A recent study on patients with breast cancer has revealed that cancer cells may use the body's natural hormonal cycles to spread during sleep. Researchers found that most circulating tumor cells (CTCs)—which are cancer cells that have broken away from a tumor and entered the bloodstream—tend to be released during the late phase of sleep, just before sunrise, rather than during the day. This challenges earlier assumptions that CTCs are released evenly throughout the day. The research, led by Nicola Aceto, a molecular oncologist at the Swiss Federal Institute of Technology in Zurich (ETH), highlights the importance of timing in medical procedures. Zoi Diamantopoulou, a biologist specializing in cancer cells and the lead author of the study, emphasizes that the timing of a biopsy can significantly affect the accuracy of a diagnosis. While the study does not suggest that sleep causes cancer, it does indicate that once cancer has developed, its progression may be influenced by sleep and the hormonal changes that accompany it. Harrison Ball, a graduate student at the University of Michigan, notes that regular sleep is essential for cancer patients to maintain a strong immune system, which plays a crucial role in fighting the disease. Sleep supports immune function, and Sunitha Nagrath, a chemical engineer at the University of Michigan Ann Arbor, explains that the immune system functions best when individuals get enough rest. Although cancer can spread aggressively at night, a well-functioning immune system can help the body defend itself. Francis Lévi, a medical oncologist at the University of Paris-Saclay, has spent three decades studying how the body's internal clock, known as the circadian rhythm, affects health and disease. His research has shown that the timing of administering anticancer drugs can influence their effectiveness and side effects, a field known as chronotherapy. Lévi has also found that these optimal times can differ between men and women. Christoph Scheiermann, an immunologist at the University of Geneva in Switzerland, acknowledges that it may take more research and clinical trials to convince medical professionals that the time of day matters in treatment and diagnosis. However, the study's findings suggest that taking blood samples at the right time could have immediate diagnostic value. Scientists have studied the biological rhythms related to the day-night cycle since the 18th century. In 1729, the French astronomer Jean-Jacques Dortous de Mairan discovered that the leaves of the sensitive mimosa continued to open and close in a 24-hour cycle even in permanent darkness, suggesting that the plant had an internal clock. The human body's biological clock is located in a cluster of about 20,000 neurons in the suprachiasmatic nuclei of the hypothalamus. This internal clock regulates the 24-hour cycle of physiological and behavioral changes known as the circadian rhythm. The neurons receive light signals from the retina and coordinate the activity of other brain regions and organs, including the liver and kidneys, by activating and deactivating many genes. Jeffrey Hall, Michael Rosbash, and Michael Young were awarded the Nobel Prize in 2017 for their discovery of essential genes that regulate this internal clock. In humans, at least 30% of all genes that produce proteins show cyclic activity in various organs, a number that may increase with more detailed analysis of gene activity. When light levels decrease, the neurons of the circadian clock secrete melatonin, a hormone that promotes sleep. Other hormones, such as leptin, which regulates hunger, and cortisol, involved in the stress response, contribute to morning alertness and numerous immune and metabolic processes. Disruptions to the 24-hour cycle, such as those experienced by people who work at night and sleep during the day, can increase the risk of developing cancer. Flight attendants and nurses, for example, have a slightly higher risk of breast cancer, possibly due to disrupted circadian rhythms. In laboratory studies, mice also showed an increased risk of developing breast tumors under simulated night shift conditions. The International Agency for Research on Cancer considers work at irregular hours, such as that of flight attendants and night nurses, as "probably carcinogenic." The risks of shift work or night work extend beyond breast cancer and include prostate cancer, cardiovascular diseases, and several other chronic conditions. According to Lévi, this population also has a higher chance of developing infections. Although the exact reasons for the increased cancer risk from frequent disruptions of sleep-wake cycles are not fully understood, studies suggest that factors like immunosuppression, chronic inflammation, or increased cell proliferation could be involved. Immune cells also have their own circadian clocks, and their function fluctuates throughout the day. Circulating white blood cell levels, which help the body fight infections and other diseases, reach their peak during the rest phase—night for humans and day for mice. When the internal circadian clock is misaligned with the external environment, it can lead to cellular dysfunction and metabolic damage. Once cells become cancerous, they appear to escape the circadian rhythm. Unlike healthy tissues, cancer cells and tumors typically do not show the oscillations that are observed in normal tissues. This is why scientists were surprised to find that key circadian rhythm hormones, such as melatonin and testosterone, directly influenced the generation of CTCs in the Zurich study. When researchers noticed discrepancies in the number of cancer cells detected in blood samples taken at different times of the day, they decided to investigate further. Diamantopoulou explains that the release of CTCs was not constant throughout the day but fluctuated. Scientists suspected that hormones such as melatonin, which regulates sleep, and corticosteroids, which balance the stress response and other essential processes, could be the signals that determine the timing of CTC release. These hormones are known regulators of the circadian rhythm and reach their peak levels in the blood between 3 am and 4:30 am. Diamantopoulou collected blood samples from thirty hospitalized breast cancer patients, once at 4 am and once at 10 am. She found that nearly 80% of the CTCs were detected in the blood samples taken at 4 am, when the patients were resting. To better understand their findings, the scientists repeated their observations in mice with experimentally induced cancer. Since mice are nocturnal, their CTC levels were up to 88 times higher during the day, when they were resting, than at night, when they were active. Disrupting the sleep-wake cycle of the mice allowed them to reduce the number of cancer cells in their blood. During the rest phase, the released cancer cells divided more rapidly than healthy cells. These cells were also more likely to develop into new tumors, suggesting that CTCs that detach during sleep are more capable of creating metastases. According to Scheiermann, these circulating tumor cells are likely released and then absorbed by another tissue. It is surprising not only that the number of CTCs was different at different times of the day, but also that the CTCs in the rest phase were more aggressive than those detected a few hours later, Nagrath adds. If melatonin increases the production of CTCs and tumor growth, then a chemical compound that blocks melatonin could reverse its effects. Insulin, on the other hand, has promoted the proliferation of tumor cells. These results suggest that cancer cells still respond to some of the signals of the day-night cycle and circadian rhythm. It is entirely logical that circulating cancer cells are more likely to develop and divide during rest, Ball states. This pattern is also observed in non-cancerous cells. The increased proliferation also produces cells that are more "aggressive," meaning more likely to spread and form secondary tumors. The results of this study could lead to new methods of taking cancer biopsies and open the subject of administering treatments at different times of the day. Although the idea of scheduling drug doses according to the patient's circadian rhythm through chronotherapy is still in its early stages, Lévi's work shows that considering the circadian clock can influence the effectiveness and tolerance of dozens of cancer drugs. Other trials have suggested that cancers of the breast, ovaries, and lungs could benefit from chronotherapy. We have observed significant differences, up to five times in terms of toxicity and nearly double the effectiveness of the same chemotherapy regimen when administered via chronomodulated infusion compared to constant infusion, Lévi describes. A trial on colorectal cancer conducted by Lévi suggests that scheduling doses according to the circadian rhythm could even offer specific advantages for men and women. According to Lévi, the results of Aceto's study constitute an important foundation, but much remains to be done. This study only looked at two points in time, which is not sufficient. The circadian rhythm can also vary from patient to patient, as observed in the mice studied. Patients can have different chronotypes, such as early risers and late sleepers. The nature of the tumor and chemotherapy can also disrupt the circadian rhythm of patients. What is the next step? According to Nagrath: It is necessary to check if these observations apply to all cancers or only to hormone-sensitive cancers such as breast cancer.