METASTASIS IS A PROCESS IN WHICH CANCER CELLS breast away from a primary tumor and enters the bloodstream. These rogue cells can establish colonies in distant sites such as the bones, liver, lungs, or brain.

A new study published in Nature hints that this cancer spread mostly occurs during the night as its host sleeps.

Today we explore how circulating tumor cells (CTCs) are present in much higher numbers in blood samples collected while women (and mice) were in a resting period (compared with an active time).

Metastasis and breast cancer

Cancer starts when healthy cells change, becoming immortal and growing out of control. Over time, the cells form a mass known as a tumor. Benign tumors can grow but do not spread to distant body sites.

On the other hand, malignant (cancerous) tumors can spread to distant sites of the body in a process known as metastasis. When breast cancer spreads — via the bloodstream or lymphatic system — to sites such as the bones, liver, lungs, or brain, the disease is metastatic breast cancer.

Once the cells settle and grow in a distant organ, new tumors develop in those sites, ultimately becoming potentially life-threatening.

Cancer doctors commonly diagnose metastatic breast cancer after a patient has previously received treatment for an earlier stage of breast cancer.

Metastasis is less commonly discovered during an initial breast cancer diagnosis. We call this “de novo” metastatic breast cancer or Stage IV (four) breast cancer.

Breast cancer spread occurs while the host sleeps

Cancer cells must first break free from the primary tumor and enter the bloodstream for cancer to metastasize to distant organs. A study recently published in Nature suggests that this spread mostly occurs while its host sleeps.

Here are the primary findings:

Circulating tumor cells (CTCs) — cancer cells that have broken free from the primary tumor in the breast to migrate to distant organs — are found in higher numbers in blood samples collected while breast cancer patients (and mice) are resting.

There had been historical speculation that biological cycles influence circulating tumor cells, as noted in a 2020 review in Genome Biology. However, the available research was not especially rigorous.

Swiss Federal Institute of Technology (Zurich) scientist Dr. Nicola Aceto and colleagues unexpectedly observed “high variation in CTC numbers, depending on the time they obtained blood samples of patients with cancer.

To better examine this variation, the researchers collected blood samples from 30 hospitalized breast cancer patients at 4:00 in the morning (while the patients rested) and at 10:00 AM on the same day. When the scientists compared the circulating tumor cells, they discovered this:

The 4:00 AM samples contained 78 percent of the total circulating tumor cells.

The researchers went a step further, repeating the experiment in four different mouse models: Blood collection occurred during the resting (daytime) period and again during the active (night) period.

The mouse results mirrored the human results: The active period blood contained 87 to 99 percent of the circulating tumor cells (CTCs).

CTCs, time, and practical implications

You may wonder about the possible meaning of these findings. The researchers provided some clues when they compared the metastatic potential of cells gathered at each time point.

The scientists injected the circulating tumor cells, gathered at each time point, into tumor-free mice. Cancer released during the resting phase appeared much better at colonizing lung tissues.

Because circulating tumor cells have a very short half-live — CTCs persist for a few hours, at most — the tumor must have been released if discovered in the bloodstream. This knowledge should facilitate developing therapies that target this specific subset of cancer cells.

The research findings get even more intriguing when Aceto and colleagues do gene expression profiles of CTCs in humans and mice.

The circulating tumor cells released during rest have higher expression levels of genes associated with cell division than CTCs from the active phase. In other words, cells shed during sleep may have a greater capacity to proliferate.

CTCs and time of day: My take

The research findings regarding chronicity and CTCs are striking but raise more questions. Do these cells operate via an internal clock? Do circadian rhythms regulate the circulating tumor cells?

The researchers give hints that glucocorticoid, androgen, and insulin receptors are highly expressed in CTCs. Without going into too much mind-numbing detail, suffice it to say that these receptors may respond to the daily oscillations of hormones.

Indeed, the study authors report that treating mice with a steroid (or a continuous application of testosterone) during sleep dropped the number of circulating tumor cells found during the rest phase. Insulin delivered during sleep inverted the proliferation cycle, with CTCs detected at lower levels during the rest cycle and increasing them during the sleep period.

I look forward to seeing these research approaches applied to various cancers. The researchers may be opening the door to treatment optimization based on the time of day.

Thank you for joining me today.