Stress hormones can trigger the formation of structures that make body tissues more susceptible to metastasis, research has found.
During the early stages of Dr Xue-Yan He’s postdoctoral training she unexpectedly observed faster tumour growth in mice after injecting the same tumour cells. “This contradicted previous lab results, and I spent months investigating,” she says. “Eventually, I discovered that changes in housing conditions were causing stress in some mice, leading to accelerated tumour growth. This experience – while we call it troubleshooting in science – has opened up the whole new direction for my research and I decided to investigate whether and how stress affects cancer.”
It was during experiments for another project in the Egeblad Laboratory run by Professor Mikala Egeblad at Cold Spring Harbor Laboratory, New York, to examine how communication between tumours and the immune system affects tumour growth and metastasis, that Dr Xue-Yan He’s research team reached a breakthrough in understanding the relationship between cancer and stress. The team uses mice and models to mimic how tumours develop in humans.
“We accidentally found that changes in the housing conditions caused some mice to experience stress, which resulted in much faster tumour growth,” says Dr He, whose thesis has led her to focus on research into the tumour microenvironment (TME). “This discovery sparked our curiosity to understand whether and how chronic stress exposure can impact metastasis.”
Stress and metastasis
Epidemiological studies done on large populations show an association between stress and an increased risk of cancer metastasis and shorter survival. “Long-lasting physical and psychological stress can contribute to the development and progression of cancer,” she says. “This is particularly important for cancer patients who undoubtedly experience stress due to concerns about their diagnosis, worries about recurrence, and potential long duration of their treatments, for example.”
The experiments involved removing tumours that had been growing in mice’s breasts and spreading cancer cells to their lungs, then exposing the mice to stress. The team found that stress hormones called glucocorticoids caused certain white blood cells called neutrophils to expel DNA and form sticky web-like structures called neutrophil extracellular traps (NETs). Normally, NETs defend against invading microorganisms, but in cancer they make body tissues more susceptible to metastasis.
“NETs have previously been found to cause metastases in mice, and to be associated with higher risk of metastasis in patients with cancer,” Dr He says.
“For example, our previous research showed that cancer cells can actually stimulate neutrophils to form NETs, and that the NETs in turn help the cancer cells metastasise.”
Dr He confirmed the new finding with three tests: removing neutrophils from the mice using antibodies, injecting them with a NET-destroying drug and using mice with neutrophils that couldn’t respond to glucocorticoids.
“The stressed mice no longer developed more metastasis,” she adds. “Our data on mice showed that targeting NETs in stressed animals significantly reduced the risk for metastases.”
Implications for treatment and prevention
Even more surprising is the finding that chronic stress caused NET formation to modify the lung tissue also in mice without cancer. “What is novel and exciting about our current work is that we have discovered that stress hormones can trigger the formation of NETs. These stress-induced NETs play a role in promoting the metastasis of breast cancer by creating a favourable environment or “niche” in the lungs that helps the breast cancer cells that get to the lung and grow more easily.”
Previous research has found that glucocorticoids have been shown to promote tumour growth by reducing the infiltration of killer T cells and to stimulate the cancer cells themselves to metastasiSe. But these studies hint that synthetic glucocorticoids might not always be beneficial in the long term.
“This new finding helps us better understand how stress can impact the spread of cancer and may provide new opportunities for treating and preventing metastasis,” Dr He says. “These findings suggest that reducing stress should be a very beneficial part of cancer treatment and prevention. Since reducing stress can be difficult for cancer patients, we also speculate that drugs preventing NET formation can be developed and used as new treatments to slow or stop cancer’s spread, offering much-needed relief.”
Xue-Yan He
- Assistant Professor at Washington University in St. Louis
- Postdoctoral Fellow at Cold Spring Harbor Laboratory
- Completed a PhD in biology/tumour biology, Nanjing University, China
Future work
Since the research was published, Dr He has established her own lab as independent Assistant Professor at the Department of Cell Biology and Physiology at Washington University School of Medicine in St. Louis. “We strive to unravel the mechanisms through which stress impacts cancer development, and identify targetable molecules that hold potential for improved treatments,” she says.
“Targeting NETs in stressed animals significantly reduced the risk for metastases”
She also mentors students, focusing on articulating scientific challenges and resolutions through scientific essays, analysis and understanding of research papers. “This experience has highlighted the stark contrast between the learning environments I was exposed to, where students had to rely solely on the instructor’s teaching methods, and the more dynamic learning environment I fostered under my mentorship.”
“My current task extends beyond conducting cancer research. It is now my responsibility as a mentor to guide the next generation of scientists, imparting not only scientific knowledge but also fostering essential skills for their development,” she adds.
Dr He and her team will continue working on understanding the systemic effects of stress, including its impact on the sympathetic nervous system, and how these effects influence cancer progression. They also plan to explore various stress reduction techniques, such as behavioural interventions or pharmaceutical interventions.
“Based on our findings that glucocorticoids induce NETs, we hope that targeted therapies specifically designed to inhibit glucocorticoid-induced NET formation might be developed in the future,” Dr He adds. “We hope further studies will pave the way for interventions and treatments that can improve the ever-stressed patients’ survival.”
Image Credit | Science Photo Library | Supplied
