Cancer ‘Awakens’ and Spreads While People Sleep
The spread of cancer cells follows a distinct time pattern. At what time of day do cancer cells spread the fastest? Scientists have found the answer: It is when people are sound asleep at night.
A Major Culprit of Cancer Metastasis
Over the past decade, cancer metastasis has been a major focus of clinical cancer research.
According to a 2021 study published in Signal Transduction and Targeted Therapy, metastasis is the most lethal aspect of cancer. For example, the earliest stage of breast cancer has a nearly 100 percent chance of survival within five years; however, when breast cancer metastasizes to other places such as the lungs and bones, the survival rate plummets to around 30 percent. Deaths due to cancer metastasis account for more than 90 percent of cancer-related deaths.
In the process of cancer metastasis, there is a type of cell called a circulating tumor cell (CTC) that plays a critical role, according to the 2021 study. Thomas Ashworth, an Australian physician, first described circulating tumor cells in 1869 when he observed “some cells” in the blood of a patient with metastatic cancer that resembled cancer cells in the primary tumors.
These cells break free from the primary tumor (e.g. a breast tumor) and enter the bloodstream. They migrate to various parts of the body as the blood flows. They maintain a certain level of survival and proliferation ability and can settle in new locations and develop into tumors. This is somewhat similar to dandelion seeds leaving the plant, floating in the air, and then settling to grow into new dandelions.
Scientists have recently discovered that cancer cells metastasize most rapidly during sleep.
Tumors Are Awake While People Sleep
Researchers at the Swiss Federal Institute of Technology in Zurich, Switzerland, conducted clinical and animal experiments on breast cancer, and they found that the amount of circulating tumor cells in the blood of breast cancer patients is not constant; rather, these cells break off from the tumor and enter the circulation in a time-dependent manner.
This process is highly active during the sleep periods of both humans and animals, but inactive during wakefulness.
“When the affected person is asleep, the tumor awakens,” said Nicola Aceto, the study leader and professor of molecular oncology at ETH Zurich.
Researchers first discovered this in mice with breast cancer; the mice had more circulating tumor cells (CTCs) in their blood when they were sleeping, and there were fewer CTCs when they were active.
Subsequently, the researchers conducted timed blood tests on 30 female patients with breast cancer, with blood samples taken at 4 a.m. and 10 a.m., respectively, corresponding to the resting and wakeful periods of humans.
The results showed that the vast majority of CTCs were present in the blood samples collected at 4 a.m., accounting for 78.3 percent, which was much higher than that of CTCs in the blood samples collected at 10 a.m., which was 21.7 percent.
In the mouse experiments, this figure was even higher, ranging from 87 to 99.2 percent. Using different calculation methods, the number of circulating tumor cells in the blood of mice at rest can reach six to 88 times that of active mice.
The researchers also found that hormones closely related to circadian rhythms, such as melatonin, may signal the promotion of the shedding of cancer cells.
They believe that circulating tumor cells do not shed continuously and that their production mainly occurs during sleep.
New Tumors Are More Likely to Form During Rest Periods
It is worth noting that the ability of CTCs in the blood to form tumors varies depending on the time period.
The researchers collected CTCs from mice during their resting and active periods, labeled them with different fluorescent markers, and then injected them back into the mice.
The results showed that most of the new tumors were derived from the CTCs collected from mice during their rest period. In other words, not only were there more CTCs from the rest period, but these were also more likely to form new tumors.
Insufficient Sleep and Irregular Circadian Rhythms Linked to Higher Cancer Risk
Does that mean that we should just stop sleeping?
No, but the key may be in having a regular sleeping pattern. Yves Dauvilliers and other researchers from the University Hospital of Montpellier in France said that there are many reasons why sleep and circadian rhythm may affect cancer. The Zurich study did not fully investigate them, and further research is required. Dauvilliers further stated that regular sleep and circadian rhythm can indeed enhance immunity and fight cancer.
According to Dauvilliers’ editorial, circadian rhythm and sleep are fundamental biological processes that regulate physiology and behavior, including hormone secretion, metabolism, DNA repair, and cell apoptosis.
One 2022 study found that patients with cancer who typically slept less than seven hours per night had a higher risk of death. Circadian disruption of mice enhanced inflammation in their bodies and brains, but reduced inflammation within tumor tissue. Healthy circadian rhythms are crucial for limiting cancer-induced inflammation.
In 2007, the International Agency for Research on Cancer (IARC) classified shift work-induced circadian rhythm disruption as a Group 2A carcinogen, meaning it is probably carcinogenic to humans. Moreover, according to a paper published in Nature Medicine, the association between night shift work and the incidence of breast and prostate cancer has been widely documented, and this risk increases with the length of the night shifts.
For example, compared with nurses who did not work nights after graduating from nursing school, those who had worked nights for 30 years or longer had a 2.21 times higher risk of developing breast cancer.
Additionally, a meta-analysis showed that night shift work is associated with an increased risk of colorectal cancer. The incidence rate of colorectal cancer increases by 11 percent for every five years of night shift work.
Impact of Circadian Rhythm on Hormones and Cancer
Although researchers at ETH Zurich found that melatonin may be a signal to promote the shedding of cancer cells, melatonin has also been shown to inhibit tumor growth in many studies.
Studies have shown that daytime blue light enhances the inhibitory effect of nighttime melatonin on the growth of prostate, liver, and breast cancer, while light exposure late at night leads to melatonin depletion, stimulating the growth of various cancers and increasing drug resistance.
Reduced melatonin excretion due to sleep disruption may also increase oxidative DNA damage and impair the repair of the damage.
Similar to melatonin, glucocorticoids are also considered anti-cancer hormones, and their levels peak in the morning. They also have a systemic influence on metabolic and immune functions. Glucocorticoid drugs have been highly effective in the treatment of leukemia, lymphoma, etc., and have also been shown to reduce the proliferation and growth of melanoma cells.
Changes in circadian rhythms can affect gene expression, and shift work can lead to epigenetic changes in DNA, according to the Nature Medicine paper. Compared to day workers, there were changes in DNA methylation patterns among shift workers; some regions exhibited increased methylation, while others showed a decrease, which could indicate that specific genes may be turned on or off.
Choosing the Right Timing to Fight Cancer Efficiently
In the Zurich study mentioned earlier, the researchers confirmed that the metastatic ability of cancer is affected by the hormone-regulated circadian rhythm. Therefore, if the timing of cancer treatments for breast cancer and other cancers is adjusted accordingly, such as scheduling treatment during sleep periods, it may maximize the anti-cancer effect.
In any case, Duvillard believes that cancer treatment should develop toward precision medicine, which includes “giving the right drug to the specific patient on the right day and the best timing during this day or night.”
