, 3000 Leuven, Belgium.
  12. Chris Verslype: Laboratory of Clinical Digestive Oncology, Department of Oncology, KU Leuven & University Hospitals Leuven and Leuven Cancer Institute (LKI), Leuven, Herestraat 49, 3000 Leuven, Belgium.
  13. Jos van Pelt: Laboratory of Clinical Digestive Oncology, Department of Oncology, KU Leuven & University Hospitals Leuven and Leuven Cancer Institute (LKI), Leuven, Herestraat 49, 3000 Leuven, Belgium. Electronic address: jos.vanpelt@kuleuven.be.
PMID: 32145636 DOI: 10.1016/j.tranon.2020.01.004

Abstract

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: 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: 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: 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.

References

Br J Cancer. 2017 Nov 21;117(11):1583-1591 [PMID: 29065107]
Cancers (Basel). 2018 Jan 03;10(1): [PMID: 29301364]
Breast Cancer Res. 2008;10(6):R105 [PMID: 19087274]
Biomed Pharmacother. 2018 Dec;108:618-624 [PMID: 30243096]
Cancer Lett. 2018 Jan 28;413:102-109 [PMID: 29111350]
Curr Opin Immunol. 2010 Apr;22(2):231-7 [PMID: 20144856]
Breast Cancer Res. 2016 Aug 11;18(1):84 [PMID: 27515302]
Endoscopy. 2016 Nov;48(11):1016-1022 [PMID: 27626319]
Immunol Cell Biol. 2014 Jul;92(6):543-52 [PMID: 24662521]
Oncogene. 2014 Jun 5;33(23):2956-67 [PMID: 23851493]
Cell Mol Life Sci. 2019 Apr;76(8):1447-1458 [PMID: 30747250]
Front Physiol. 2013 Nov 01;4:318 [PMID: 24198790]
Biochim Biophys Acta. 2012 Aug;1826(1):170-8 [PMID: 22521638]
Cell. 2011 Mar 4;144(5):646-74 [PMID: 21376230]
J Natl Cancer Inst. 2015 Jan 31;107(2): [PMID: 25638248]
Adv Drug Deliv Rev. 2016 Apr 1;99(Pt B):180-185 [PMID: 26621196]
J Control Release. 2016 Feb 10;223:165-177 [PMID: 26742942]
Cancer Discov. 2015 Jan;5(1):52-63 [PMID: 25361845]
Cancer Lett. 2017 Apr 10;391:38-49 [PMID: 28093284]
Theranostics. 2017 Sep 26;7(17):4276-4288 [PMID: 29158825]
Biochim Biophys Acta. 2014 Sep;1841(9):1329-35 [PMID: 24960101]
Am J Transl Res. 2019 Feb 15;11(2):765-779 [PMID: 30899378]
BMC Cancer. 2016 Aug 12;16:632 [PMID: 27520560]
Nature. 2015 Nov 26;527(7579):525-530 [PMID: 26560028]
Cell Immunol. 2017 Jun;316:1-10 [PMID: 28433198]
Cancer Cell. 2013 Feb 11;23(2):249-62 [PMID: 23410977]
Cancer Immunol Immunother. 2005 Sep;54(9):915-25 [PMID: 15782312]
Cancer Cell. 2013 Mar 18;23(3):277-86 [PMID: 23518347]
J Innate Immun. 2014;6(6):716-26 [PMID: 25138714]
Clin Cancer Res. 2014 Apr 15;20(8):2192-204 [PMID: 24563479]
Eur J Cancer. 2014 Jul;50(11):1900-8 [PMID: 24835032]
Sci Rep. 2017 Dec 4;7(1):16878 [PMID: 29203879]
Invest New Drugs. 2013 Jun;31(3):760-8 [PMID: 22907596]
Nat Cell Biol. 2017 May;19(5):518-529 [PMID: 28414315]
Cell Death Dis. 2018 Apr 18;9(5):453 [PMID: 29670110]
J Exp Clin Cancer Res. 2016 Feb 16;35:33 [PMID: 26879926]
Nat Rev Urol. 2013 Aug;10(8):441-51 [PMID: 23857181]
Trends Immunol. 2012 Mar;33(3):119-26 [PMID: 22277903]
Int J Cancer. 2014 Aug 15;135(4):843-61 [PMID: 24458546]
Int J Oncol. 2015 Mar;46(3):1109-20 [PMID: 25502147]
Biochim Biophys Acta Gen Subj. 2017 Feb;1861(2):296-306 [PMID: 27750041]
Cancer Res. 2006 Dec 1;66(23):11238-46 [PMID: 17114237]
Cell Rep. 2017 Aug 15;20(7):1654-1666 [PMID: 28813676]
Front Immunol. 2015 May 05;6:212 [PMID: 25999950]
Gut. 2019 Oct;68(10):1872-1883 [PMID: 30580251]
Nat Rev Drug Discov. 2012 Feb 03;11(3):215-33 [PMID: 22301798]
Cytokine. 2017 Jan;89:194-200 [PMID: 26868086]
Nat Med. 2011 Apr;17(4):500-3 [PMID: 21460848]
Nature. 2002 Dec 19-26;420(6917):860-7 [PMID: 12490959]
Lab Invest. 2013 Jul;93(7):844-54 [PMID: 23752129]
Cancer Res. 2005 Apr 15;65(8):3437-46 [PMID: 15833879]
Connect Tissue Res. 2015;56(5):403-13 [PMID: 26291767]
J Immunol Res. 2016;2016:6031486 [PMID: 27376091]
Clin Cancer Res. 2012 Aug 15;18(16):4266-76 [PMID: 22896693]
Cell Metab. 2019 Jun 4;29(6):1390-1399.e6 [PMID: 30827862]
Nature. 2005 Jun 9;435(7043):752-3 [PMID: 15944689]
Am J Transl Res. 2012;4(4):376-89 [PMID: 23145206]
J Clin Invest. 2012 Mar;122(3):787-95 [PMID: 22378047]
Eur J Immunol. 2016 Jan;46(1):13-21 [PMID: 26643360]
Elife. 2017 Oct 05;6: [PMID: 28980940]
Cell Immunol. 2018 Aug;330:54-59 [PMID: 29395037]
Hepatobiliary Pancreat Dis Int. 2014 Aug;13(4):371-80 [PMID: 25100121]
Nat Rev Cancer. 2004 Jan;4(1):71-8 [PMID: 14708027]
BMC Cancer. 2012 Jan 24;12:35 [PMID: 22273460]
Autophagy. 2018;14(8):1335-1346 [PMID: 29940792]
BMC Genomics. 2018 Jan 5;19(1):19 [PMID: 29304755]
Cancer Lett. 2016 Oct 10;381(1):211-6 [PMID: 26708507]
Bioinformatics. 2012 Jun 15;28(12):i172-8 [PMID: 22689758]
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