Tumor-Associated Macrophages Suppress the Cytotoxic Activity of Antimitotic Agents.

Details

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State: Public
Version: Final published version
Serval ID
serval:BIB_D85BBAB8A64B
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Tumor-Associated Macrophages Suppress the Cytotoxic Activity of Antimitotic Agents.
Journal
Cell reports
Author(s)
Olson O.C., Kim H., Quail D.F., Foley E.A., Joyce J.A.
ISSN
2211-1247 (Electronic)
Publication state
Published
Issued date
04/04/2017
Peer-reviewed
Oui
Volume
19
Number
1
Pages
101-113
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Abstract
Antimitotic agents, including Taxol, disrupt microtubule dynamics and cause a protracted mitotic arrest and subsequent cell death. Despite the broad utility of these drugs in breast cancer and other tumor types, clinical response remains variable. Tumor-associated macrophages (TAMs) suppress the duration of Taxol-induced mitotic arrest in breast cancer cells and promote earlier mitotic slippage. This correlates with a decrease in the phosphorylated form of histone H2AX (γH2AX), decreased p53 activation, and reduced cancer cell death in interphase. TAMs promote cancer cell viability following mitotic slippage in a manner sensitive to MAPK/ERK kinase (MEK) inhibition. Acute depletion of major histocompatibility complex class II low (MHCIIlo) TAMs increased Taxol-induced DNA damage and apoptosis in cancer cells, leading to greater efficacy in intervention trials. MEK inhibition blocked the protective capacity of TAMs and phenocopied the effects of TAM depletion on Taxol treatment. TAMs suppress the cytotoxic effects of Taxol, in part through cell non-autonomous modulation of mitotic arrest in cancer cells, and targeting TAM-cancer cell interactions potentiates Taxol efficacy.

Keywords
Animals, Antimitotic Agents/pharmacology, Antimitotic Agents/therapeutic use, Apoptosis/drug effects, Benzothiazoles/pharmacology, Breast Neoplasms/drug therapy, Cell Survival/drug effects, DNA Damage, Endothelial Cells/drug effects, Female, Histones/metabolism, Humans, Macrophages/drug effects, Macrophages/immunology, Major Histocompatibility Complex, Mice, Mice, Transgenic, Mitogen-Activated Protein Kinase Kinases, Mitosis/drug effects, Paclitaxel/pharmacology, Paclitaxel/therapeutic use, Picolinic Acids/pharmacology, Tumor Cells, Cultured, Tumor Suppressor Protein p53/metabolism, Taxol, antimitotic, breast cancer, chemoresistance, chemotherapy, macrophage, microenvironment, mitotic arrest, mitotic slippage, tetraploid
Pubmed
Web of science
Open Access
Yes
Create date
11/04/2017 16:41
Last modification date
20/08/2019 15:57
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