Tumors may grow faster at night, Israeli study shows

Studying mice and human cells, scientists in Israel have discovered that malignant tumors may grow faster at night, so that may be the best time to administer some anti-cancer drugs.

Inspired by analysis of human cells, the scientists found in mice that a cell receptor involved in the growth and migration of cells, including cancer cells, was more active at night, when the mice were sleeping, than it was during the day.

In a possibly related finding, the scientists were able to better fight cancer growth in mice by giving them cancer drugs at night, as they slept. The data, published in the journal Nature Communications last week, offer surprising new evidence that nighttime could be the right time to administer fast-acting cancer drugs.

“It seems to be an issue of timing,” said Prof. Yosef Yarden, a molecular biologist at the Weizmann Institute of Science, who oversaw the study. “Cancer treatments are often administered in the daytime, just when the patient’s body is suppressing the spread of the cancer on its own. What we propose is not a new treatment, but rather a new treatment schedule for some of the current drugs.” Years of research are likely needed to confirm the results.

Dr. Mattia Lauriola, a postdoctoral fellow in Yarden’s lab, led the study in collaboration with Prof. Eytan Domany, a systems biologist at the Weizmann Institute of Science. Though the study is basic science that needs to be verified, doctors who buy into this theory could try switching their patients’ treatment schedules.

The four-year study started with the aim of investigating the complex and only partially understood way that cell receptors interact. Receptors are proteins that bind to biochemical messengers and initiate cellular actions in response. The scientists ended up focusing on two receptors: the epidermal growth factor receptor and the glucocorticoid receptor.

The epidermal growth factor receptor promotes growth and migration of cells, including cancer cells. The glucocorticoid receptor binds to a steroid hormone, glucocorticoid, which plays a role in maintaining the body’s energy levels during the day. Often called the “stress hormone,” glucocorticoid is released by the adrenal glands in stressful situations, quickly readying the body for action.

Cells have multiple receptors and receive all sorts of messages at once. Some of these messages can take precedence over others. By molecular gene analysis of human cell lines, the scientists found that cell migration is suppressed when the glucocorticoid receptor is active.

Based on daily fluctuations in glucorticoid levels, it appears that the glucorticoid receptor is less active at night. To check for a corresponding increase in the activity of the epidermal growth factor receptor, the scientists analyzed gene expression in tissue collected from mice during both the day and the night. As expected, the scientists found that genes that activate the epidermal growth factor receptor were more plentiful at night.

Although the study looked at normal cells, cancer cells have the same receptors. The scientists say their results suggest that increased epidermal growth factor receptor activity helps cancer to grow and spread more at night.

“We think that when glucorticoid levels dip at night, the epidermal growth factor receptor has free reign to bring growth factor into the DNA of cells in the body, as well as cancer cells, helping them to develop, to divide, and to move around the body,” said Lauriola.

The last step was to test cancer drugs during sleep. The scientists gave Lapatinib — a new generation breast cancer drug — to mice. They found that mice that were given the drug at night grew significantly smaller tumors than did mice that were given the drug during the day.

More research is needed to make sense of the correlations the study found — between high glucorticoid and low epidermal growth factor receptor and between nighttime drug administration and smaller tumors — and to replicate them in humans. The scientists are now studying exactly how the two receptors interact in mice.

Still, the study provides some of the strongest proof yet that short-acting cancer drugs, like Lapatinib, may be more effective when administered around the time a patient goes to sleep, the scientists say. That way, they suggest, the drugs’ peak activity may compensate for what appears to be the body’s increased vulnerability during sleep.