July 17, 2024

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Paclitaxel Chemotherapy Leading Breast Cancer Cells to “Revive” from Dormancy

Paclitaxel Chemotherapy Leading Breast Cancer Cells to “Revive” from Dormancy



 

Paclitaxel Chemotherapy Leading Breast Cancer Cells to “Revive” from Dormancy.

Discovery of the Mechanism by which Paclitaxel Awakens Dormant Cancer Cells!

Scientists Uncover that Paclitaxel Chemotherapy Induces Stroma Damage, Leading Breast Cancer Cells to “Revive” from Dormancy | Significant Scientific Breakthrough.

In recent years, there has been a proliferation of talent in the field of anti-tumor therapies, with clinical trial data continually surpassing expectations. It can be said that humanity is gradually gaining the upper hand in the ongoing battle against cancer.

However, a complete victory remains elusive, primarily because cancer cells are notoriously difficult to eradicate. Faced with the relentless assault of anti-cancer drugs, cancer cells can cunningly choose to go into dormancy and lie dormant for several years, even decades, before reawakening, resulting in cancer relapse. Research data indicates that 6%-23% of breast cancer patients experience local or metastatic relapse within 5 years.

What triggers the awakening of cancer cells from dormancy? A recent study suggests that chemotherapy, which is supposed to be an anti-cancer measure, might be the culprit.

A research team from Emory University, in a publication in PLOS Biology, found that paclitaxel chemotherapy damages stromal cells, causing them to release cytokines such as IL-6 and G-CSF, which promote the proliferation of dormant cancer cells. Fortunately, the researchers also confirmed that using antibodies targeting IL-6 and/or G-CSF or drugs that inhibit the MEK/ERK signaling pathway could effectively prevent dormant cancer cells from causing trouble.

 

Paclitaxel Chemotherapy Leading Breast Cancer Cells to "Revive" from Dormancy

 

 

To elucidate the details of cancer cell revival, researchers designed a tumor stroma organoid (TSO) model for breast cancer, which can effectively simulate cancer cell dormancy.

Researchers tested different concentrations of paclitaxel ranging from 0.01 to 10 μM in the TSO model, within the physiological concentration range of paclitaxel. The experimental results showed that even at the highest concentration of 10 μM, cancer cell activity was not affected, but at 1 μM, stromal cell activity significantly decreased.

Following paclitaxel treatment, researchers observed a significant increase in cancer cells expressing Ki67, while stromal cells expressing Ki67 decreased. Additionally, paclitaxel treatment enhanced the invasiveness of cancer cells.

Paclitaxel Chemotherapy Leading Breast Cancer Cells to "Revive" from Dormancy

Cancer cells become more invasive after docetaxel treatment

 

 

Multiple cytokine assays revealed that after paclitaxel treatment, levels of cytokines such as G-CSF and IL-6 in the TSO model significantly increased, and these cytokines originated from stromal cells in the model. Administering neutralizing antibodies against IL-6 or G-CSF in advance effectively inhibited chemotherapy-induced cancer cell proliferation.

Transcriptomic analysis of the TSO model showed activation of various pathways related to cancer initiation, cytokine signaling, cell proliferation, and anti-apoptotic pathways. Upregulation of several Mek-related genes controlling cell proliferation, in particular, caught the researchers’ attention.

Treatment of the TSO model with MEK1/2 inhibitor selumetinib prevented paclitaxel-induced dormancy escape in cancer cells without affecting stromal cell cytotoxicity.

In summary, paclitaxel appears to induce the awakening of dormant cancer cells by damaging stromal cells and releasing IL-6 and G-CSF, which activate the MEK/ERK signaling pathway in cancer cells.

Experimental validation was also conducted in mouse models of in situ and metastatic dormancy, revealing that paclitaxel can induce the awakening of dormant cancer cells in vivo.

 

 

Paclitaxel Chemotherapy Leading Breast Cancer Cells to "Revive" from Dormancy

Docetaxel induces dormant cancer cells to awaken in vivo

 

 

 

Similarly, researchers observed a significant increase in plasma levels of IL-6 and G-CSF in mice, both of which could induce neutrophil infiltration, modulate effector T cell function, and promote cancer progression.

Analyzing the tumor immune landscape showed significant proliferation of cancer cells and an increase in immunosuppressive myeloid cells after paclitaxel treatment, with no change observed in mononuclear cells and M1 macrophages.

Using neutralizing antibodies against IL-6 and/or G-CSF, as well as selumetinib treatment in mice, significantly inhibited chemotherapy-induced awakening of dormant cancer cells.

 

Paclitaxel Chemotherapy Leading Breast Cancer Cells to "Revive" from Dormancy

IL-6 and G-CSF neutralizing antibodies, as well as selumetinib, can significantly inhibit the awakening of dormant cancer cells induced by chemotherapy.

 

 

This study not only uncovers a critical mechanism behind cancer recurrence but also identifies potential solutions. IL-6 and G-CSF could serve as crucial markers for breast cancer relapse, making this research a triple win.

In recent years, the tumor microenvironment has gained increasing attention in research. It appears that not only immune cells but also stromal cells play a significant role in this complex landscape.

 

 

 

 

Paclitaxel Chemotherapy Leading Breast Cancer Cells to “Revive” from Dormancy

Reference:

[1] Ganesan R, Bhasin SS, Bakhtiary M, Krishnan U, Cheemarla NR, et al. (2023) Taxane chemotherapy induces stromal injury that leads to breast cancer dormancy escape. PLOS Biology 21(9): e3002275. https://doi.org/10.1371/journal.pbio.3002275.

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