Breast Cancer’s Spread Accelerates During Sleep

Breast cancer metastases spread far more efficiently during sleep, according to a Swiss study.

While it has been assumed that circulating tumor cells (CTCs) are constantly shedding from growing tumors, or as a result of mechanical insults, there’s a “striking and unexpected pattern of CTC generation dynamics in both patients with breast cancer and mouse models, highlighting that most spontaneous CTC intravasation events occur during sleep,” wrote Nicola Aceto, PhD, of the Swiss Federal Institute of Technology in Zurich, and colleagues.

Furthermore, CTCs are more prone to metastasize during a body’s resting phase, while those generated during a body’s active phase are not, they noted in Nature.

“In our view, these findings may indicate the need for healthcare professionals to systematically record the time at which they perform biopsies,” Aceto said in a press release. “It may help to make the data truly comparable.”

For this study, the researchers collected blood samples from 30 patients with breast cancer at times representing the body’s resting phase (4 a.m.) and active phase (10 a.m.).

“Strikingly … we found most CTCs (78.3%) in samples obtained at night time during the rest phase, including single CTCs, CTC clusters and CTC-white blood cell clusters,” they noted.

To test whether these results could be duplicated using another system, Aceto and colleagues conducted a similar experiment using a series of representative mouse models.

They found that the level of CTCs fluctuated depending on the rodents’ resting (corresponding to daylight time given the fact that mice have a circadian rhythm opposite that of humans) and active phases. Moreover, when they focused on the two most representative time points for the rest and active phases in mice, CTC levels peaked during the day at a concentration up to 88 times higher than baseline.

The researchers also monitored CTC levels when the circadian rhythms of the mice were disrupted through different means, including by treatment with the hormone melatonin and by alterations in light cycles to provoke a “jet-lag” effect, as well as CTC levels in mice that had been genetically engineered to have disrupted circadian rhythms. In each of these models, CTC levels were highest while the mice were resting.

In addition, Aceto and colleagues investigated whether CTCs generated during different circadian rhythm phases have different capacities to successfully metastasize by injecting rest- and active-phase CTCs into healthy, tumor-free mice during various phases of their circadian cycles, finding that CTCs from the rest phase “exhibit an extraordinary metastasis-forming capacity” compared with CTCs that are obtained during an active phase. Furthermore, these CTCs were more likely to form tumors when injected into resting mice than active mice.

“Together, these results paint a remarkable picture that demonstrates how CTC biology changes over a 24-hour period in response to the body’s rhythms,” wrote Harrison Ball, BS, and Sunitha Nagrath, PhD, both of the University of Michigan in Ann Arbor, in an accompanying commentary.

This research has “striking implications for the field of CTC studies and for cancer treatment in the clinic,” they noted, adding that it remains to be seen whether the results hold true for tumors other than breast cancer.

While the data “suggest that doctors might need to become more conscious of when to administer specific treatments,” Nagrath and Ball pointed out that the research from this study was validated using mouse models. “The findings will therefore need to be tested through large-scale clinical trials before any consideration of circadian rhythms is incorporated into standard practice.”

“The evidence presented suggests that a more holistic approach to studying CTCs, including harnessing technologies for continuous in vivo monitoring, might be necessary to fully understand the dynamics of cancer metastasis,” they concluded. “A new chapter in blood-based biomarker studies can now start — taking into account how various regulators, such as hormones, affect the proliferation and spread of cancer.”