Uncovering how chronic stress induces metastasis

Reading time: 8 minutes

Colin Ong

For most of us, stress is an inevitable facet of life. Any internal or external stimulus such as encountering a bear while hiking will trigger stress in our bodies. Remarkably, our bodies respond through a series of orchestrated biochemical and physiological changes as a way of coping with stress. Stress can be short term (acute) or long term (chronic). 

The stress response initiates in the brain. Upon sensing a threat, our eyes and/or ears send signals to the amygdala, a part of the brain that is responsible for emotional processing. The amygdala, in turn, sends a signal to the hypothalamus, a gland in the brain. In chronic stress, a network involving the hypothalamus, pituitary, and adrenal glands also known as the HPA axis is continuously activated, resulting in the secretion of glucocorticoid, an anti-inflammatory hormone, from the adrenal gland. This dysregulation affects the functions of the brain, gastrointestinal tract, immune and cardiovascular systems (Figure 1)^2,6.

Figure1. Effects of chronic stress on cancer as mediated through the sympathetic nervous system and HPA axis (reproduced from Cui B et al.)²

Stress has been shown to promote cancer progression and metastasis in animal models. In addition, studies show that stress is correlated with poorer survival outcomes in cancer patients. Animal studies allow for the synchronization of the impact of stress on a critical phase in cancer progression such as survival of tumor cells in circulation where stress may have a more potent impact than during non-synchronized periods. Such studies are difficult to conduct in clinical contexts as some critical phases are unrecognizable³.  To date, the underlying mechanisms as to how chronic stress induces metastasis are not well understood. 

A recent report published in Cancer Cell has shed some light as to how metastasis is promoted by chronic stress⁴. He and colleagues showed that stress promotes cancer invasion through neutrophil-mediated changes to the tumor microenvironment. Using a mouse model for breast cancer, they first demonstrated that when these mice were exposed to stress by physical confinement, tumor size doubled, metastasis to the lung was elevated 2- to 4-fold, and the levels of glucocorticoid were increased⁴. They also showed that the number of metastatic lesions elevated in these mice when they were treated with glucocorticoid alone. As a hormone, glucocorticoid acts by interacting with its binding partner in the cell, a glucocorticoid receptor. This glucocorticoid-glucocorticoid receptor protein complex then moves into the nucleus of the cell to turn on and off target genes. He and co-workers tested if the effects of glucocorticoid leading to metastasis were mediated through the actions of the hormone in the breast cancer cells. They generated mice whose breast cancer cells did not produce the glucocorticoid receptor. These mice were stressed and they found that metastasis was still detected, suggesting that the receptor in cancer cells was not required for stress-induced metastasis.

Chronic stress promotes a pro-metastatic microenvironment

He and co-workers then hypothesized that changes in the tumor microenvironment were important for stress-promoted metastasis. Gene expression analysis in the lung tissue of stressed mice revealed an elevation of fibronectin, a metastasis-promoting protein that supports and provides structure to cells. Furthermore, genes involved in T-cell activation and adaptive immune responses were downregulated. They also observed an elevation of neutrophil infiltration in the lung as well as an increase in the percentage of neutrophils in blood. Neutrophils, being the most abundant type of white blood cells, are best known for fighting infections by engulfing microbes (phagocytosis) and releasing enzymes that can kill microbes. Evaluation of neutrophil-depleted mice exposed to stress showed that metastasis was not increased in these mice. These data indicated that neutrophils play a role in mediating stress-promoted metastasis. 

Stress promotes neutrophil extracellular trap formation

To understand how neutrophils play a role in stress-promoted metastasis, He and co-workers analyzed neutrophils of chronically stressed mice versus control mice. The neutrophils of stressed mice tend to form more neutrophil extracellular traps as compared to control mice. Neutrophil extracellular traps are macromolecular complexes consisting of DNA and proteins extruded by neutrophils into the extracellular space to trap microbial pathogens (Figure 2)¹. Similarly, the scientists detected more neutrophil extracellular traps in the blood of chronically stressed mice than in the blood of control mice. The blood and lungs of glucocorticoid-treated mice exhibited higher levels of neutrophil extracellular traps compared to their control counterparts. However, in mice that had their adrenal glands removed prior to stress exposure, blood neutrophil extracellular trap levels were not raised. The data suggest that glucocorticoids released from the adrenal gland during stress are required for neutrophil extracellular trap generation. 

Figure 2. Neutrophil extracellular traps (modified from Flickr.com)

Using genetic engineering tools and chemical inhibitors, He and colleagues further demonstrated that the neutrophil-mediated extracellular trap formation required glucocorticoid receptors, generation of reactive oxygen species, activation of proteins involved in regulation of cell division namely, cyclin D3, cyclin dependent kinase 4, cyclin dependent kinase 6, and a protein kinase known as p38 in neutrophils. Thus, glucocorticoid signaling in neutrophils leading to neutrophil extracellular trap formation was necessary for chronic stress-induced metastasis. 

Suppressing metastasis by targeting stress-promoted neutrophil extracellular traps

He and co-workers tested if neutrophil extracellular traps were necessary for stress-induced metastasis. Chronically stressed mice were exposed daily to DNase I, an enzyme that degrades DNA in neutrophil extracellular traps. After 48 days of treatment, the neutrophil extracellular trap levels in the blood were reduced by approximately 65% in Dnase I-treated mice which were chronically stressed compared to mice that were subjected to stress alone. In addition, He and co-workers also found that in Dnase I-treated and stress-induced mice, deposition of fibronectin in the lungs was abrogated. This observation suggests a role for neutrophil extracellular traps in fibronectin deposition. Metastasis was significantly suppressed in Dnase I-treated and chronically stressed mice compared to mice that were stressed but not treated with the enzyme.     

In conclusion, chronic stress promotes metastasis in mice. Chronic stress induces the release of glucocorticoids from the adrenal glands. The secreted glucocorticoids then bind to the glucocorticoid receptors in neutrophils to mediate gene expression changes.  These expression changes led to the formation of neutrophil extracellular traps in blood which in turn promote metastasis. Targeting neutrophil extracellular traps by digesting them with Dnase I enzyme suppresses metastasis. Currently, no clinical studies using DNase to treat cancer patients are being conducted although the enzyme has been used to treat cystic fibrosis, empyema, and more recently, the enzyme was tested in a Phase I trial for SARS-COV-2 patients⁵. 

Edited by Melanie Padalino

Works cited

1. Adrover JM, McDowell SAC, He XY, Quail DF, Egeblad M. NETworking with cancer: The bidirectional interplay between cancer and neutrophil extracellular traps. Cancer Cell. 2023 Mar 13;41(3):505-526. doi: 10.1016/j.ccell.2023.02.001.

2. Cui B, Peng F, Lu J, He B, Su Q, Luo H, Deng Z, Jiang T, Su K, Huang Y, Ud Din Z, Lam EW, Kelley KW, Liu Q. Cancer and stress: NextGen strategies. Brain Behav Immun. 2021 Mar;93:368-383. doi: 10.1016/j.bbi.2020.11.005.

3. Eckerling A, Ricon-Becker I, Sorski L, Sandbank E, Ben-Eliyahu S. Stress and cancer: mechanisms, significance and future directions. Nat Rev Cancer. 2021 Dec;21(12):767-785. doi: 10.1038/s41568-021-00395-5.

4. He XY, Gao Y, Ng D, Michalopoulou E, George S, Adrover JM, Sun L, Albrengues J, Daßler-Plenker J, Han X, Wan L, Wu XS, Shui LS, Huang YH, Liu B, Su C, Spector DL, Vakoc CR, Van Aelst L, Egeblad M. Chronic stress increases metastasis via neutrophil-mediated changes to the microenvironment. Cancer Cell. 2024 Mar 11;42(3):474-486.e12. doi: 10.1016/j.ccell.2024.01.013.

5. Shahzad MH, Feng L, Su X, Brassard A, Dhoparee-Doomah I, Ferri LE, Spicer JD, Cools-Lartigue JJ. Neutrophil Extracellular Traps in Cancer Therapy Resistance. Cancers (Basel). 2022 Mar 7;14(5):1359. doi: 10.3390/cancers14051359.
6. Yaribeygi H, Panahi Y, Sahraei H, Johnston TP, Sahebkar A. The impact of stress on body function: A review. EXCLI J. 2017 Jul 21;16:1057-1072. doi: 10.17179/excli2017-480..