Cancer cells go through a process known as metastasis in which cancer/tumor cells disseminate from the primary tumor and via the bloodstream, affects other regions of the human body.
Researchers first stumbled across this aspect of cancer spread when they noticed unexplainable differences in the number of circulating tumor cells (CTCs) in samples analyzed at different times of the day. “Some of my colleagues work early in the morning or late in the evening; sometimes they’ll also analyze blood at unusual hours,” said Nicola Aceto, the study’s senior author, and Professor of Molecular Oncology at ETH Zurich.
About the study
A recent study involving 30 female breast cancer patients demonstrated that the number and activity (cell division and multiplication) of CTC or breast cancer cells in the bloodstream increases during the night. This indicates that cancer cells are more likely to attack healthy tissues at night when the affected person is asleep. The study was published in the Nature and was a collaborative effort of researchers from ETH Zurich (Swiss Federal Institute of Technology), the University of Basel, and the University Hospital, Basel.
Among the 30 female participants with breast cancer, 21 patients had early breast cancer that had not metastasized, and nine patients had stage IV metastatic disease. Most CTCs (78.3%) were detected in blood samples obtained during the night whereas CTCs in daytime samples were much lower in number.
The research team performed one set of experiments where they gave some mice jet lag by altering the light-dark routine. Circadian rhythm alterations led to massive reductions in the CTC concentrations in mice.
In another experiment, the team determined whether administering hormones to mice that were similar to those found in the body when mice are awake would impact the CTC cell counts when mice are at rest. Mice were injected with testosterone, insulin (blood sugar-regulating hormone), and dexamethasone (a synthetic chemical that acts like cortisol, the stress hormone, and is a long-acting corticosteroid). The researchers found a remarkable decrease in the CTC counts in blood samples obtained when mice were at rest (when the tumor would have been more aggressive). The in vitro findings in mice underpinned the previous findings of increased cancer spread during rest (night for humans) since mice sleep during the day.
Further, genetic analysis showed that breast tumor cells of mice and humans at rest demonstrated an upregulation of mitotic genes, making them better at metastasizing since mitotic genes control cell division. Intriguingly, the tumor cells collected during the rest period were “highly prone to metastasize, whereas circulating tumor cells generated during the active phase are devoid of metastatic ability“, the researchers said.
The CTCs, during the night, gain more potential to metastasize. CTC escape from the primary tumor into the bloodstream is controlled by melatonin, a hormone that regulates the day-night rhythms of the body. “Our research shows that the escape of circulating cancer cells from the original tumor is controlled by hormones such as melatonin, which determine our rhythms of day and night,” said Zoi Diamantopoulou, the first author of the study and a Molecular Oncology researcher at ETH Zurich.
Clinical implications of the study
The study provides a striking finding and has overturned the assumption that breast cancers metastasize at the same rate during the day. Furthermore, the study provided valuable insights into how the timing of tests and sample collection could influence oncology findings and could change the timing of blood sample collection from cancer patients in the future.
“In our view, these findings may indicate the need for healthcare professionals to systematically record the time at which they perform biopsies. It may help to make the data truly comparable,” said Aceto.
The study also lays the foundation for potential modifications in cancer therapy. The researchers have aimed to determine whether the efficacy of existing anti-cancer or oncolytic therapies could be enhanced if administered to the patients at different times of the day.