Cancer has been one of the greatest threats to health for decades. Despite the many discoveries and advances in other areas of medicine, unknowns remain in several aspects of this disease.
In fact, although progress has been made in understanding the biology of cancer, and new avenues of treatment have been found, there are still key gaps in the understanding of this disease that need to be addressed. One of them is related to the way the disease spreads from one organ to another in the body, which is known as metastasis.
A recent study led by Swiss researchers from the ETH Zurich, University Hospital Basel and the University of Basel and published by the journal Nature found that the deadly spread of cancer occurs predominantly during sleep, as revealed an analysis of human tumor cells migrating in the bloodstream.
And although the researchers acknowledge that “it is necessary to validate in clinical studies”, they assure that “the aggressive migration of cancer, associated with metastasis, and 90% of deaths from the disease, would preferentially occur during sleeping hours”.
“Among the many phenomena that occur during cancer development, none may be more important to understand than the process, called metastasis, by which cancer spreads from its tissue of origin to grow in other parts of the body,” he began. explain Zoi Diamantopoulou, the principal investigator of the work.
Metastasis is linked to up to 90% of all cancer deaths, and a major area of clinical research over the past decade has been the study of how tumor cells can circulate throughout the body. “In people with cancer, the cellular progenitors of metastasis are theorized to be cancer cells found in the blood, called circulating tumor cells (CTCs),” the researchers explained in publishing their findings. CTCs that have “broken off” from the tumor at its original site (the primary tumor) can retain their ability to proliferate and survive even in the harsh circulatory environment.”
The researchers found that CTCs can circulate in the bloodstream either as individual cells or as aggregates of two or more cells, known as CTC clusters. “These clusters are often seen alongside other non-cancerous cells, such as immune cells, which could increase the connection to our sleep cycle,” they noted. Over a 24-hour period, our bodies go through a series of mental and physical changes that correlate with our daily sleep-wake cycle, which is called the circadian rhythm.”
And after assuring that “in general, however, the temporal dynamics that dictate the generation of metastasis-competent CTCs are largely uncharacterized and it is often assumed that CTCs are constantly cleared from growing tumors or are cleared as a consequence of mechanical insults,” the researchers observed “a striking and unexpected pattern of CTC generation dynamics in both breast cancer patients and mouse models, highlighting that most CTC intravasation events Spontaneous CTCs occur during sleep. “Furthermore, we show that resting-phase CTCs are highly prone to metastasize, while CTCs generated during the active phase lack metastatic ability,” they added.
The work suggests that circadian rhythms could be related to the release of CTC from the primary tumor.
The regulation of hormones such as melatonin (which acts to regulate sleep) and cortisol (which helps control blood sugar levels) is a key function of this cycle. Circadian rhythm disturbance is linked to a number of chronic diseases, including cancer. Previous epidemiological and experimental studies indicate that the circadian rhythm may influence cancer development.
Diamantopoulou and her colleagues collected blood samples from 30 people with breast cancer, taking samples
at 4 am and 10 am, hours that represent the “rest” and “activity” phases of the body, respectively. Surprisingly, they found that more than 78% of all CTCs obtained came from samples taken during the resting phase.
To test whether results consistent with these data could be obtained using another system, the authors carried out a similar type of experiment using a series of representative mouse models. The level of CTC in the animals fluctuated, peaking while the mice were at rest.
The authors monitored CTC levels when the mice’s circadian rhythms were disrupted by different means, including treatment with the hormone melatonin and by alterations in light cycles; they also monitored levels in mice that had been genetically modified to alter circadian rhythms. In each model, the findings were consistent with the authors’ previous results: CTC levels were higher while the mice were resting.
For the genetically modified mice, the levels were lower than those of the unmodified control animals. An increase in CTCs does not necessarily mean that a person’s cancer is successfully progressing and spreading to secondary locations. This is because most CTCs are killed in the circulation, suggesting that only a particularly aggressive subset of these cells have the propensity to form tumors at secondary sites.
Finally, the researchers noted that “the evidence presented suggests that a more holistic approach to studying CTCs, including harnessing technologies for continuous in vivo monitoring, may be needed to fully understand the dynamics of cancer metastasis.”
What is certain is that the new finding could start a new chapter in blood biomarker studies, considering how various regulators, such as hormones, affect the proliferation and spread of cancer.