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Tumor-Associated Macrophages Suppress the Cytotoxic Activity of Antimitotic Agents
Oakley C Olson1, Hyunjung Kim2, Daniela F Quail1
1Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
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.
Insights
Tumor-associated macrophages (TAMs) protect breast cancer cells from Taxol treatment by shortening mitotic arrest. Inhibiting TAMs or MEK kinase enhances Taxol
Area of Science:
- Oncology
- Immunology
- Cell Biology
Background:
- Antimitotic agents like Taxol are crucial in cancer therapy but show variable clinical efficacy.
- Tumor-associated macrophages (TAMs) can influence treatment response in breast cancer.
Purpose of the Study:
- To investigate the role of TAMs in mediating resistance to Taxol in breast cancer.
- To explore therapeutic strategies targeting TAM-cancer cell interactions to enhance Taxol efficacy.
Main Methods:
- Utilized breast cancer models to study the effects of TAMs on Taxol-induced mitotic arrest.
- Assessed DNA damage, apoptosis, and cell death markers following Taxol treatment in the presence or absence of TAMs.
- Investigated the impact of MEK inhibition on TAM-mediated protection and Taxol efficacy.
Main Results:
- TAMs were found to suppress the duration of Taxol-induced mitotic arrest and promote cancer cell survival.
- Depletion of specific TAM populations (MHCIIlow) enhanced Taxol-induced DNA damage, apoptosis, and treatment efficacy.
- MEK inhibition reversed the protective effects of TAMs, mimicking the outcome of TAM depletion.
Conclusions:
- TAMs suppress Taxol's cytotoxic effects through non-autonomous mechanisms modulating mitotic arrest in cancer cells.
- Targeting the interaction between TAMs and cancer cells, potentially via MEK inhibition, represents a promising strategy to potentiate Taxol efficacy in breast cancer treatment.