Beta-Blockers Emerge as a Promising Strategy to Prevent Cancer Recurrence by Targeting Stress-Induced Reactivation of Dormant Tumor Cells

At the onset of tumor growth, some cells migrate to sites near or distant from the primary tumor and enter a state of dormancy. These cells are unaffected by surgery or chemotherapy, acting like “time bombs” embedded within the body; they can reactivate from dormancy at some point and grow into new tumors. Consequently, even in patients who have undergone “complete resection” of the tumor, recurrence may occur years later. Therefore, elucidating the mechanisms that drive the reactivation of dormant tumor cells is crucial for cancer therapy.

In a study published in Science Translational Medicine on December 2, researchers from institutions including AstraZeneca and the Wistar Institute discovered that the reactivation of tumor cells depends on neutrophils and stress hormones, and that β-blockers can prevent the reactivation of tumor cells in mice. This offers promising therapeutic strategies for delaying or preventing tumor recurrence.

Source: Science Translational Medicine

Epidemiological and clinical studies have demonstrated an association between chronic stress and cancer progression. In mouse models of disseminated dormant tumor cells, researchers found that stress hormones, such as epinephrine, norepinephrine, and cortisol, can induce the rapid and substantial release of pro-inflammatory S100A8/A9 proteins by neutrophils via β2-adrenergic receptors.

S100A8/A9 can induce the activation of myeloperoxidase (MPO), leading to the accumulation of oxidized lipids in neutrophils. Upon release of these oxidized lipids, the fibroblast growth factor receptor (FGFR) pathway is upregulated in tumor cells, thereby reactivating dormant tumor cells and forming new tumor foci.

Researchers tested two drugs. Among them, the specific β2-adrenergic receptor antagonist (β-blocker, β-receptor blocker) ICI-118551 was able to stop neutrophils from secreting S100A8/A9, and ICI-118551 had no cytotoxic effect on neutrophils.

β-Blockers Inhibit Neutrophil S100A8/A9 Secretion (Source: Science Translational Medicine)

Another drug, the S100A8/A9 blocker tasquinimod, significantly reduces the incidence of tumor lesions in stressed mice.

Imiquimod Inhibits Tumorigenesis (Source: Science Translational Medicine)

The researchers also collected serum samples from 80 lung cancer patients who underwent surgical tumor resection. They found that high concentrations of S100A8/A9 in the serum of these lung cancer patients were associated with shorter recurrence times.

Relationship Between S100A8/A9 and Recurrence Time in Lung Cancer Patients (Source: Science Translational Medicine)

Based on these findings, researchers recommend the use of beta-blockers in cancer patients, which may be an effective strategy for preventing the recurrence of certain types of cancer. Furthermore, drugs that inhibit the production of S100A8/A9 may represent a superior therapeutic approach.

“We hope to develop targeted therapies to disrupt this mechanism, thereby significantly prolonging tumor remission,” said Dr. Dmitry Gabrilovich, Chief Scientist of Cancer Immunology at AstraZeneca and corresponding author of the paper.

References:

1# Michela Perego et al. Reactivation of dormant tumor cells by modified lipids derived from stress-activated neutrophils. Science Translational Medicine (2020)

2# Stress Can Activate Neutrophils, a Type of Immune Cell, to Reawaken Dormant Tumor Cells and Trigger Cancer Recurrence (Source: The Wistar Institute)

3# High Levels of Stress Hormones May Reactivate Cancer Cells (Source: Healthing.ca)