New studies reveal that glioblastoma has its own internal clock, aligning its daily cycles with those of its host to optimize growth. This means that these brain tumors react to the host’s daily fluctuations of steroid hormones, such as cortisol.
Every cell in the human body has an internal clock that receives signals from a main clock located in the brain. This biological mechanism, known as synchrony, allows the central clock to organize daily rhythms throughout the body, ensuring that every cell and tissue acknowledges the same time of day.
This awareness of time aids our body in managing vital functions, such as sleep patterns, eating schedules, and temperature regulation, among other essential tasks.
However, a dangerous adversary is also keeping track of time.
Glioblastoma is a particularly aggressive and incurable form of brain cancer that ranks as the most common malignant brain tumor in adults. Recent research from Washington University in St. Louis highlights that glioblastoma possesses its internal clock, syncing its rhythms to exploit the daily cycles of its host. This synchronization allows tumors to flourish based on the host’s daily hormone release, like cortisol.
Researchers discovered that disrupting circadian signals significantly curtailed glioblastoma growth and the progression of the disease. This was observed in both laboratory cell cultures and in live tumor-bearing animals, according to their study published on December 12 in Cancer Cell.
“Glioblastoma responds to hormones released by the same central clock in the host that regulates the body’s daily rhythms,” explained Erik D. Herzog, PhD, a Viktor Hamburger Distinguished Professor and biology professor in Arts & Sciences, who is the senior author of the study. “By obstructing the daily surge of glucocorticoid signaling, we can desynchronize the tumor’s rhythms from its host, markedly slowing disease progression in mice with tumors.”
“Our earlier research identified a pattern,” noted Maria F. Gonzalez-Aponte, PhD, the first author of the study. “From clinical data to patient-derived cells and mouse models of glioblastoma tumors, chemotherapy consistently proved most effective aligned with normal waking hours. This led us to theorize that these tumors could sense the time outside.”
“This study further illustrates how placing research in the real-world biological context is vital for enhancing cancer treatment. It was not necessary to develop new drugs; I could extend survival just by syncing treatment to circadian time,” stated Joshua B. Rubin, MD, PhD, a professor of pediatrics and neuroscience at WashU Medicine and a co-author of the study.
The implications of these findings are significant, particularly concerning the tumor’s reaction to a medication known as dexamethasone (DEX), a synthetic steroid frequently prescribed to glioblastoma patients to alleviate brain swelling after surgery and radiation. The study indicates that administering DEX in the morning encourages tumor growth in mice, while evening administration suppresses it.
“The use of DEX for glioblastoma has been contentious for years, with studies showing both growth-promoting and growth-suppressing effects,” Gonzalez-Aponte revealed. “Recognizing that glioblastoma has daily rhythms led us to investigate whether the timing of DEX administration could clarify these conflicting findings, and it appears to do so.”
“The relationship between brain tumors and circadian rhythms could be a viable target for refining treatment strategies,” Herzog noted.
Rescheduling the Clock
Each day, just before an individual awakens, the brain signals the adrenal glands to release a spike of steroid hormones called glucocorticoids in response to light and other environmental indicators. These hormones contribute to the well-known fight-or-flight response, but they also oversee a variety of critical biological functions, including metabolism and immune responses.
“Under normal circumstances, glucocorticoid levels surge each day right before waking,” Gonzalez-Aponte explained. She and Herzog proposed that glioblastoma utilizes this dependable daily release of glucocorticoids to synchronize its clock with that of its host.
To test their hypothesis, Gonzalez-Aponte sought to disrupt the tumor’s timing by resetting the daily rhythms of its host.
She placed tumor-bearing mice in cages that could alternate between light and dark using a timer. By changing the timing of the lights, she encouraged the mice to adopt a reversed schedule, which she verified by observing their activity levels on running wheels.
“Mice tend to be more active at night than during the day,” Gonzalez-Aponte noted. “By flipping their light and dark schedules, it’s comparable to flying from St. Louis to India. We’re forcing them to reestablish synchronization.”
As the mice adapted to their altered schedules, the researchers monitored the cancer cells within their brains for any changes. They employed an innovative method to image clock gene expression in the tumors of freely moving mice, collecting data every minute for several continuous days. They found that the expression of two clock genes, Bmal1 and Per2, adjusted their cycles to match the new schedule of the mice.
“We discovered that Bmal1 and Per2 adjusted their schedules in tandem with the mice’s movements,” Gonzalez-Aponte stated. “The cancer cells are resynchronizing their daily rhythms just as the mice adjust their activity patterns.”
Moreover, the tumors remained in sync with their host even when the mice followed their own circadian cycles without any external timing cues.
More than Just a Wake-up Signal
Glucocorticoids are merely one type of circadian signal known to regulate cellular clocks throughout the body. They hold particular importance in cancer care, as synthetic versions of these steroid hormones are sometimes administered in high doses to alleviate symptoms in cancer patients following surgery and treatment.
DEX is an example of these synthetic glucocorticoids, often given alongside chemotherapy to manage brain swelling that can occur after surgery and radiation. Despite its common use, mixed results regarding DEX’s efficacy have been reported. Some studies indicate it suppresses tumor growth, while others suggest it may encourage glioblastoma cell proliferation.
Gonzalez-Aponte and Herzog suspected that if glioblastoma does have consistent circadian rhythms, then its response to DEX could vary based on the timing of administration.
In their additional experiments, they found that the effects of glucocorticoids on glioblastoma cell growth depend on the time of day. In mice with glioblastoma, tumors grew significantly larger when DEX was administered in the morning compared to evening or control doses.
These findings, observed in mice, underscore the necessity for careful consideration regarding the use of glucocorticoids like DEX in clinical settings, according to Gonzalez-Aponte. Further research is essential to identify optimal times for DEX administration to manage brain swelling without stimulating tumor growth.
“As we advance our understanding of this brain tumor—how it grows, its interaction with other brain cells, and its reactions to therapies—it’s crucial to recognize that timing plays a significant role,” Gonzalez-Aponte emphasized.
Data from a publicly accessible cancer database also indicated that glioblastoma patients seem to have a 60% longer survival when their tumors showed lower levels of glucocorticoid receptors. This observation drives the researchers to pursue clinical trials focused on avoiding DEX treatments in the morning.
“To effectively explore the potential for chronotherapy in various cancers, we need to account for how daily rhythms develop and synchronize within specific tissues,” Herzog stated.
“Understanding the influence of circadian rhythms on tumor biology within a specific cell and tissue context is important,” Herzog concluded. “We believe that this approach has the potential to personalize patient care by determining the optimal timing for therapies based on individual circadian rhythms.”
