Tumor-Associated Macrophages Suppress the Cytotoxic Activity of Antimitotic Agents
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 dur...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2017-04-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124717303844 |
| _version_ | 1831517761419870208 |
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| author | Oakley C. Olson Hyunjung Kim Daniela F. Quail Emily A. Foley Johanna A. Joyce |
| author_facet | Oakley C. Olson Hyunjung Kim Daniela F. Quail Emily A. Foley Johanna A. Joyce |
| author_sort | Oakley C. Olson |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-11T18:13:35Z |
| format | Article |
| id | doaj.art-9dad58b820ea4d0293b4ee84ab062913 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-11T18:13:35Z |
| publishDate | 2017-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-9dad58b820ea4d0293b4ee84ab0629132022-12-22T00:55:29ZengElsevierCell Reports2211-12472017-04-0119110111310.1016/j.celrep.2017.03.038Tumor-Associated Macrophages Suppress the Cytotoxic Activity of Antimitotic AgentsOakley C. Olson0Hyunjung Kim1Daniela F. Quail2Emily A. Foley3Johanna A. Joyce4Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USACell Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USACancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USACell Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USACancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USAAntimitotic 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.http://www.sciencedirect.com/science/article/pii/S2211124717303844macrophageTaxolantimitoticmitotic arrestmitotic slippagetetraploidchemotherapychemoresistancemicroenvironmentbreast cancer |
| spellingShingle | Oakley C. Olson Hyunjung Kim Daniela F. Quail Emily A. Foley Johanna A. Joyce Tumor-Associated Macrophages Suppress the Cytotoxic Activity of Antimitotic Agents Cell Reports macrophage Taxol antimitotic mitotic arrest mitotic slippage tetraploid chemotherapy chemoresistance microenvironment breast cancer |
| title | Tumor-Associated Macrophages Suppress the Cytotoxic Activity of Antimitotic Agents |
| title_full | Tumor-Associated Macrophages Suppress the Cytotoxic Activity of Antimitotic Agents |
| title_fullStr | Tumor-Associated Macrophages Suppress the Cytotoxic Activity of Antimitotic Agents |
| title_full_unstemmed | Tumor-Associated Macrophages Suppress the Cytotoxic Activity of Antimitotic Agents |
| title_short | Tumor-Associated Macrophages Suppress the Cytotoxic Activity of Antimitotic Agents |
| title_sort | tumor associated macrophages suppress the cytotoxic activity of antimitotic agents |
| topic | macrophage Taxol antimitotic mitotic arrest mitotic slippage tetraploid chemotherapy chemoresistance microenvironment breast cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2211124717303844 |
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