Virtually every cell in the human body has an internal clock. These clocks take their cues from a central clock in the brain. In a normal, biological process called synchrony, the central clock coordinates daily rhythms around the body, so that every cell and tissue recognizes the same external time of day.
Knowing local time helps our bodies to regulate essential processes, including when to sleep and wake, when to eat and what temperature to maintain, among many other important functions.
But a deadly interloper is keeping time the same way.
Glioblastoma is an aggressive, incurable brain cancer that is the most common malignant brain tumor in adults. New research from Washington University in St. Louis shows that glioblastoma has an internal clock and syncs its daily rhythms to match — and take advantage of — the rhythms of its host. In this way, brain tumors grow in response to the host’s daily release of steroid hormones like cortisol.
Blocking circadian signals dramatically slowed glioblastoma growth and disease progression, the WashU scientists discovered. This process worked both in cells in a dish and in tumor-bearing animals, according to the study published Dec. 12 in Cancer Cell.
“Glioblastoma takes its cues from hormones released by the same central clock in the host that establishes the body’s regular daily rhythms,” said Erik D. Herzog, PhD, the Viktor Hamburger Distinguished Professor and a professor of biology in Arts & Sciences, senior author of the study. “Blocking the daily surge in glucocorticoid signaling desynchronizes circadian rhythms in glioblastoma from the host and dramatically slows disease progression in tumor-bearing mice.”
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“Our previous research helped us to see a pattern,” said Maria F. Gonzalez-Aponte, PhD, first author of the study. “Whether we were looking at clinical data, or patient-derived cells or mice with model glioblastoma tumors, chemotherapy treatment always worked best around normal waking time. That’s what led us to think that these tumors knew the time of day outside.”
“This study provides yet another example of how important contextualizing research in real-life biology is to improving cancer treatment. It was possible to extend survival by synchronizing treatment to circadian time. No new drug was required,” said Joshua B. Rubin, MD, PhD, a professor of pediatrics and of neuroscience at WashU Medicine, a longtime collaborator with the Herzog laboratory and a co-author on the paper. Herzog and Rubin are research members of Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine.
The findings are important in part because they affect the way that glioblastoma tumors respond to a drug called dexamethasone (DEX), a synthetic steroid that is commonly given to glioblastoma patients to reduce brain edema after radiation and surgery. This study finds that giving DEX in the morning promotes tumor growth in mice, while giving it in the evening suppresses growth.