Depletion of Macrophages Improves Therapeutic Response to Gemcitabine in Murine Pancreas Cancer

Cancers
Soeren M BuchholzA Neesse

Abstract

The tumor microenvironment (TME) is composed of fibro-inflammatory cells and extracellular matrix (ECM) components. However, the exact contribution of the various TME compartments towards therapeutic response is unknown. Here, we aim to dissect the specific contribution of tumor-associated macrophages (TAMs) towards drug delivery and response in pancreatic ductal adenocarcinoma (PDAC). The effect of gemcitabine was assessed in human and murine macrophages, human pancreatic stellate cells (hPSCs), and tumor cells (L3.6pl, BxPC3 and KPC) in vitro. The drug metabolism of gemcitabine was analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Preclinical studies were conducted using KrasG12D;p48-Cre and KrasG12D;p53172H;Pdx-Cre mice to investigate gemcitabine delivery at different stages of tumor progression and upon pharmacological TAM depletion. Gemcitabine accumulation was significantly increased in murine PDAC tissue compared to pancreatic intraepithelial neoplasia (PanIN) lesions and healthy control pancreas tissue. In vitro, macrophages accumulated and rapidly metabolized gemcitabine resulting in a significant drug scavenging effect for gemcitabine. Finally, pharmacological TAM depletion enhanced therapeutic re...Continue Reading

References

Aug 1, 1980·International Journal of Cancer. Journal International Du Cancer·S TsuchiyaK Tada
Sep 14, 1994·Journal of Immunological Methods·N Van Rooijen, A Sanders
Jan 7, 2004·Cancer Cell·Sunil R HingoraniDavid A Tuveson
Aug 30, 2005·Laboratory Investigation; a Journal of Technical Methods and Pathology·Ralf JesnowskiMatthias Löhr
Oct 3, 2007·Cancer Research·Carolyn E ClarkRobert H Vonderheide
Feb 5, 2008·Cancer Research·Rosa F HwangCraig D Logsdon
Jun 28, 2011·The Journal of Histochemistry and Cytochemistry : Official Journal of the Histochemistry Society·Alexander FranckeRuediger C Braun-Dullaeus
Jul 10, 2013·Proceedings of the National Academy of Sciences of the United States of America·Albrecht NeesseDavid A Tuveson
Feb 13, 2016·Scientific Reports·Chunmei LiDavid L Kaplan
Sep 16, 2016·Nature Communications·Nicole M AielloBen Z Stanger
Apr 24, 2018·Journal of Visualized Experiments : JoVE·Robert-Guenther GoetzeAlbrecht Neesse
Oct 24, 2018·Frontiers in Immunology·Emile J ClappaertDamya Laoui
Mar 5, 2019·Cell Metabolism·Christopher J HalbrookCostas A Lyssiotis
Apr 17, 2020·Physiological Reviews·Elisabeth HessmannAlbrecht Neesse

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Citations

Mar 27, 2021·Signal Transduction and Targeted Therapy·Zhaojun Duan, Yunping Luo
Oct 31, 2020·Cancer Letters·Jian YangHanxiang Zhan

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Methods Mentioned

BETA
biopsies

Software Mentioned

GraphPad Prism

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